The Immune System in Occupational Disease

DeLisa Fairweather PhD

Division of Molecular ampTranslational Toxicology

Johns Hopkins Bloomberg School of Public Health

7 March 2012 Chesapeake AIHA ASSE Educational Seminar

Objective To describe recent findings on how occupational exposures alter the immune response leading to chronic diseases like CVD autoimmune diseases and lung diseases

Key points

bull Leading US causes of death involve inflammation

bull Infections and chemicals activate innate immunity

bull infections and chemicals alter the adaptive immune response

bull All major chronic diseases vary by sex

54

14

11

6

5

33 2 2

Global death by leading cause 2002

Kent amp Yin (2006) Controlling Infectious Diseases Population Bulletin Vol 61

Source WHO The World Health Report 2004 (2005) annex table 2

54 Non-communicable diseases

14 Injury amp other

6 Respiratory infections

5 HIV

3 Diarrheal diseases

3 TB

2 Malaria

2 Childhood diseases pertussis poliomyelitis diphtheria measles amp tetanus

11 other infectious diseases

32

Geographical Sub-Saharan Africa

Leading causes of death for Males amp Females in US 2002 (in thousands)

American Heart Assoc Heart Disease amp Stroke Statistics- 2006 Update

Source CDC NCHS (National Center for Health Statistics)

Men Women

0

100000

200000

300000

400000

500000

600000

1 2 3 4 5 6 7 8 9 10

Death

s i

n t

ho

usan

ds

A B C D E A B D F E

A CVD B Cancer C Accidents D Chronic lower respiratory diseases E Diabetes F Alzheimerrsquos Disease

Men Women

All major causes of death in Western populations are due to ldquochronic inflammatory diseasesrdquo

Progression from Acute to Chronic inflammation

Fairweather et al 2001 J Autoimm 16 175-186

Resolution of Acute inflammation

7

InflammationbullFirst described in Egyptian papyrus (3000 BC)

bullCelsus Roman writer from 1st century AD described 4 signs of inflammation

ndashrubor (redness)

ndashtumor (swelling)

ndashcalor (heat)

ndashdolor (pain)

ndashVirchow later added functio laesa (loss of function)

bullJohn Hunter Scottish surgeon 1793 ldquoInflammation is not a disease but a nonspecific response of the hostrdquo

bullMetchnikoff amp Erlich (shared Nobel prize 1908) purpose of inflammation is to bring cells and soluble mediators to site of infection damage

8

What causes disease

bullGenetic- intrinsic

bullEnvironment- acquired

bullEpigenetic- intrinsic amp acquired

The Exposome

Characterizing the exposome The exposome represents the combined exposures from all sources that reach the internal chemical environment Toxicologically important classes of exposome chemicals are shown Signatures and biomarkers can detect these agents in blood or serum

External Environment

Reactive electrophilesMetalsEndocrine disruptersImmune modulatorsReceptor-binding proteins

Radiation

Stress

Life-style

Infections

Drugs

Diet

Pollution

Internal EnvXenobiotics

InflammationPre-existing

diseaseLipid

peroxidationOxidative

stressGut flora

HEALTH DISEASE

Organ System

Infections Physical injury Toxins

Inflammation

Causes of Cell Injury

bullOxygen deprivation (hypoxia) vs ischemia

bullPhysical agents ie mechanical trauma extremes of temperature

radiation

bullChemicals and Drugs

bullInfections

bullImmune Response

bullGenetic defects

bullNutritional imbalances ie starvation vitamin deficiencies

obesity

Example of Apoptosis (programmed cell death)

When a cell undergoes apoptosis macrophages consume cell debris

ghrnlmnihgovghr pictureapoptosis_macrophage

Fluorescence micrograph of an isolated HeLa cell nucleus that has undergone apoptosis in vitro in our cell free system The bright regions are DNA stained with DAPI One of the eyes looks suspiciously like the other one but everything else is as it was Photo -Kumiko Samejima Data massage - Bill Earnshaw

webbioedacuk earnshawApoptosishtm

Apoptotic body

7 March 2012 Chesapeake AIHA ASSE Educational Seminar

Objective To describe recent findings on how occupational exposures alter the immune response leading to chronic diseases like CVD autoimmune diseases and lung diseases

Key points

bull Leading US causes of death involve inflammation

bull Infections and chemicals activate innate immunity

bull infections and chemicals alter the adaptive immune response

bull All major chronic diseases vary by sex

54

14

11

6

5

33 2 2

Global death by leading cause 2002

Kent amp Yin (2006) Controlling Infectious Diseases Population Bulletin Vol 61

Source WHO The World Health Report 2004 (2005) annex table 2

54 Non-communicable diseases

14 Injury amp other

6 Respiratory infections

5 HIV

3 Diarrheal diseases

3 TB

2 Malaria

2 Childhood diseases pertussis poliomyelitis diphtheria measles amp tetanus

11 other infectious diseases

32

Geographical Sub-Saharan Africa

Leading causes of death for Males amp Females in US 2002 (in thousands)

American Heart Assoc Heart Disease amp Stroke Statistics- 2006 Update

Source CDC NCHS (National Center for Health Statistics)

Men Women

0

100000

200000

300000

400000

500000

600000

1 2 3 4 5 6 7 8 9 10

Death

s i

n t

ho

usan

ds

A B C D E A B D F E

A CVD B Cancer C Accidents D Chronic lower respiratory diseases E Diabetes F Alzheimerrsquos Disease

Men Women

All major causes of death in Western populations are due to ldquochronic inflammatory diseasesrdquo

Progression from Acute to Chronic inflammation

Fairweather et al 2001 J Autoimm 16 175-186

Resolution of Acute inflammation

7

InflammationbullFirst described in Egyptian papyrus (3000 BC)

bullCelsus Roman writer from 1st century AD described 4 signs of inflammation

ndashrubor (redness)

ndashtumor (swelling)

ndashcalor (heat)

ndashdolor (pain)

ndashVirchow later added functio laesa (loss of function)

bullJohn Hunter Scottish surgeon 1793 ldquoInflammation is not a disease but a nonspecific response of the hostrdquo

bullMetchnikoff amp Erlich (shared Nobel prize 1908) purpose of inflammation is to bring cells and soluble mediators to site of infection damage

8

What causes disease

bullGenetic- intrinsic

bullEnvironment- acquired

bullEpigenetic- intrinsic amp acquired

The Exposome

Characterizing the exposome The exposome represents the combined exposures from all sources that reach the internal chemical environment Toxicologically important classes of exposome chemicals are shown Signatures and biomarkers can detect these agents in blood or serum

External Environment

Reactive electrophilesMetalsEndocrine disruptersImmune modulatorsReceptor-binding proteins

Radiation

Stress

Life-style

Infections

Drugs

Diet

Pollution

Internal EnvXenobiotics

InflammationPre-existing

diseaseLipid

peroxidationOxidative

stressGut flora

HEALTH DISEASE

Organ System

Infections Physical injury Toxins

Inflammation

Causes of Cell Injury

bullOxygen deprivation (hypoxia) vs ischemia

bullPhysical agents ie mechanical trauma extremes of temperature

radiation

bullChemicals and Drugs

bullInfections

bullImmune Response

bullGenetic defects

bullNutritional imbalances ie starvation vitamin deficiencies

obesity

Example of Apoptosis (programmed cell death)

When a cell undergoes apoptosis macrophages consume cell debris

ghrnlmnihgovghr pictureapoptosis_macrophage

Fluorescence micrograph of an isolated HeLa cell nucleus that has undergone apoptosis in vitro in our cell free system The bright regions are DNA stained with DAPI One of the eyes looks suspiciously like the other one but everything else is as it was Photo -Kumiko Samejima Data massage - Bill Earnshaw

webbioedacuk earnshawApoptosishtm

Apoptotic body

54

14

11

6

5

33 2 2

Global death by leading cause 2002

Kent amp Yin (2006) Controlling Infectious Diseases Population Bulletin Vol 61

Source WHO The World Health Report 2004 (2005) annex table 2

54 Non-communicable diseases

14 Injury amp other

6 Respiratory infections

5 HIV

3 Diarrheal diseases

3 TB

2 Malaria

2 Childhood diseases pertussis poliomyelitis diphtheria measles amp tetanus

11 other infectious diseases

32

Geographical Sub-Saharan Africa

Leading causes of death for Males amp Females in US 2002 (in thousands)

American Heart Assoc Heart Disease amp Stroke Statistics- 2006 Update

Source CDC NCHS (National Center for Health Statistics)

Men Women

0

100000

200000

300000

400000

500000

600000

1 2 3 4 5 6 7 8 9 10

Death

s i

n t

ho

usan

ds

A B C D E A B D F E

A CVD B Cancer C Accidents D Chronic lower respiratory diseases E Diabetes F Alzheimerrsquos Disease

Men Women

All major causes of death in Western populations are due to ldquochronic inflammatory diseasesrdquo

Progression from Acute to Chronic inflammation

Fairweather et al 2001 J Autoimm 16 175-186

Resolution of Acute inflammation

7

InflammationbullFirst described in Egyptian papyrus (3000 BC)

bullCelsus Roman writer from 1st century AD described 4 signs of inflammation

ndashrubor (redness)

ndashtumor (swelling)

ndashcalor (heat)

ndashdolor (pain)

ndashVirchow later added functio laesa (loss of function)

bullJohn Hunter Scottish surgeon 1793 ldquoInflammation is not a disease but a nonspecific response of the hostrdquo

bullMetchnikoff amp Erlich (shared Nobel prize 1908) purpose of inflammation is to bring cells and soluble mediators to site of infection damage

8

What causes disease

bullGenetic- intrinsic

bullEnvironment- acquired

bullEpigenetic- intrinsic amp acquired

The Exposome

Characterizing the exposome The exposome represents the combined exposures from all sources that reach the internal chemical environment Toxicologically important classes of exposome chemicals are shown Signatures and biomarkers can detect these agents in blood or serum

External Environment

Reactive electrophilesMetalsEndocrine disruptersImmune modulatorsReceptor-binding proteins

Radiation

Stress

Life-style

Infections

Drugs

Diet

Pollution

Internal EnvXenobiotics

InflammationPre-existing

diseaseLipid

peroxidationOxidative

stressGut flora

HEALTH DISEASE

Organ System

Infections Physical injury Toxins

Inflammation

Causes of Cell Injury

bullOxygen deprivation (hypoxia) vs ischemia

bullPhysical agents ie mechanical trauma extremes of temperature

radiation

bullChemicals and Drugs

bullInfections

bullImmune Response

bullGenetic defects

bullNutritional imbalances ie starvation vitamin deficiencies

obesity

Example of Apoptosis (programmed cell death)

When a cell undergoes apoptosis macrophages consume cell debris

ghrnlmnihgovghr pictureapoptosis_macrophage

Fluorescence micrograph of an isolated HeLa cell nucleus that has undergone apoptosis in vitro in our cell free system The bright regions are DNA stained with DAPI One of the eyes looks suspiciously like the other one but everything else is as it was Photo -Kumiko Samejima Data massage - Bill Earnshaw

webbioedacuk earnshawApoptosishtm

Apoptotic body

Leading causes of death for Males amp Females in US 2002 (in thousands)

American Heart Assoc Heart Disease amp Stroke Statistics- 2006 Update

Source CDC NCHS (National Center for Health Statistics)

Men Women

0

100000

200000

300000

400000

500000

600000

1 2 3 4 5 6 7 8 9 10

Death

s i

n t

ho

usan

ds

A B C D E A B D F E

A CVD B Cancer C Accidents D Chronic lower respiratory diseases E Diabetes F Alzheimerrsquos Disease

Men Women

All major causes of death in Western populations are due to ldquochronic inflammatory diseasesrdquo

Progression from Acute to Chronic inflammation

Fairweather et al 2001 J Autoimm 16 175-186

Resolution of Acute inflammation

7

InflammationbullFirst described in Egyptian papyrus (3000 BC)

bullCelsus Roman writer from 1st century AD described 4 signs of inflammation

ndashrubor (redness)

ndashtumor (swelling)

ndashcalor (heat)

ndashdolor (pain)

ndashVirchow later added functio laesa (loss of function)

bullJohn Hunter Scottish surgeon 1793 ldquoInflammation is not a disease but a nonspecific response of the hostrdquo

bullMetchnikoff amp Erlich (shared Nobel prize 1908) purpose of inflammation is to bring cells and soluble mediators to site of infection damage

8

What causes disease

bullGenetic- intrinsic

bullEnvironment- acquired

bullEpigenetic- intrinsic amp acquired

The Exposome

Characterizing the exposome The exposome represents the combined exposures from all sources that reach the internal chemical environment Toxicologically important classes of exposome chemicals are shown Signatures and biomarkers can detect these agents in blood or serum

External Environment

Reactive electrophilesMetalsEndocrine disruptersImmune modulatorsReceptor-binding proteins

Radiation

Stress

Life-style

Infections

Drugs

Diet

Pollution

Internal EnvXenobiotics

InflammationPre-existing

diseaseLipid

peroxidationOxidative

stressGut flora

HEALTH DISEASE

Organ System

Infections Physical injury Toxins

Inflammation

Causes of Cell Injury

bullOxygen deprivation (hypoxia) vs ischemia

bullPhysical agents ie mechanical trauma extremes of temperature

radiation

bullChemicals and Drugs

bullInfections

bullImmune Response

bullGenetic defects

bullNutritional imbalances ie starvation vitamin deficiencies

obesity

Example of Apoptosis (programmed cell death)

When a cell undergoes apoptosis macrophages consume cell debris

ghrnlmnihgovghr pictureapoptosis_macrophage

Fluorescence micrograph of an isolated HeLa cell nucleus that has undergone apoptosis in vitro in our cell free system The bright regions are DNA stained with DAPI One of the eyes looks suspiciously like the other one but everything else is as it was Photo -Kumiko Samejima Data massage - Bill Earnshaw

webbioedacuk earnshawApoptosishtm

Apoptotic body

All major causes of death in Western populations are due to ldquochronic inflammatory diseasesrdquo

Progression from Acute to Chronic inflammation

Fairweather et al 2001 J Autoimm 16 175-186

Resolution of Acute inflammation

7

InflammationbullFirst described in Egyptian papyrus (3000 BC)

bullCelsus Roman writer from 1st century AD described 4 signs of inflammation

ndashrubor (redness)

ndashtumor (swelling)

ndashcalor (heat)

ndashdolor (pain)

ndashVirchow later added functio laesa (loss of function)

bullJohn Hunter Scottish surgeon 1793 ldquoInflammation is not a disease but a nonspecific response of the hostrdquo

bullMetchnikoff amp Erlich (shared Nobel prize 1908) purpose of inflammation is to bring cells and soluble mediators to site of infection damage

8

What causes disease

bullGenetic- intrinsic

bullEnvironment- acquired

bullEpigenetic- intrinsic amp acquired

The Exposome

Characterizing the exposome The exposome represents the combined exposures from all sources that reach the internal chemical environment Toxicologically important classes of exposome chemicals are shown Signatures and biomarkers can detect these agents in blood or serum

External Environment

Reactive electrophilesMetalsEndocrine disruptersImmune modulatorsReceptor-binding proteins

Radiation

Stress

Life-style

Infections

Drugs

Diet

Pollution

Internal EnvXenobiotics

InflammationPre-existing

diseaseLipid

peroxidationOxidative

stressGut flora

HEALTH DISEASE

Organ System

Infections Physical injury Toxins

Inflammation

Causes of Cell Injury

bullOxygen deprivation (hypoxia) vs ischemia

bullPhysical agents ie mechanical trauma extremes of temperature

radiation

bullChemicals and Drugs

bullInfections

bullImmune Response

bullGenetic defects

bullNutritional imbalances ie starvation vitamin deficiencies

obesity

Example of Apoptosis (programmed cell death)

When a cell undergoes apoptosis macrophages consume cell debris

ghrnlmnihgovghr pictureapoptosis_macrophage

Fluorescence micrograph of an isolated HeLa cell nucleus that has undergone apoptosis in vitro in our cell free system The bright regions are DNA stained with DAPI One of the eyes looks suspiciously like the other one but everything else is as it was Photo -Kumiko Samejima Data massage - Bill Earnshaw

webbioedacuk earnshawApoptosishtm

Apoptotic body

Progression from Acute to Chronic inflammation

Fairweather et al 2001 J Autoimm 16 175-186

Resolution of Acute inflammation

7

InflammationbullFirst described in Egyptian papyrus (3000 BC)

bullCelsus Roman writer from 1st century AD described 4 signs of inflammation

ndashrubor (redness)

ndashtumor (swelling)

ndashcalor (heat)

ndashdolor (pain)

ndashVirchow later added functio laesa (loss of function)

bullJohn Hunter Scottish surgeon 1793 ldquoInflammation is not a disease but a nonspecific response of the hostrdquo

bullMetchnikoff amp Erlich (shared Nobel prize 1908) purpose of inflammation is to bring cells and soluble mediators to site of infection damage

8

What causes disease

bullGenetic- intrinsic

bullEnvironment- acquired

bullEpigenetic- intrinsic amp acquired

The Exposome

Characterizing the exposome The exposome represents the combined exposures from all sources that reach the internal chemical environment Toxicologically important classes of exposome chemicals are shown Signatures and biomarkers can detect these agents in blood or serum

External Environment

Reactive electrophilesMetalsEndocrine disruptersImmune modulatorsReceptor-binding proteins

Radiation

Stress

Life-style

Infections

Drugs

Diet

Pollution

Internal EnvXenobiotics

InflammationPre-existing

diseaseLipid

peroxidationOxidative

stressGut flora

HEALTH DISEASE

Organ System

Infections Physical injury Toxins

Inflammation

Causes of Cell Injury

bullOxygen deprivation (hypoxia) vs ischemia

bullPhysical agents ie mechanical trauma extremes of temperature

radiation

bullChemicals and Drugs

bullInfections

bullImmune Response

bullGenetic defects

bullNutritional imbalances ie starvation vitamin deficiencies

obesity

Example of Apoptosis (programmed cell death)

When a cell undergoes apoptosis macrophages consume cell debris

ghrnlmnihgovghr pictureapoptosis_macrophage

Fluorescence micrograph of an isolated HeLa cell nucleus that has undergone apoptosis in vitro in our cell free system The bright regions are DNA stained with DAPI One of the eyes looks suspiciously like the other one but everything else is as it was Photo -Kumiko Samejima Data massage - Bill Earnshaw

webbioedacuk earnshawApoptosishtm

Apoptotic body

7

InflammationbullFirst described in Egyptian papyrus (3000 BC)

bullCelsus Roman writer from 1st century AD described 4 signs of inflammation

ndashrubor (redness)

ndashtumor (swelling)

ndashcalor (heat)

ndashdolor (pain)

ndashVirchow later added functio laesa (loss of function)

bullJohn Hunter Scottish surgeon 1793 ldquoInflammation is not a disease but a nonspecific response of the hostrdquo

bullMetchnikoff amp Erlich (shared Nobel prize 1908) purpose of inflammation is to bring cells and soluble mediators to site of infection damage

8

What causes disease

bullGenetic- intrinsic

bullEnvironment- acquired

bullEpigenetic- intrinsic amp acquired

The Exposome

Characterizing the exposome The exposome represents the combined exposures from all sources that reach the internal chemical environment Toxicologically important classes of exposome chemicals are shown Signatures and biomarkers can detect these agents in blood or serum

External Environment

Reactive electrophilesMetalsEndocrine disruptersImmune modulatorsReceptor-binding proteins

Radiation

Stress

Life-style

Infections

Drugs

Diet

Pollution

Internal EnvXenobiotics

InflammationPre-existing

diseaseLipid

peroxidationOxidative

stressGut flora

HEALTH DISEASE

Organ System

Infections Physical injury Toxins

Inflammation

Causes of Cell Injury

bullOxygen deprivation (hypoxia) vs ischemia

bullPhysical agents ie mechanical trauma extremes of temperature

radiation

bullChemicals and Drugs

bullInfections

bullImmune Response

bullGenetic defects

bullNutritional imbalances ie starvation vitamin deficiencies

obesity

Example of Apoptosis (programmed cell death)

When a cell undergoes apoptosis macrophages consume cell debris

ghrnlmnihgovghr pictureapoptosis_macrophage

Fluorescence micrograph of an isolated HeLa cell nucleus that has undergone apoptosis in vitro in our cell free system The bright regions are DNA stained with DAPI One of the eyes looks suspiciously like the other one but everything else is as it was Photo -Kumiko Samejima Data massage - Bill Earnshaw

webbioedacuk earnshawApoptosishtm

Apoptotic body

8

What causes disease

bullGenetic- intrinsic

bullEnvironment- acquired

bullEpigenetic- intrinsic amp acquired

The Exposome

Characterizing the exposome The exposome represents the combined exposures from all sources that reach the internal chemical environment Toxicologically important classes of exposome chemicals are shown Signatures and biomarkers can detect these agents in blood or serum

External Environment

Reactive electrophilesMetalsEndocrine disruptersImmune modulatorsReceptor-binding proteins

Radiation

Stress

Life-style

Infections

Drugs

Diet

Pollution

Internal EnvXenobiotics

InflammationPre-existing

diseaseLipid

peroxidationOxidative

stressGut flora

HEALTH DISEASE

Organ System

Infections Physical injury Toxins

Inflammation

Causes of Cell Injury

bullOxygen deprivation (hypoxia) vs ischemia

bullPhysical agents ie mechanical trauma extremes of temperature

radiation

bullChemicals and Drugs

bullInfections

bullImmune Response

bullGenetic defects

bullNutritional imbalances ie starvation vitamin deficiencies

obesity

Example of Apoptosis (programmed cell death)

When a cell undergoes apoptosis macrophages consume cell debris

ghrnlmnihgovghr pictureapoptosis_macrophage

Fluorescence micrograph of an isolated HeLa cell nucleus that has undergone apoptosis in vitro in our cell free system The bright regions are DNA stained with DAPI One of the eyes looks suspiciously like the other one but everything else is as it was Photo -Kumiko Samejima Data massage - Bill Earnshaw

webbioedacuk earnshawApoptosishtm

Apoptotic body

The Exposome

Characterizing the exposome The exposome represents the combined exposures from all sources that reach the internal chemical environment Toxicologically important classes of exposome chemicals are shown Signatures and biomarkers can detect these agents in blood or serum

External Environment

Reactive electrophilesMetalsEndocrine disruptersImmune modulatorsReceptor-binding proteins

Radiation

Stress

Life-style

Infections

Drugs

Diet

Pollution

Internal EnvXenobiotics

InflammationPre-existing

diseaseLipid

peroxidationOxidative

stressGut flora

HEALTH DISEASE

Organ System

Infections Physical injury Toxins

Inflammation

Causes of Cell Injury

bullOxygen deprivation (hypoxia) vs ischemia

bullPhysical agents ie mechanical trauma extremes of temperature

radiation

bullChemicals and Drugs

bullInfections

bullImmune Response

bullGenetic defects

bullNutritional imbalances ie starvation vitamin deficiencies

obesity

Example of Apoptosis (programmed cell death)

When a cell undergoes apoptosis macrophages consume cell debris

ghrnlmnihgovghr pictureapoptosis_macrophage

Fluorescence micrograph of an isolated HeLa cell nucleus that has undergone apoptosis in vitro in our cell free system The bright regions are DNA stained with DAPI One of the eyes looks suspiciously like the other one but everything else is as it was Photo -Kumiko Samejima Data massage - Bill Earnshaw

webbioedacuk earnshawApoptosishtm

Apoptotic body

HEALTH DISEASE

Organ System

Infections Physical injury Toxins

Inflammation

Causes of Cell Injury

bullOxygen deprivation (hypoxia) vs ischemia

bullPhysical agents ie mechanical trauma extremes of temperature

radiation

bullChemicals and Drugs

bullInfections

bullImmune Response

bullGenetic defects

bullNutritional imbalances ie starvation vitamin deficiencies

obesity

Example of Apoptosis (programmed cell death)

When a cell undergoes apoptosis macrophages consume cell debris

ghrnlmnihgovghr pictureapoptosis_macrophage

Fluorescence micrograph of an isolated HeLa cell nucleus that has undergone apoptosis in vitro in our cell free system The bright regions are DNA stained with DAPI One of the eyes looks suspiciously like the other one but everything else is as it was Photo -Kumiko Samejima Data massage - Bill Earnshaw

webbioedacuk earnshawApoptosishtm

Apoptotic body

Causes of Cell Injury

bullOxygen deprivation (hypoxia) vs ischemia

bullPhysical agents ie mechanical trauma extremes of temperature

radiation

bullChemicals and Drugs

bullInfections

bullImmune Response

bullGenetic defects

bullNutritional imbalances ie starvation vitamin deficiencies

obesity

Example of Apoptosis (programmed cell death)

When a cell undergoes apoptosis macrophages consume cell debris

ghrnlmnihgovghr pictureapoptosis_macrophage

Fluorescence micrograph of an isolated HeLa cell nucleus that has undergone apoptosis in vitro in our cell free system The bright regions are DNA stained with DAPI One of the eyes looks suspiciously like the other one but everything else is as it was Photo -Kumiko Samejima Data massage - Bill Earnshaw

webbioedacuk earnshawApoptosishtm

Apoptotic body

Example of Apoptosis (programmed cell death)

When a cell undergoes apoptosis macrophages consume cell debris

ghrnlmnihgovghr pictureapoptosis_macrophage

Fluorescence micrograph of an isolated HeLa cell nucleus that has undergone apoptosis in vitro in our cell free system The bright regions are DNA stained with DAPI One of the eyes looks suspiciously like the other one but everything else is as it was Photo -Kumiko Samejima Data massage - Bill Earnshaw

webbioedacuk earnshawApoptosishtm

Apoptotic body

Examples of Necrosis

necrosis caused by downy mildew on a grape leaf

wwwapsnetorg PhotosN-Rnecrosishtm

wwwsomuqeduau histotechphotographshtml

Inflammatory Response

wwwbiologymadcom

15

Acute Inflammation

The inflammatory response is closely intertwined with the process of repair

bullProtective ie microbes toxins necrotic cells

bullHarmful ie chronic inflammatory diseases

17

Chronic Inflammation

Active inflammation

Tissue destruction

Attempts at repair

ie fibrosis

18

Chronic Inflammation amp Fibrosis (blue)

Outcomes of Acute Inflammation

Injury Acute inflammation

Resolution

Chronic inflammation

Healing regeneration amp scarring

Acute inflammation

leads to chronic disease in

susceptible individuals

Coronado MJ et al 2012 Am J PhysiolHeart Circ Physiol In press

Progression from Acute to Chronic inflammation

Fairweather et al 2001 J Autoimm 16 175-186

Resolution of Acute inflammation

HEALTH DISEASE

Organ System

Infections Physical injury Toxins Chemicals

Inflammation

TLRs inflammasome

TLRs inflammasome

TLRs inflammasome

Infections injury amp toxins chemicals activate the Innate Immune Response using similar mechanisms

What is the role of Innate Immunity in the pathogenesis of chronic diseases

bull Innate Immunity initiates inflammation ie Toll-like receptors (TLRs)

bull Innate Immunity determines the nature phenotype of the adaptive immune response ie T helper type (Th)1 vs Th2 vs Th17

bull Innate Immunity initiates regulatory mechanisms ie T regulatory cells and regulatory cytokines

bull The balance between a proinflammatory response and regulation of the response and regulation of repair mechanisms determines whether injury proceeds to chronic disease

threats to the body

Protection requires being able to distinguish ldquoselfrdquo from ldquonon-selfrdquo

PRRs detect PAMPs

bullPRRs recognize similar design patterns on microbes not present on host cells in order to destroy the pathogen

bullEx Toll-like receptors (TLRs) on immune amp other host cells

bullTLRrsquos important in cytokine production amp inflammation

bullPRRs can be found on ldquoinnaterdquo or ldquoadaptiverdquo immune cells

Human TLR 1-11

www2ujf-grenoblefrcurrenttlrgif

Inflammation

External threats activate PRRs

bull TLR1-13bull Dectin Rsbull Mannan Rsbull Inflammasome =

NODs and NALPsbull Results in activation

of NFkBbull Rarely do specific

infections relate to chronic diseases

Karen M et al 2006 Cell 124 823

TLRs recognize ldquodamaged selfrdquo

2009 J Immunol 18327-31

Particularly TLR2 amp TLR4

Endogenously derived ligands (self tissues) activate PRRs

bull Hsp= heat shock proteins induced by cell damage

bull ICs = immune complex with DNA or RNA

bull AC = apoptotic cells

bull SR = scavenger Rs

bull HMG-B1 = chromatin component (DAMP)

bull IL-33 (DAMP)

Karen M et al 2006 Cell 124 823

Immune responses do not follow normal Dose-Response relationships

Casarett amp Doullrsquos Essentials of Toxicology 2003

A single stimuli can launch an ldquoarmyrdquo of immune cells

Low doses that appear to ldquodo no harmrdquo(ie do not result in death of cells and

tissues)can potentially stimulate a harmful

immune response

The Inflammasome

wwwinvivogencomIL-33

2010 Science 327296The NLRP3 Inflammasome A Sensor for Metabolic DangerKate Schroder12 Rongbin Zhou1

Jurg Tschopp1

Activator class Activator Disease associations

Whole pathogen Candida albicans Infection

Saccharomyces

cerevisiae

Infection

Staphylococcus aureus Infection

Listeria monocytogenes Infection

Influenza virus Infection

Sendai virus Infection

Adenovirus Infection

Pathogen-associated

molecules

Bacterial porendashforming

toxins

Infection

Hemozoin Cerebral malaria

Environmental insults Silica Silicosis

Asbestos Asbestosis

Skin irritants Contact hypersensitivity

reactions

Ultraviolet light Sunburn

Endogenous danger

signals

ATP Injury or necrotic cell

death

Glucose Metabolic syndrome

MSU Gout

Calcium pyrophosphate

dihydrate (CPPD)

Pseudogout

Amyloid β Alzheimerrsquos disease

Hyaluronan Injury

Adjuvant Alum Th2 responses

Table 1 NLRP3 inflammasome activators Details of individual NLRP3 inflammasome activators are reviewed in (

Infections toxins amp environmental agents activate the inflammasome

Increased Th2 response

The inflammasome and alum-mediated adjuvanticitySuk-Jo Kang and Richard M Locksley

F1000 Biology Reports 2009 1 15 (doi 103410B1-15)

Figure 1 Alum-induced NLRP3 inflammasome activation

bull Phagocytosed alum-containing lysosomes rupture and release their components to the cytosol by an unknown mechanism The released contents and molecules generated during this process contribute to NLRP3ASCcaspase-1 inflammasome activation which in turn processes the proforms of IL-1 family members to active forms Either IL-1 family member cytokines or the products from NLRP3 inflammasome activation may elicit various immunostimulatory effects in vivo When and how potassium efflux and reactive oxygen species (ROS) play a role awaits further investigation DC dendritic cell MSU monosodium urate

15

Acute Inflammation

The inflammatory response is closely intertwined with the process of repair

bullProtective ie microbes toxins necrotic cells

bullHarmful ie chronic inflammatory diseases

17

Chronic Inflammation

Active inflammation

Tissue destruction

Attempts at repair

ie fibrosis

18

Chronic Inflammation amp Fibrosis (blue)

Outcomes of Acute Inflammation

Injury Acute inflammation

Resolution

Chronic inflammation

Healing regeneration amp scarring

Acute inflammation

leads to chronic disease in

susceptible individuals

Coronado MJ et al 2012 Am J PhysiolHeart Circ Physiol In press

Progression from Acute to Chronic inflammation

Fairweather et al 2001 J Autoimm 16 175-186

Resolution of Acute inflammation

HEALTH DISEASE

Organ System

Infections Physical injury Toxins Chemicals

Inflammation

TLRs inflammasome

TLRs inflammasome

TLRs inflammasome

Infections injury amp toxins chemicals activate the Innate Immune Response using similar mechanisms

What is the role of Innate Immunity in the pathogenesis of chronic diseases

bull Innate Immunity initiates inflammation ie Toll-like receptors (TLRs)

bull Innate Immunity determines the nature phenotype of the adaptive immune response ie T helper type (Th)1 vs Th2 vs Th17

bull Innate Immunity initiates regulatory mechanisms ie T regulatory cells and regulatory cytokines

bull The balance between a proinflammatory response and regulation of the response and regulation of repair mechanisms determines whether injury proceeds to chronic disease

threats to the body

Protection requires being able to distinguish ldquoselfrdquo from ldquonon-selfrdquo

PRRs detect PAMPs

bullPRRs recognize similar design patterns on microbes not present on host cells in order to destroy the pathogen

bullEx Toll-like receptors (TLRs) on immune amp other host cells

bullTLRrsquos important in cytokine production amp inflammation

bullPRRs can be found on ldquoinnaterdquo or ldquoadaptiverdquo immune cells

Human TLR 1-11

www2ujf-grenoblefrcurrenttlrgif

Inflammation

External threats activate PRRs

bull TLR1-13bull Dectin Rsbull Mannan Rsbull Inflammasome =

NODs and NALPsbull Results in activation

of NFkBbull Rarely do specific

infections relate to chronic diseases

Karen M et al 2006 Cell 124 823

TLRs recognize ldquodamaged selfrdquo

2009 J Immunol 18327-31

Particularly TLR2 amp TLR4

Endogenously derived ligands (self tissues) activate PRRs

bull Hsp= heat shock proteins induced by cell damage

bull ICs = immune complex with DNA or RNA

bull AC = apoptotic cells

bull SR = scavenger Rs

bull HMG-B1 = chromatin component (DAMP)

bull IL-33 (DAMP)

Karen M et al 2006 Cell 124 823

Immune responses do not follow normal Dose-Response relationships

Casarett amp Doullrsquos Essentials of Toxicology 2003

A single stimuli can launch an ldquoarmyrdquo of immune cells

Low doses that appear to ldquodo no harmrdquo(ie do not result in death of cells and

tissues)can potentially stimulate a harmful

immune response

The Inflammasome

wwwinvivogencomIL-33

2010 Science 327296The NLRP3 Inflammasome A Sensor for Metabolic DangerKate Schroder12 Rongbin Zhou1

Jurg Tschopp1

Activator class Activator Disease associations

Whole pathogen Candida albicans Infection

Saccharomyces

cerevisiae

Infection

Staphylococcus aureus Infection

Listeria monocytogenes Infection

Influenza virus Infection

Sendai virus Infection

Adenovirus Infection

Pathogen-associated

molecules

Bacterial porendashforming

toxins

Infection

Hemozoin Cerebral malaria

Environmental insults Silica Silicosis

Asbestos Asbestosis

Skin irritants Contact hypersensitivity

reactions

Ultraviolet light Sunburn

Endogenous danger

signals

ATP Injury or necrotic cell

death

Glucose Metabolic syndrome

MSU Gout

Calcium pyrophosphate

dihydrate (CPPD)

Pseudogout

Amyloid β Alzheimerrsquos disease

Hyaluronan Injury

Adjuvant Alum Th2 responses

Table 1 NLRP3 inflammasome activators Details of individual NLRP3 inflammasome activators are reviewed in (

Infections toxins amp environmental agents activate the inflammasome

Increased Th2 response

The inflammasome and alum-mediated adjuvanticitySuk-Jo Kang and Richard M Locksley

F1000 Biology Reports 2009 1 15 (doi 103410B1-15)

Figure 1 Alum-induced NLRP3 inflammasome activation

bull Phagocytosed alum-containing lysosomes rupture and release their components to the cytosol by an unknown mechanism The released contents and molecules generated during this process contribute to NLRP3ASCcaspase-1 inflammasome activation which in turn processes the proforms of IL-1 family members to active forms Either IL-1 family member cytokines or the products from NLRP3 inflammasome activation may elicit various immunostimulatory effects in vivo When and how potassium efflux and reactive oxygen species (ROS) play a role awaits further investigation DC dendritic cell MSU monosodium urate

The inflammatory response is closely intertwined with the process of repair

bullProtective ie microbes toxins necrotic cells

bullHarmful ie chronic inflammatory diseases

17

Chronic Inflammation

Active inflammation

Tissue destruction

Attempts at repair

ie fibrosis

18

Chronic Inflammation amp Fibrosis (blue)

Outcomes of Acute Inflammation

Injury Acute inflammation

Resolution

Chronic inflammation

Healing regeneration amp scarring

Acute inflammation

leads to chronic disease in

susceptible individuals

Coronado MJ et al 2012 Am J PhysiolHeart Circ Physiol In press

Progression from Acute to Chronic inflammation

Fairweather et al 2001 J Autoimm 16 175-186

Resolution of Acute inflammation

HEALTH DISEASE

Organ System

Infections Physical injury Toxins Chemicals

Inflammation

TLRs inflammasome

TLRs inflammasome

TLRs inflammasome

Infections injury amp toxins chemicals activate the Innate Immune Response using similar mechanisms

What is the role of Innate Immunity in the pathogenesis of chronic diseases

bull Innate Immunity initiates inflammation ie Toll-like receptors (TLRs)

bull Innate Immunity determines the nature phenotype of the adaptive immune response ie T helper type (Th)1 vs Th2 vs Th17

bull Innate Immunity initiates regulatory mechanisms ie T regulatory cells and regulatory cytokines

bull The balance between a proinflammatory response and regulation of the response and regulation of repair mechanisms determines whether injury proceeds to chronic disease

threats to the body

Protection requires being able to distinguish ldquoselfrdquo from ldquonon-selfrdquo

PRRs detect PAMPs

bullPRRs recognize similar design patterns on microbes not present on host cells in order to destroy the pathogen

bullEx Toll-like receptors (TLRs) on immune amp other host cells

bullTLRrsquos important in cytokine production amp inflammation

bullPRRs can be found on ldquoinnaterdquo or ldquoadaptiverdquo immune cells

Human TLR 1-11

www2ujf-grenoblefrcurrenttlrgif

Inflammation

External threats activate PRRs

bull TLR1-13bull Dectin Rsbull Mannan Rsbull Inflammasome =

NODs and NALPsbull Results in activation

of NFkBbull Rarely do specific

infections relate to chronic diseases

Karen M et al 2006 Cell 124 823

TLRs recognize ldquodamaged selfrdquo

2009 J Immunol 18327-31

Particularly TLR2 amp TLR4

Endogenously derived ligands (self tissues) activate PRRs

bull Hsp= heat shock proteins induced by cell damage

bull ICs = immune complex with DNA or RNA

bull AC = apoptotic cells

bull SR = scavenger Rs

bull HMG-B1 = chromatin component (DAMP)

bull IL-33 (DAMP)

Karen M et al 2006 Cell 124 823

Immune responses do not follow normal Dose-Response relationships

Casarett amp Doullrsquos Essentials of Toxicology 2003

A single stimuli can launch an ldquoarmyrdquo of immune cells

Low doses that appear to ldquodo no harmrdquo(ie do not result in death of cells and

tissues)can potentially stimulate a harmful

immune response

The Inflammasome

wwwinvivogencomIL-33

2010 Science 327296The NLRP3 Inflammasome A Sensor for Metabolic DangerKate Schroder12 Rongbin Zhou1

Jurg Tschopp1

Activator class Activator Disease associations

Whole pathogen Candida albicans Infection

Saccharomyces

cerevisiae

Infection

Staphylococcus aureus Infection

Listeria monocytogenes Infection

Influenza virus Infection

Sendai virus Infection

Adenovirus Infection

Pathogen-associated

molecules

Bacterial porendashforming

toxins

Infection

Hemozoin Cerebral malaria

Environmental insults Silica Silicosis

Asbestos Asbestosis

Skin irritants Contact hypersensitivity

reactions

Ultraviolet light Sunburn

Endogenous danger

signals

ATP Injury or necrotic cell

death

Glucose Metabolic syndrome

MSU Gout

Calcium pyrophosphate

dihydrate (CPPD)

Pseudogout

Amyloid β Alzheimerrsquos disease

Hyaluronan Injury

Adjuvant Alum Th2 responses

Table 1 NLRP3 inflammasome activators Details of individual NLRP3 inflammasome activators are reviewed in (

Infections toxins amp environmental agents activate the inflammasome

Increased Th2 response

The inflammasome and alum-mediated adjuvanticitySuk-Jo Kang and Richard M Locksley

F1000 Biology Reports 2009 1 15 (doi 103410B1-15)

Figure 1 Alum-induced NLRP3 inflammasome activation

bull Phagocytosed alum-containing lysosomes rupture and release their components to the cytosol by an unknown mechanism The released contents and molecules generated during this process contribute to NLRP3ASCcaspase-1 inflammasome activation which in turn processes the proforms of IL-1 family members to active forms Either IL-1 family member cytokines or the products from NLRP3 inflammasome activation may elicit various immunostimulatory effects in vivo When and how potassium efflux and reactive oxygen species (ROS) play a role awaits further investigation DC dendritic cell MSU monosodium urate

17

Chronic Inflammation

Active inflammation

Tissue destruction

Attempts at repair

ie fibrosis

18

Chronic Inflammation amp Fibrosis (blue)

Outcomes of Acute Inflammation

Injury Acute inflammation

Resolution

Chronic inflammation

Healing regeneration amp scarring

Acute inflammation

leads to chronic disease in

susceptible individuals

Coronado MJ et al 2012 Am J PhysiolHeart Circ Physiol In press

Progression from Acute to Chronic inflammation

Fairweather et al 2001 J Autoimm 16 175-186

Resolution of Acute inflammation

HEALTH DISEASE

Organ System

Infections Physical injury Toxins Chemicals

Inflammation

TLRs inflammasome

TLRs inflammasome

TLRs inflammasome

Infections injury amp toxins chemicals activate the Innate Immune Response using similar mechanisms

What is the role of Innate Immunity in the pathogenesis of chronic diseases

bull Innate Immunity initiates inflammation ie Toll-like receptors (TLRs)

bull Innate Immunity determines the nature phenotype of the adaptive immune response ie T helper type (Th)1 vs Th2 vs Th17

bull Innate Immunity initiates regulatory mechanisms ie T regulatory cells and regulatory cytokines

bull The balance between a proinflammatory response and regulation of the response and regulation of repair mechanisms determines whether injury proceeds to chronic disease

threats to the body

Protection requires being able to distinguish ldquoselfrdquo from ldquonon-selfrdquo

PRRs detect PAMPs

bullPRRs recognize similar design patterns on microbes not present on host cells in order to destroy the pathogen

bullEx Toll-like receptors (TLRs) on immune amp other host cells

bullTLRrsquos important in cytokine production amp inflammation

bullPRRs can be found on ldquoinnaterdquo or ldquoadaptiverdquo immune cells

Human TLR 1-11

www2ujf-grenoblefrcurrenttlrgif

Inflammation

External threats activate PRRs

bull TLR1-13bull Dectin Rsbull Mannan Rsbull Inflammasome =

NODs and NALPsbull Results in activation

of NFkBbull Rarely do specific

infections relate to chronic diseases

Karen M et al 2006 Cell 124 823

TLRs recognize ldquodamaged selfrdquo

2009 J Immunol 18327-31

Particularly TLR2 amp TLR4

Endogenously derived ligands (self tissues) activate PRRs

bull Hsp= heat shock proteins induced by cell damage

bull ICs = immune complex with DNA or RNA

bull AC = apoptotic cells

bull SR = scavenger Rs

bull HMG-B1 = chromatin component (DAMP)

bull IL-33 (DAMP)

Karen M et al 2006 Cell 124 823

Immune responses do not follow normal Dose-Response relationships

Casarett amp Doullrsquos Essentials of Toxicology 2003

A single stimuli can launch an ldquoarmyrdquo of immune cells

Low doses that appear to ldquodo no harmrdquo(ie do not result in death of cells and

tissues)can potentially stimulate a harmful

immune response

The Inflammasome

wwwinvivogencomIL-33

2010 Science 327296The NLRP3 Inflammasome A Sensor for Metabolic DangerKate Schroder12 Rongbin Zhou1

Jurg Tschopp1

Activator class Activator Disease associations

Whole pathogen Candida albicans Infection

Saccharomyces

cerevisiae

Infection

Staphylococcus aureus Infection

Listeria monocytogenes Infection

Influenza virus Infection

Sendai virus Infection

Adenovirus Infection

Pathogen-associated

molecules

Bacterial porendashforming

toxins

Infection

Hemozoin Cerebral malaria

Environmental insults Silica Silicosis

Asbestos Asbestosis

Skin irritants Contact hypersensitivity

reactions

Ultraviolet light Sunburn

Endogenous danger

signals

ATP Injury or necrotic cell

death

Glucose Metabolic syndrome

MSU Gout

Calcium pyrophosphate

dihydrate (CPPD)

Pseudogout

Amyloid β Alzheimerrsquos disease

Hyaluronan Injury

Adjuvant Alum Th2 responses

Table 1 NLRP3 inflammasome activators Details of individual NLRP3 inflammasome activators are reviewed in (

Infections toxins amp environmental agents activate the inflammasome

Increased Th2 response

The inflammasome and alum-mediated adjuvanticitySuk-Jo Kang and Richard M Locksley

F1000 Biology Reports 2009 1 15 (doi 103410B1-15)

Figure 1 Alum-induced NLRP3 inflammasome activation

bull Phagocytosed alum-containing lysosomes rupture and release their components to the cytosol by an unknown mechanism The released contents and molecules generated during this process contribute to NLRP3ASCcaspase-1 inflammasome activation which in turn processes the proforms of IL-1 family members to active forms Either IL-1 family member cytokines or the products from NLRP3 inflammasome activation may elicit various immunostimulatory effects in vivo When and how potassium efflux and reactive oxygen species (ROS) play a role awaits further investigation DC dendritic cell MSU monosodium urate

18

Chronic Inflammation amp Fibrosis (blue)

Outcomes of Acute Inflammation

Injury Acute inflammation

Resolution

Chronic inflammation

Healing regeneration amp scarring

Acute inflammation

leads to chronic disease in

susceptible individuals

Coronado MJ et al 2012 Am J PhysiolHeart Circ Physiol In press

Progression from Acute to Chronic inflammation

Fairweather et al 2001 J Autoimm 16 175-186

Resolution of Acute inflammation

HEALTH DISEASE

Organ System

Infections Physical injury Toxins Chemicals

Inflammation

TLRs inflammasome

TLRs inflammasome

TLRs inflammasome

Infections injury amp toxins chemicals activate the Innate Immune Response using similar mechanisms

What is the role of Innate Immunity in the pathogenesis of chronic diseases

bull Innate Immunity initiates inflammation ie Toll-like receptors (TLRs)

bull Innate Immunity determines the nature phenotype of the adaptive immune response ie T helper type (Th)1 vs Th2 vs Th17

bull Innate Immunity initiates regulatory mechanisms ie T regulatory cells and regulatory cytokines

bull The balance between a proinflammatory response and regulation of the response and regulation of repair mechanisms determines whether injury proceeds to chronic disease

threats to the body

Protection requires being able to distinguish ldquoselfrdquo from ldquonon-selfrdquo

PRRs detect PAMPs

bullPRRs recognize similar design patterns on microbes not present on host cells in order to destroy the pathogen

bullEx Toll-like receptors (TLRs) on immune amp other host cells

bullTLRrsquos important in cytokine production amp inflammation

bullPRRs can be found on ldquoinnaterdquo or ldquoadaptiverdquo immune cells

Human TLR 1-11

www2ujf-grenoblefrcurrenttlrgif

Inflammation

External threats activate PRRs

bull TLR1-13bull Dectin Rsbull Mannan Rsbull Inflammasome =

NODs and NALPsbull Results in activation

of NFkBbull Rarely do specific

infections relate to chronic diseases

Karen M et al 2006 Cell 124 823

TLRs recognize ldquodamaged selfrdquo

2009 J Immunol 18327-31

Particularly TLR2 amp TLR4

Endogenously derived ligands (self tissues) activate PRRs

bull Hsp= heat shock proteins induced by cell damage

bull ICs = immune complex with DNA or RNA

bull AC = apoptotic cells

bull SR = scavenger Rs

bull HMG-B1 = chromatin component (DAMP)

bull IL-33 (DAMP)

Karen M et al 2006 Cell 124 823

Immune responses do not follow normal Dose-Response relationships

Casarett amp Doullrsquos Essentials of Toxicology 2003

A single stimuli can launch an ldquoarmyrdquo of immune cells

Low doses that appear to ldquodo no harmrdquo(ie do not result in death of cells and

tissues)can potentially stimulate a harmful

immune response

The Inflammasome

wwwinvivogencomIL-33

2010 Science 327296The NLRP3 Inflammasome A Sensor for Metabolic DangerKate Schroder12 Rongbin Zhou1

Jurg Tschopp1

Activator class Activator Disease associations

Whole pathogen Candida albicans Infection

Saccharomyces

cerevisiae

Infection

Staphylococcus aureus Infection

Listeria monocytogenes Infection

Influenza virus Infection

Sendai virus Infection

Adenovirus Infection

Pathogen-associated

molecules

Bacterial porendashforming

toxins

Infection

Hemozoin Cerebral malaria

Environmental insults Silica Silicosis

Asbestos Asbestosis

Skin irritants Contact hypersensitivity

reactions

Ultraviolet light Sunburn

Endogenous danger

signals

ATP Injury or necrotic cell

death

Glucose Metabolic syndrome

MSU Gout

Calcium pyrophosphate

dihydrate (CPPD)

Pseudogout

Amyloid β Alzheimerrsquos disease

Hyaluronan Injury

Adjuvant Alum Th2 responses

Table 1 NLRP3 inflammasome activators Details of individual NLRP3 inflammasome activators are reviewed in (

Infections toxins amp environmental agents activate the inflammasome

Increased Th2 response

The inflammasome and alum-mediated adjuvanticitySuk-Jo Kang and Richard M Locksley

F1000 Biology Reports 2009 1 15 (doi 103410B1-15)

Figure 1 Alum-induced NLRP3 inflammasome activation

bull Phagocytosed alum-containing lysosomes rupture and release their components to the cytosol by an unknown mechanism The released contents and molecules generated during this process contribute to NLRP3ASCcaspase-1 inflammasome activation which in turn processes the proforms of IL-1 family members to active forms Either IL-1 family member cytokines or the products from NLRP3 inflammasome activation may elicit various immunostimulatory effects in vivo When and how potassium efflux and reactive oxygen species (ROS) play a role awaits further investigation DC dendritic cell MSU monosodium urate

Outcomes of Acute Inflammation

Injury Acute inflammation

Resolution

Chronic inflammation

Healing regeneration amp scarring

Acute inflammation

leads to chronic disease in

susceptible individuals

Coronado MJ et al 2012 Am J PhysiolHeart Circ Physiol In press

Progression from Acute to Chronic inflammation

Fairweather et al 2001 J Autoimm 16 175-186

Resolution of Acute inflammation

HEALTH DISEASE

Organ System

Infections Physical injury Toxins Chemicals

Inflammation

TLRs inflammasome

TLRs inflammasome

TLRs inflammasome

Infections injury amp toxins chemicals activate the Innate Immune Response using similar mechanisms

What is the role of Innate Immunity in the pathogenesis of chronic diseases

bull Innate Immunity initiates inflammation ie Toll-like receptors (TLRs)

bull Innate Immunity determines the nature phenotype of the adaptive immune response ie T helper type (Th)1 vs Th2 vs Th17

bull Innate Immunity initiates regulatory mechanisms ie T regulatory cells and regulatory cytokines

bull The balance between a proinflammatory response and regulation of the response and regulation of repair mechanisms determines whether injury proceeds to chronic disease

threats to the body

Protection requires being able to distinguish ldquoselfrdquo from ldquonon-selfrdquo

PRRs detect PAMPs

bullPRRs recognize similar design patterns on microbes not present on host cells in order to destroy the pathogen

bullEx Toll-like receptors (TLRs) on immune amp other host cells

bullTLRrsquos important in cytokine production amp inflammation

bullPRRs can be found on ldquoinnaterdquo or ldquoadaptiverdquo immune cells

Human TLR 1-11

www2ujf-grenoblefrcurrenttlrgif

Inflammation

External threats activate PRRs

bull TLR1-13bull Dectin Rsbull Mannan Rsbull Inflammasome =

NODs and NALPsbull Results in activation

of NFkBbull Rarely do specific

infections relate to chronic diseases

Karen M et al 2006 Cell 124 823

TLRs recognize ldquodamaged selfrdquo

2009 J Immunol 18327-31

Particularly TLR2 amp TLR4

Endogenously derived ligands (self tissues) activate PRRs

bull Hsp= heat shock proteins induced by cell damage

bull ICs = immune complex with DNA or RNA

bull AC = apoptotic cells

bull SR = scavenger Rs

bull HMG-B1 = chromatin component (DAMP)

bull IL-33 (DAMP)

Karen M et al 2006 Cell 124 823

Immune responses do not follow normal Dose-Response relationships

Casarett amp Doullrsquos Essentials of Toxicology 2003

A single stimuli can launch an ldquoarmyrdquo of immune cells

Low doses that appear to ldquodo no harmrdquo(ie do not result in death of cells and

tissues)can potentially stimulate a harmful

immune response

The Inflammasome

wwwinvivogencomIL-33

2010 Science 327296The NLRP3 Inflammasome A Sensor for Metabolic DangerKate Schroder12 Rongbin Zhou1

Jurg Tschopp1

Activator class Activator Disease associations

Whole pathogen Candida albicans Infection

Saccharomyces

cerevisiae

Infection

Staphylococcus aureus Infection

Listeria monocytogenes Infection

Influenza virus Infection

Sendai virus Infection

Adenovirus Infection

Pathogen-associated

molecules

Bacterial porendashforming

toxins

Infection

Hemozoin Cerebral malaria

Environmental insults Silica Silicosis

Asbestos Asbestosis

Skin irritants Contact hypersensitivity

reactions

Ultraviolet light Sunburn

Endogenous danger

signals

ATP Injury or necrotic cell

death

Glucose Metabolic syndrome

MSU Gout

Calcium pyrophosphate

dihydrate (CPPD)

Pseudogout

Amyloid β Alzheimerrsquos disease

Hyaluronan Injury

Adjuvant Alum Th2 responses

Table 1 NLRP3 inflammasome activators Details of individual NLRP3 inflammasome activators are reviewed in (

Infections toxins amp environmental agents activate the inflammasome

Increased Th2 response

The inflammasome and alum-mediated adjuvanticitySuk-Jo Kang and Richard M Locksley

F1000 Biology Reports 2009 1 15 (doi 103410B1-15)

Figure 1 Alum-induced NLRP3 inflammasome activation

bull Phagocytosed alum-containing lysosomes rupture and release their components to the cytosol by an unknown mechanism The released contents and molecules generated during this process contribute to NLRP3ASCcaspase-1 inflammasome activation which in turn processes the proforms of IL-1 family members to active forms Either IL-1 family member cytokines or the products from NLRP3 inflammasome activation may elicit various immunostimulatory effects in vivo When and how potassium efflux and reactive oxygen species (ROS) play a role awaits further investigation DC dendritic cell MSU monosodium urate

Acute inflammation

leads to chronic disease in

susceptible individuals

Coronado MJ et al 2012 Am J PhysiolHeart Circ Physiol In press

Progression from Acute to Chronic inflammation

Fairweather et al 2001 J Autoimm 16 175-186

Resolution of Acute inflammation

HEALTH DISEASE

Organ System

Infections Physical injury Toxins Chemicals

Inflammation

TLRs inflammasome

TLRs inflammasome

TLRs inflammasome

Infections injury amp toxins chemicals activate the Innate Immune Response using similar mechanisms

What is the role of Innate Immunity in the pathogenesis of chronic diseases

bull Innate Immunity initiates inflammation ie Toll-like receptors (TLRs)

bull Innate Immunity determines the nature phenotype of the adaptive immune response ie T helper type (Th)1 vs Th2 vs Th17

bull Innate Immunity initiates regulatory mechanisms ie T regulatory cells and regulatory cytokines

bull The balance between a proinflammatory response and regulation of the response and regulation of repair mechanisms determines whether injury proceeds to chronic disease

threats to the body

Protection requires being able to distinguish ldquoselfrdquo from ldquonon-selfrdquo

PRRs detect PAMPs

bullPRRs recognize similar design patterns on microbes not present on host cells in order to destroy the pathogen

bullEx Toll-like receptors (TLRs) on immune amp other host cells

bullTLRrsquos important in cytokine production amp inflammation

bullPRRs can be found on ldquoinnaterdquo or ldquoadaptiverdquo immune cells

Human TLR 1-11

www2ujf-grenoblefrcurrenttlrgif

Inflammation

External threats activate PRRs

bull TLR1-13bull Dectin Rsbull Mannan Rsbull Inflammasome =

NODs and NALPsbull Results in activation

of NFkBbull Rarely do specific

infections relate to chronic diseases

Karen M et al 2006 Cell 124 823

TLRs recognize ldquodamaged selfrdquo

2009 J Immunol 18327-31

Particularly TLR2 amp TLR4

Endogenously derived ligands (self tissues) activate PRRs

bull Hsp= heat shock proteins induced by cell damage

bull ICs = immune complex with DNA or RNA

bull AC = apoptotic cells

bull SR = scavenger Rs

bull HMG-B1 = chromatin component (DAMP)

bull IL-33 (DAMP)

Karen M et al 2006 Cell 124 823

Immune responses do not follow normal Dose-Response relationships

Casarett amp Doullrsquos Essentials of Toxicology 2003

A single stimuli can launch an ldquoarmyrdquo of immune cells

Low doses that appear to ldquodo no harmrdquo(ie do not result in death of cells and

tissues)can potentially stimulate a harmful

immune response

The Inflammasome

wwwinvivogencomIL-33

2010 Science 327296The NLRP3 Inflammasome A Sensor for Metabolic DangerKate Schroder12 Rongbin Zhou1

Jurg Tschopp1

Activator class Activator Disease associations

Whole pathogen Candida albicans Infection

Saccharomyces

cerevisiae

Infection

Staphylococcus aureus Infection

Listeria monocytogenes Infection

Influenza virus Infection

Sendai virus Infection

Adenovirus Infection

Pathogen-associated

molecules

Bacterial porendashforming

toxins

Infection

Hemozoin Cerebral malaria

Environmental insults Silica Silicosis

Asbestos Asbestosis

Skin irritants Contact hypersensitivity

reactions

Ultraviolet light Sunburn

Endogenous danger

signals

ATP Injury or necrotic cell

death

Glucose Metabolic syndrome

MSU Gout

Calcium pyrophosphate

dihydrate (CPPD)

Pseudogout

Amyloid β Alzheimerrsquos disease

Hyaluronan Injury

Adjuvant Alum Th2 responses

Table 1 NLRP3 inflammasome activators Details of individual NLRP3 inflammasome activators are reviewed in (

Infections toxins amp environmental agents activate the inflammasome

Increased Th2 response

The inflammasome and alum-mediated adjuvanticitySuk-Jo Kang and Richard M Locksley

F1000 Biology Reports 2009 1 15 (doi 103410B1-15)

Figure 1 Alum-induced NLRP3 inflammasome activation

bull Phagocytosed alum-containing lysosomes rupture and release their components to the cytosol by an unknown mechanism The released contents and molecules generated during this process contribute to NLRP3ASCcaspase-1 inflammasome activation which in turn processes the proforms of IL-1 family members to active forms Either IL-1 family member cytokines or the products from NLRP3 inflammasome activation may elicit various immunostimulatory effects in vivo When and how potassium efflux and reactive oxygen species (ROS) play a role awaits further investigation DC dendritic cell MSU monosodium urate

Progression from Acute to Chronic inflammation

Fairweather et al 2001 J Autoimm 16 175-186

Resolution of Acute inflammation

HEALTH DISEASE

Organ System

Infections Physical injury Toxins Chemicals

Inflammation

TLRs inflammasome

TLRs inflammasome

TLRs inflammasome

Infections injury amp toxins chemicals activate the Innate Immune Response using similar mechanisms

What is the role of Innate Immunity in the pathogenesis of chronic diseases

bull Innate Immunity initiates inflammation ie Toll-like receptors (TLRs)

bull Innate Immunity determines the nature phenotype of the adaptive immune response ie T helper type (Th)1 vs Th2 vs Th17

bull Innate Immunity initiates regulatory mechanisms ie T regulatory cells and regulatory cytokines

bull The balance between a proinflammatory response and regulation of the response and regulation of repair mechanisms determines whether injury proceeds to chronic disease

threats to the body

Protection requires being able to distinguish ldquoselfrdquo from ldquonon-selfrdquo

PRRs detect PAMPs

bullPRRs recognize similar design patterns on microbes not present on host cells in order to destroy the pathogen

bullEx Toll-like receptors (TLRs) on immune amp other host cells

bullTLRrsquos important in cytokine production amp inflammation

bullPRRs can be found on ldquoinnaterdquo or ldquoadaptiverdquo immune cells

Human TLR 1-11

www2ujf-grenoblefrcurrenttlrgif

Inflammation

External threats activate PRRs

bull TLR1-13bull Dectin Rsbull Mannan Rsbull Inflammasome =

NODs and NALPsbull Results in activation

of NFkBbull Rarely do specific

infections relate to chronic diseases

Karen M et al 2006 Cell 124 823

TLRs recognize ldquodamaged selfrdquo

2009 J Immunol 18327-31

Particularly TLR2 amp TLR4

Endogenously derived ligands (self tissues) activate PRRs

bull Hsp= heat shock proteins induced by cell damage

bull ICs = immune complex with DNA or RNA

bull AC = apoptotic cells

bull SR = scavenger Rs

bull HMG-B1 = chromatin component (DAMP)

bull IL-33 (DAMP)

Karen M et al 2006 Cell 124 823

Immune responses do not follow normal Dose-Response relationships

Casarett amp Doullrsquos Essentials of Toxicology 2003

A single stimuli can launch an ldquoarmyrdquo of immune cells

Low doses that appear to ldquodo no harmrdquo(ie do not result in death of cells and

tissues)can potentially stimulate a harmful

immune response

The Inflammasome

wwwinvivogencomIL-33

2010 Science 327296The NLRP3 Inflammasome A Sensor for Metabolic DangerKate Schroder12 Rongbin Zhou1

Jurg Tschopp1

Activator class Activator Disease associations

Whole pathogen Candida albicans Infection

Saccharomyces

cerevisiae

Infection

Staphylococcus aureus Infection

Listeria monocytogenes Infection

Influenza virus Infection

Sendai virus Infection

Adenovirus Infection

Pathogen-associated

molecules

Bacterial porendashforming

toxins

Infection

Hemozoin Cerebral malaria

Environmental insults Silica Silicosis

Asbestos Asbestosis

Skin irritants Contact hypersensitivity

reactions

Ultraviolet light Sunburn

Endogenous danger

signals

ATP Injury or necrotic cell

death

Glucose Metabolic syndrome

MSU Gout

Calcium pyrophosphate

dihydrate (CPPD)

Pseudogout

Amyloid β Alzheimerrsquos disease

Hyaluronan Injury

Adjuvant Alum Th2 responses

Table 1 NLRP3 inflammasome activators Details of individual NLRP3 inflammasome activators are reviewed in (

Infections toxins amp environmental agents activate the inflammasome

Increased Th2 response

The inflammasome and alum-mediated adjuvanticitySuk-Jo Kang and Richard M Locksley

F1000 Biology Reports 2009 1 15 (doi 103410B1-15)

Figure 1 Alum-induced NLRP3 inflammasome activation

bull Phagocytosed alum-containing lysosomes rupture and release their components to the cytosol by an unknown mechanism The released contents and molecules generated during this process contribute to NLRP3ASCcaspase-1 inflammasome activation which in turn processes the proforms of IL-1 family members to active forms Either IL-1 family member cytokines or the products from NLRP3 inflammasome activation may elicit various immunostimulatory effects in vivo When and how potassium efflux and reactive oxygen species (ROS) play a role awaits further investigation DC dendritic cell MSU monosodium urate

HEALTH DISEASE

Organ System

Infections Physical injury Toxins Chemicals

Inflammation

TLRs inflammasome

TLRs inflammasome

TLRs inflammasome

Infections injury amp toxins chemicals activate the Innate Immune Response using similar mechanisms

What is the role of Innate Immunity in the pathogenesis of chronic diseases

bull Innate Immunity initiates inflammation ie Toll-like receptors (TLRs)

bull Innate Immunity determines the nature phenotype of the adaptive immune response ie T helper type (Th)1 vs Th2 vs Th17

bull Innate Immunity initiates regulatory mechanisms ie T regulatory cells and regulatory cytokines

bull The balance between a proinflammatory response and regulation of the response and regulation of repair mechanisms determines whether injury proceeds to chronic disease

threats to the body

Protection requires being able to distinguish ldquoselfrdquo from ldquonon-selfrdquo

PRRs detect PAMPs

bullPRRs recognize similar design patterns on microbes not present on host cells in order to destroy the pathogen

bullEx Toll-like receptors (TLRs) on immune amp other host cells

bullTLRrsquos important in cytokine production amp inflammation

bullPRRs can be found on ldquoinnaterdquo or ldquoadaptiverdquo immune cells

Human TLR 1-11

www2ujf-grenoblefrcurrenttlrgif

Inflammation

External threats activate PRRs

bull TLR1-13bull Dectin Rsbull Mannan Rsbull Inflammasome =

NODs and NALPsbull Results in activation

of NFkBbull Rarely do specific

infections relate to chronic diseases

Karen M et al 2006 Cell 124 823

TLRs recognize ldquodamaged selfrdquo

2009 J Immunol 18327-31

Particularly TLR2 amp TLR4

Endogenously derived ligands (self tissues) activate PRRs

bull Hsp= heat shock proteins induced by cell damage

bull ICs = immune complex with DNA or RNA

bull AC = apoptotic cells

bull SR = scavenger Rs

bull HMG-B1 = chromatin component (DAMP)

bull IL-33 (DAMP)

Karen M et al 2006 Cell 124 823

Immune responses do not follow normal Dose-Response relationships

Casarett amp Doullrsquos Essentials of Toxicology 2003

A single stimuli can launch an ldquoarmyrdquo of immune cells

Low doses that appear to ldquodo no harmrdquo(ie do not result in death of cells and

tissues)can potentially stimulate a harmful

immune response

The Inflammasome

wwwinvivogencomIL-33

2010 Science 327296The NLRP3 Inflammasome A Sensor for Metabolic DangerKate Schroder12 Rongbin Zhou1

Jurg Tschopp1

Activator class Activator Disease associations

Whole pathogen Candida albicans Infection

Saccharomyces

cerevisiae

Infection

Staphylococcus aureus Infection

Listeria monocytogenes Infection

Influenza virus Infection

Sendai virus Infection

Adenovirus Infection

Pathogen-associated

molecules

Bacterial porendashforming

toxins

Infection

Hemozoin Cerebral malaria

Environmental insults Silica Silicosis

Asbestos Asbestosis

Skin irritants Contact hypersensitivity

reactions

Ultraviolet light Sunburn

Endogenous danger

signals

ATP Injury or necrotic cell

death

Glucose Metabolic syndrome

MSU Gout

Calcium pyrophosphate

dihydrate (CPPD)

Pseudogout

Amyloid β Alzheimerrsquos disease

Hyaluronan Injury

Adjuvant Alum Th2 responses

Table 1 NLRP3 inflammasome activators Details of individual NLRP3 inflammasome activators are reviewed in (

Infections toxins amp environmental agents activate the inflammasome

Increased Th2 response

The inflammasome and alum-mediated adjuvanticitySuk-Jo Kang and Richard M Locksley

F1000 Biology Reports 2009 1 15 (doi 103410B1-15)

Figure 1 Alum-induced NLRP3 inflammasome activation

bull Phagocytosed alum-containing lysosomes rupture and release their components to the cytosol by an unknown mechanism The released contents and molecules generated during this process contribute to NLRP3ASCcaspase-1 inflammasome activation which in turn processes the proforms of IL-1 family members to active forms Either IL-1 family member cytokines or the products from NLRP3 inflammasome activation may elicit various immunostimulatory effects in vivo When and how potassium efflux and reactive oxygen species (ROS) play a role awaits further investigation DC dendritic cell MSU monosodium urate

What is the role of Innate Immunity in the pathogenesis of chronic diseases

bull Innate Immunity initiates inflammation ie Toll-like receptors (TLRs)

bull Innate Immunity determines the nature phenotype of the adaptive immune response ie T helper type (Th)1 vs Th2 vs Th17

bull Innate Immunity initiates regulatory mechanisms ie T regulatory cells and regulatory cytokines

bull The balance between a proinflammatory response and regulation of the response and regulation of repair mechanisms determines whether injury proceeds to chronic disease

threats to the body

Protection requires being able to distinguish ldquoselfrdquo from ldquonon-selfrdquo

PRRs detect PAMPs

bullPRRs recognize similar design patterns on microbes not present on host cells in order to destroy the pathogen

bullEx Toll-like receptors (TLRs) on immune amp other host cells

bullTLRrsquos important in cytokine production amp inflammation

bullPRRs can be found on ldquoinnaterdquo or ldquoadaptiverdquo immune cells

Human TLR 1-11

www2ujf-grenoblefrcurrenttlrgif

Inflammation

External threats activate PRRs

bull TLR1-13bull Dectin Rsbull Mannan Rsbull Inflammasome =

NODs and NALPsbull Results in activation

of NFkBbull Rarely do specific

infections relate to chronic diseases

Karen M et al 2006 Cell 124 823

TLRs recognize ldquodamaged selfrdquo

2009 J Immunol 18327-31

Particularly TLR2 amp TLR4

Endogenously derived ligands (self tissues) activate PRRs

bull Hsp= heat shock proteins induced by cell damage

bull ICs = immune complex with DNA or RNA

bull AC = apoptotic cells

bull SR = scavenger Rs

bull HMG-B1 = chromatin component (DAMP)

bull IL-33 (DAMP)

Karen M et al 2006 Cell 124 823

Immune responses do not follow normal Dose-Response relationships

Casarett amp Doullrsquos Essentials of Toxicology 2003

A single stimuli can launch an ldquoarmyrdquo of immune cells

Low doses that appear to ldquodo no harmrdquo(ie do not result in death of cells and

tissues)can potentially stimulate a harmful

immune response

The Inflammasome

wwwinvivogencomIL-33

2010 Science 327296The NLRP3 Inflammasome A Sensor for Metabolic DangerKate Schroder12 Rongbin Zhou1

Jurg Tschopp1

Activator class Activator Disease associations

Whole pathogen Candida albicans Infection

Saccharomyces

cerevisiae

Infection

Staphylococcus aureus Infection

Listeria monocytogenes Infection

Influenza virus Infection

Sendai virus Infection

Adenovirus Infection

Pathogen-associated

molecules

Bacterial porendashforming

toxins

Infection

Hemozoin Cerebral malaria

Environmental insults Silica Silicosis

Asbestos Asbestosis

Skin irritants Contact hypersensitivity

reactions

Ultraviolet light Sunburn

Endogenous danger

signals

ATP Injury or necrotic cell

death

Glucose Metabolic syndrome

MSU Gout

Calcium pyrophosphate

dihydrate (CPPD)

Pseudogout

Amyloid β Alzheimerrsquos disease

Hyaluronan Injury

Adjuvant Alum Th2 responses

Table 1 NLRP3 inflammasome activators Details of individual NLRP3 inflammasome activators are reviewed in (

Infections toxins amp environmental agents activate the inflammasome

Increased Th2 response

The inflammasome and alum-mediated adjuvanticitySuk-Jo Kang and Richard M Locksley

F1000 Biology Reports 2009 1 15 (doi 103410B1-15)

Figure 1 Alum-induced NLRP3 inflammasome activation

bull Phagocytosed alum-containing lysosomes rupture and release their components to the cytosol by an unknown mechanism The released contents and molecules generated during this process contribute to NLRP3ASCcaspase-1 inflammasome activation which in turn processes the proforms of IL-1 family members to active forms Either IL-1 family member cytokines or the products from NLRP3 inflammasome activation may elicit various immunostimulatory effects in vivo When and how potassium efflux and reactive oxygen species (ROS) play a role awaits further investigation DC dendritic cell MSU monosodium urate

threats to the body

Protection requires being able to distinguish ldquoselfrdquo from ldquonon-selfrdquo

PRRs detect PAMPs

bullPRRs recognize similar design patterns on microbes not present on host cells in order to destroy the pathogen

bullEx Toll-like receptors (TLRs) on immune amp other host cells

bullTLRrsquos important in cytokine production amp inflammation

bullPRRs can be found on ldquoinnaterdquo or ldquoadaptiverdquo immune cells

Human TLR 1-11

www2ujf-grenoblefrcurrenttlrgif

Inflammation

External threats activate PRRs

bull TLR1-13bull Dectin Rsbull Mannan Rsbull Inflammasome =

NODs and NALPsbull Results in activation

of NFkBbull Rarely do specific

infections relate to chronic diseases

Karen M et al 2006 Cell 124 823

TLRs recognize ldquodamaged selfrdquo

2009 J Immunol 18327-31

Particularly TLR2 amp TLR4

Endogenously derived ligands (self tissues) activate PRRs

bull Hsp= heat shock proteins induced by cell damage

bull ICs = immune complex with DNA or RNA

bull AC = apoptotic cells

bull SR = scavenger Rs

bull HMG-B1 = chromatin component (DAMP)

bull IL-33 (DAMP)

Karen M et al 2006 Cell 124 823

Immune responses do not follow normal Dose-Response relationships

Casarett amp Doullrsquos Essentials of Toxicology 2003

A single stimuli can launch an ldquoarmyrdquo of immune cells

Low doses that appear to ldquodo no harmrdquo(ie do not result in death of cells and

tissues)can potentially stimulate a harmful

immune response

The Inflammasome

wwwinvivogencomIL-33

2010 Science 327296The NLRP3 Inflammasome A Sensor for Metabolic DangerKate Schroder12 Rongbin Zhou1

Jurg Tschopp1

Activator class Activator Disease associations

Whole pathogen Candida albicans Infection

Saccharomyces

cerevisiae

Infection

Staphylococcus aureus Infection

Listeria monocytogenes Infection

Influenza virus Infection

Sendai virus Infection

Adenovirus Infection

Pathogen-associated

molecules

Bacterial porendashforming

toxins

Infection

Hemozoin Cerebral malaria

Environmental insults Silica Silicosis

Asbestos Asbestosis

Skin irritants Contact hypersensitivity

reactions

Ultraviolet light Sunburn

Endogenous danger

signals

ATP Injury or necrotic cell

death

Glucose Metabolic syndrome

MSU Gout

Calcium pyrophosphate

dihydrate (CPPD)

Pseudogout

Amyloid β Alzheimerrsquos disease

Hyaluronan Injury

Adjuvant Alum Th2 responses

Table 1 NLRP3 inflammasome activators Details of individual NLRP3 inflammasome activators are reviewed in (

Infections toxins amp environmental agents activate the inflammasome

Increased Th2 response

The inflammasome and alum-mediated adjuvanticitySuk-Jo Kang and Richard M Locksley

F1000 Biology Reports 2009 1 15 (doi 103410B1-15)

Figure 1 Alum-induced NLRP3 inflammasome activation

bull Phagocytosed alum-containing lysosomes rupture and release their components to the cytosol by an unknown mechanism The released contents and molecules generated during this process contribute to NLRP3ASCcaspase-1 inflammasome activation which in turn processes the proforms of IL-1 family members to active forms Either IL-1 family member cytokines or the products from NLRP3 inflammasome activation may elicit various immunostimulatory effects in vivo When and how potassium efflux and reactive oxygen species (ROS) play a role awaits further investigation DC dendritic cell MSU monosodium urate

PRRs detect PAMPs

bullPRRs recognize similar design patterns on microbes not present on host cells in order to destroy the pathogen

bullEx Toll-like receptors (TLRs) on immune amp other host cells

bullTLRrsquos important in cytokine production amp inflammation

bullPRRs can be found on ldquoinnaterdquo or ldquoadaptiverdquo immune cells

Human TLR 1-11

www2ujf-grenoblefrcurrenttlrgif

Inflammation

External threats activate PRRs

bull TLR1-13bull Dectin Rsbull Mannan Rsbull Inflammasome =

NODs and NALPsbull Results in activation

of NFkBbull Rarely do specific

infections relate to chronic diseases

Karen M et al 2006 Cell 124 823

TLRs recognize ldquodamaged selfrdquo

2009 J Immunol 18327-31

Particularly TLR2 amp TLR4

Endogenously derived ligands (self tissues) activate PRRs

bull Hsp= heat shock proteins induced by cell damage

bull ICs = immune complex with DNA or RNA

bull AC = apoptotic cells

bull SR = scavenger Rs

bull HMG-B1 = chromatin component (DAMP)

bull IL-33 (DAMP)

Karen M et al 2006 Cell 124 823

Immune responses do not follow normal Dose-Response relationships

Casarett amp Doullrsquos Essentials of Toxicology 2003

A single stimuli can launch an ldquoarmyrdquo of immune cells

Low doses that appear to ldquodo no harmrdquo(ie do not result in death of cells and

tissues)can potentially stimulate a harmful

immune response

The Inflammasome

wwwinvivogencomIL-33

2010 Science 327296The NLRP3 Inflammasome A Sensor for Metabolic DangerKate Schroder12 Rongbin Zhou1

Jurg Tschopp1

Activator class Activator Disease associations

Whole pathogen Candida albicans Infection

Saccharomyces

cerevisiae

Infection

Staphylococcus aureus Infection

Listeria monocytogenes Infection

Influenza virus Infection

Sendai virus Infection

Adenovirus Infection

Pathogen-associated

molecules

Bacterial porendashforming

toxins

Infection

Hemozoin Cerebral malaria

Environmental insults Silica Silicosis

Asbestos Asbestosis

Skin irritants Contact hypersensitivity

reactions

Ultraviolet light Sunburn

Endogenous danger

signals

ATP Injury or necrotic cell

death

Glucose Metabolic syndrome

MSU Gout

Calcium pyrophosphate

dihydrate (CPPD)

Pseudogout

Amyloid β Alzheimerrsquos disease

Hyaluronan Injury

Adjuvant Alum Th2 responses

Table 1 NLRP3 inflammasome activators Details of individual NLRP3 inflammasome activators are reviewed in (

Infections toxins amp environmental agents activate the inflammasome

Increased Th2 response

The inflammasome and alum-mediated adjuvanticitySuk-Jo Kang and Richard M Locksley

F1000 Biology Reports 2009 1 15 (doi 103410B1-15)

Figure 1 Alum-induced NLRP3 inflammasome activation

bull Phagocytosed alum-containing lysosomes rupture and release their components to the cytosol by an unknown mechanism The released contents and molecules generated during this process contribute to NLRP3ASCcaspase-1 inflammasome activation which in turn processes the proforms of IL-1 family members to active forms Either IL-1 family member cytokines or the products from NLRP3 inflammasome activation may elicit various immunostimulatory effects in vivo When and how potassium efflux and reactive oxygen species (ROS) play a role awaits further investigation DC dendritic cell MSU monosodium urate

Human TLR 1-11

www2ujf-grenoblefrcurrenttlrgif

Inflammation

External threats activate PRRs

bull TLR1-13bull Dectin Rsbull Mannan Rsbull Inflammasome =

NODs and NALPsbull Results in activation

of NFkBbull Rarely do specific

infections relate to chronic diseases

Karen M et al 2006 Cell 124 823

TLRs recognize ldquodamaged selfrdquo

2009 J Immunol 18327-31

Particularly TLR2 amp TLR4

Endogenously derived ligands (self tissues) activate PRRs

bull Hsp= heat shock proteins induced by cell damage

bull ICs = immune complex with DNA or RNA

bull AC = apoptotic cells

bull SR = scavenger Rs

bull HMG-B1 = chromatin component (DAMP)

bull IL-33 (DAMP)

Karen M et al 2006 Cell 124 823

Immune responses do not follow normal Dose-Response relationships

Casarett amp Doullrsquos Essentials of Toxicology 2003

A single stimuli can launch an ldquoarmyrdquo of immune cells

Low doses that appear to ldquodo no harmrdquo(ie do not result in death of cells and

tissues)can potentially stimulate a harmful

immune response

The Inflammasome

wwwinvivogencomIL-33

2010 Science 327296The NLRP3 Inflammasome A Sensor for Metabolic DangerKate Schroder12 Rongbin Zhou1

Jurg Tschopp1

Activator class Activator Disease associations

Whole pathogen Candida albicans Infection

Saccharomyces

cerevisiae

Infection

Staphylococcus aureus Infection

Listeria monocytogenes Infection

Influenza virus Infection

Sendai virus Infection

Adenovirus Infection

Pathogen-associated

molecules

Bacterial porendashforming

toxins

Infection

Hemozoin Cerebral malaria

Environmental insults Silica Silicosis

Asbestos Asbestosis

Skin irritants Contact hypersensitivity

reactions

Ultraviolet light Sunburn

Endogenous danger

signals

ATP Injury or necrotic cell

death

Glucose Metabolic syndrome

MSU Gout

Calcium pyrophosphate

dihydrate (CPPD)

Pseudogout

Amyloid β Alzheimerrsquos disease

Hyaluronan Injury

Adjuvant Alum Th2 responses

Table 1 NLRP3 inflammasome activators Details of individual NLRP3 inflammasome activators are reviewed in (

Infections toxins amp environmental agents activate the inflammasome

Increased Th2 response

The inflammasome and alum-mediated adjuvanticitySuk-Jo Kang and Richard M Locksley

F1000 Biology Reports 2009 1 15 (doi 103410B1-15)

Figure 1 Alum-induced NLRP3 inflammasome activation

bull Phagocytosed alum-containing lysosomes rupture and release their components to the cytosol by an unknown mechanism The released contents and molecules generated during this process contribute to NLRP3ASCcaspase-1 inflammasome activation which in turn processes the proforms of IL-1 family members to active forms Either IL-1 family member cytokines or the products from NLRP3 inflammasome activation may elicit various immunostimulatory effects in vivo When and how potassium efflux and reactive oxygen species (ROS) play a role awaits further investigation DC dendritic cell MSU monosodium urate

External threats activate PRRs

bull TLR1-13bull Dectin Rsbull Mannan Rsbull Inflammasome =

NODs and NALPsbull Results in activation

of NFkBbull Rarely do specific

infections relate to chronic diseases

Karen M et al 2006 Cell 124 823

TLRs recognize ldquodamaged selfrdquo

2009 J Immunol 18327-31

Particularly TLR2 amp TLR4

Endogenously derived ligands (self tissues) activate PRRs

bull Hsp= heat shock proteins induced by cell damage

bull ICs = immune complex with DNA or RNA

bull AC = apoptotic cells

bull SR = scavenger Rs

bull HMG-B1 = chromatin component (DAMP)

bull IL-33 (DAMP)

Karen M et al 2006 Cell 124 823

Immune responses do not follow normal Dose-Response relationships

Casarett amp Doullrsquos Essentials of Toxicology 2003

A single stimuli can launch an ldquoarmyrdquo of immune cells

Low doses that appear to ldquodo no harmrdquo(ie do not result in death of cells and

tissues)can potentially stimulate a harmful

immune response

The Inflammasome

wwwinvivogencomIL-33

2010 Science 327296The NLRP3 Inflammasome A Sensor for Metabolic DangerKate Schroder12 Rongbin Zhou1

Jurg Tschopp1

Activator class Activator Disease associations

Whole pathogen Candida albicans Infection

Saccharomyces

cerevisiae

Infection

Staphylococcus aureus Infection

Listeria monocytogenes Infection

Influenza virus Infection

Sendai virus Infection

Adenovirus Infection

Pathogen-associated

molecules

Bacterial porendashforming

toxins

Infection

Hemozoin Cerebral malaria

Environmental insults Silica Silicosis

Asbestos Asbestosis

Skin irritants Contact hypersensitivity

reactions

Ultraviolet light Sunburn

Endogenous danger

signals

ATP Injury or necrotic cell

death

Glucose Metabolic syndrome

MSU Gout

Calcium pyrophosphate

dihydrate (CPPD)

Pseudogout

Amyloid β Alzheimerrsquos disease

Hyaluronan Injury

Adjuvant Alum Th2 responses

Table 1 NLRP3 inflammasome activators Details of individual NLRP3 inflammasome activators are reviewed in (

Infections toxins amp environmental agents activate the inflammasome

Increased Th2 response

The inflammasome and alum-mediated adjuvanticitySuk-Jo Kang and Richard M Locksley

F1000 Biology Reports 2009 1 15 (doi 103410B1-15)

Figure 1 Alum-induced NLRP3 inflammasome activation

bull Phagocytosed alum-containing lysosomes rupture and release their components to the cytosol by an unknown mechanism The released contents and molecules generated during this process contribute to NLRP3ASCcaspase-1 inflammasome activation which in turn processes the proforms of IL-1 family members to active forms Either IL-1 family member cytokines or the products from NLRP3 inflammasome activation may elicit various immunostimulatory effects in vivo When and how potassium efflux and reactive oxygen species (ROS) play a role awaits further investigation DC dendritic cell MSU monosodium urate

TLRs recognize ldquodamaged selfrdquo

2009 J Immunol 18327-31

Particularly TLR2 amp TLR4

Endogenously derived ligands (self tissues) activate PRRs

bull Hsp= heat shock proteins induced by cell damage

bull ICs = immune complex with DNA or RNA

bull AC = apoptotic cells

bull SR = scavenger Rs

bull HMG-B1 = chromatin component (DAMP)

bull IL-33 (DAMP)

Karen M et al 2006 Cell 124 823

Immune responses do not follow normal Dose-Response relationships

Casarett amp Doullrsquos Essentials of Toxicology 2003

A single stimuli can launch an ldquoarmyrdquo of immune cells

Low doses that appear to ldquodo no harmrdquo(ie do not result in death of cells and

tissues)can potentially stimulate a harmful

immune response

The Inflammasome

wwwinvivogencomIL-33

2010 Science 327296The NLRP3 Inflammasome A Sensor for Metabolic DangerKate Schroder12 Rongbin Zhou1

Jurg Tschopp1

Activator class Activator Disease associations

Whole pathogen Candida albicans Infection

Saccharomyces

cerevisiae

Infection

Staphylococcus aureus Infection

Listeria monocytogenes Infection

Influenza virus Infection

Sendai virus Infection

Adenovirus Infection

Pathogen-associated

molecules

Bacterial porendashforming

toxins

Infection

Hemozoin Cerebral malaria

Environmental insults Silica Silicosis

Asbestos Asbestosis

Skin irritants Contact hypersensitivity

reactions

Ultraviolet light Sunburn

Endogenous danger

signals

ATP Injury or necrotic cell

death

Glucose Metabolic syndrome

MSU Gout

Calcium pyrophosphate

dihydrate (CPPD)

Pseudogout

Amyloid β Alzheimerrsquos disease

Hyaluronan Injury

Adjuvant Alum Th2 responses

Table 1 NLRP3 inflammasome activators Details of individual NLRP3 inflammasome activators are reviewed in (

Infections toxins amp environmental agents activate the inflammasome

Increased Th2 response

The inflammasome and alum-mediated adjuvanticitySuk-Jo Kang and Richard M Locksley

F1000 Biology Reports 2009 1 15 (doi 103410B1-15)

Figure 1 Alum-induced NLRP3 inflammasome activation

bull Phagocytosed alum-containing lysosomes rupture and release their components to the cytosol by an unknown mechanism The released contents and molecules generated during this process contribute to NLRP3ASCcaspase-1 inflammasome activation which in turn processes the proforms of IL-1 family members to active forms Either IL-1 family member cytokines or the products from NLRP3 inflammasome activation may elicit various immunostimulatory effects in vivo When and how potassium efflux and reactive oxygen species (ROS) play a role awaits further investigation DC dendritic cell MSU monosodium urate

Endogenously derived ligands (self tissues) activate PRRs

bull Hsp= heat shock proteins induced by cell damage

bull ICs = immune complex with DNA or RNA

bull AC = apoptotic cells

bull SR = scavenger Rs

bull HMG-B1 = chromatin component (DAMP)

bull IL-33 (DAMP)

Karen M et al 2006 Cell 124 823

Immune responses do not follow normal Dose-Response relationships

Casarett amp Doullrsquos Essentials of Toxicology 2003

A single stimuli can launch an ldquoarmyrdquo of immune cells

Low doses that appear to ldquodo no harmrdquo(ie do not result in death of cells and

tissues)can potentially stimulate a harmful

immune response

The Inflammasome

wwwinvivogencomIL-33

2010 Science 327296The NLRP3 Inflammasome A Sensor for Metabolic DangerKate Schroder12 Rongbin Zhou1

Jurg Tschopp1

Activator class Activator Disease associations

Whole pathogen Candida albicans Infection

Saccharomyces

cerevisiae

Infection

Staphylococcus aureus Infection

Listeria monocytogenes Infection

Influenza virus Infection

Sendai virus Infection

Adenovirus Infection

Pathogen-associated

molecules

Bacterial porendashforming

toxins

Infection

Hemozoin Cerebral malaria

Environmental insults Silica Silicosis

Asbestos Asbestosis

Skin irritants Contact hypersensitivity

reactions

Ultraviolet light Sunburn

Endogenous danger

signals

ATP Injury or necrotic cell

death

Glucose Metabolic syndrome

MSU Gout

Calcium pyrophosphate

dihydrate (CPPD)

Pseudogout

Amyloid β Alzheimerrsquos disease

Hyaluronan Injury

Adjuvant Alum Th2 responses

Table 1 NLRP3 inflammasome activators Details of individual NLRP3 inflammasome activators are reviewed in (

Infections toxins amp environmental agents activate the inflammasome

Increased Th2 response

The inflammasome and alum-mediated adjuvanticitySuk-Jo Kang and Richard M Locksley

F1000 Biology Reports 2009 1 15 (doi 103410B1-15)

Figure 1 Alum-induced NLRP3 inflammasome activation

bull Phagocytosed alum-containing lysosomes rupture and release their components to the cytosol by an unknown mechanism The released contents and molecules generated during this process contribute to NLRP3ASCcaspase-1 inflammasome activation which in turn processes the proforms of IL-1 family members to active forms Either IL-1 family member cytokines or the products from NLRP3 inflammasome activation may elicit various immunostimulatory effects in vivo When and how potassium efflux and reactive oxygen species (ROS) play a role awaits further investigation DC dendritic cell MSU monosodium urate

Immune responses do not follow normal Dose-Response relationships

Casarett amp Doullrsquos Essentials of Toxicology 2003

A single stimuli can launch an ldquoarmyrdquo of immune cells

Low doses that appear to ldquodo no harmrdquo(ie do not result in death of cells and

tissues)can potentially stimulate a harmful

immune response

The Inflammasome

wwwinvivogencomIL-33

2010 Science 327296The NLRP3 Inflammasome A Sensor for Metabolic DangerKate Schroder12 Rongbin Zhou1

Jurg Tschopp1

Activator class Activator Disease associations

Whole pathogen Candida albicans Infection

Saccharomyces

cerevisiae

Infection

Staphylococcus aureus Infection

Listeria monocytogenes Infection

Influenza virus Infection

Sendai virus Infection

Adenovirus Infection

Pathogen-associated

molecules

Bacterial porendashforming

toxins

Infection

Hemozoin Cerebral malaria

Environmental insults Silica Silicosis

Asbestos Asbestosis

Skin irritants Contact hypersensitivity

reactions

Ultraviolet light Sunburn

Endogenous danger

signals

ATP Injury or necrotic cell

death

Glucose Metabolic syndrome

MSU Gout

Calcium pyrophosphate

dihydrate (CPPD)

Pseudogout

Amyloid β Alzheimerrsquos disease

Hyaluronan Injury

Adjuvant Alum Th2 responses

Table 1 NLRP3 inflammasome activators Details of individual NLRP3 inflammasome activators are reviewed in (

Infections toxins amp environmental agents activate the inflammasome

Increased Th2 response

The inflammasome and alum-mediated adjuvanticitySuk-Jo Kang and Richard M Locksley

F1000 Biology Reports 2009 1 15 (doi 103410B1-15)

Figure 1 Alum-induced NLRP3 inflammasome activation

bull Phagocytosed alum-containing lysosomes rupture and release their components to the cytosol by an unknown mechanism The released contents and molecules generated during this process contribute to NLRP3ASCcaspase-1 inflammasome activation which in turn processes the proforms of IL-1 family members to active forms Either IL-1 family member cytokines or the products from NLRP3 inflammasome activation may elicit various immunostimulatory effects in vivo When and how potassium efflux and reactive oxygen species (ROS) play a role awaits further investigation DC dendritic cell MSU monosodium urate

A single stimuli can launch an ldquoarmyrdquo of immune cells

Low doses that appear to ldquodo no harmrdquo(ie do not result in death of cells and

tissues)can potentially stimulate a harmful

immune response

The Inflammasome

wwwinvivogencomIL-33

2010 Science 327296The NLRP3 Inflammasome A Sensor for Metabolic DangerKate Schroder12 Rongbin Zhou1

Jurg Tschopp1

Activator class Activator Disease associations

Whole pathogen Candida albicans Infection

Saccharomyces

cerevisiae

Infection

Staphylococcus aureus Infection

Listeria monocytogenes Infection

Influenza virus Infection

Sendai virus Infection

Adenovirus Infection

Pathogen-associated

molecules

Bacterial porendashforming

toxins

Infection

Hemozoin Cerebral malaria

Environmental insults Silica Silicosis

Asbestos Asbestosis

Skin irritants Contact hypersensitivity

reactions

Ultraviolet light Sunburn

Endogenous danger

signals

ATP Injury or necrotic cell

death

Glucose Metabolic syndrome

MSU Gout

Calcium pyrophosphate

dihydrate (CPPD)

Pseudogout

Amyloid β Alzheimerrsquos disease

Hyaluronan Injury

Adjuvant Alum Th2 responses

Table 1 NLRP3 inflammasome activators Details of individual NLRP3 inflammasome activators are reviewed in (

Infections toxins amp environmental agents activate the inflammasome

Increased Th2 response

The inflammasome and alum-mediated adjuvanticitySuk-Jo Kang and Richard M Locksley

F1000 Biology Reports 2009 1 15 (doi 103410B1-15)

Figure 1 Alum-induced NLRP3 inflammasome activation

bull Phagocytosed alum-containing lysosomes rupture and release their components to the cytosol by an unknown mechanism The released contents and molecules generated during this process contribute to NLRP3ASCcaspase-1 inflammasome activation which in turn processes the proforms of IL-1 family members to active forms Either IL-1 family member cytokines or the products from NLRP3 inflammasome activation may elicit various immunostimulatory effects in vivo When and how potassium efflux and reactive oxygen species (ROS) play a role awaits further investigation DC dendritic cell MSU monosodium urate

Low doses that appear to ldquodo no harmrdquo(ie do not result in death of cells and

tissues)can potentially stimulate a harmful

immune response

The Inflammasome

wwwinvivogencomIL-33

2010 Science 327296The NLRP3 Inflammasome A Sensor for Metabolic DangerKate Schroder12 Rongbin Zhou1

Jurg Tschopp1

Activator class Activator Disease associations

Whole pathogen Candida albicans Infection

Saccharomyces

cerevisiae

Infection

Staphylococcus aureus Infection

Listeria monocytogenes Infection

Influenza virus Infection

Sendai virus Infection

Adenovirus Infection

Pathogen-associated

molecules

Bacterial porendashforming

toxins

Infection

Hemozoin Cerebral malaria

Environmental insults Silica Silicosis

Asbestos Asbestosis

Skin irritants Contact hypersensitivity

reactions

Ultraviolet light Sunburn

Endogenous danger

signals

ATP Injury or necrotic cell

death

Glucose Metabolic syndrome

MSU Gout

Calcium pyrophosphate

dihydrate (CPPD)

Pseudogout

Amyloid β Alzheimerrsquos disease

Hyaluronan Injury

Adjuvant Alum Th2 responses

Table 1 NLRP3 inflammasome activators Details of individual NLRP3 inflammasome activators are reviewed in (

Infections toxins amp environmental agents activate the inflammasome

Increased Th2 response

The inflammasome and alum-mediated adjuvanticitySuk-Jo Kang and Richard M Locksley

F1000 Biology Reports 2009 1 15 (doi 103410B1-15)

Figure 1 Alum-induced NLRP3 inflammasome activation

bull Phagocytosed alum-containing lysosomes rupture and release their components to the cytosol by an unknown mechanism The released contents and molecules generated during this process contribute to NLRP3ASCcaspase-1 inflammasome activation which in turn processes the proforms of IL-1 family members to active forms Either IL-1 family member cytokines or the products from NLRP3 inflammasome activation may elicit various immunostimulatory effects in vivo When and how potassium efflux and reactive oxygen species (ROS) play a role awaits further investigation DC dendritic cell MSU monosodium urate

The Inflammasome

wwwinvivogencomIL-33

2010 Science 327296The NLRP3 Inflammasome A Sensor for Metabolic DangerKate Schroder12 Rongbin Zhou1

Jurg Tschopp1

Activator class Activator Disease associations

Whole pathogen Candida albicans Infection

Saccharomyces

cerevisiae

Infection

Staphylococcus aureus Infection

Listeria monocytogenes Infection

Influenza virus Infection

Sendai virus Infection

Adenovirus Infection

Pathogen-associated

molecules

Bacterial porendashforming

toxins

Infection

Hemozoin Cerebral malaria

Environmental insults Silica Silicosis

Asbestos Asbestosis

Skin irritants Contact hypersensitivity

reactions

Ultraviolet light Sunburn

Endogenous danger

signals

ATP Injury or necrotic cell

death

Glucose Metabolic syndrome

MSU Gout

Calcium pyrophosphate

dihydrate (CPPD)

Pseudogout

Amyloid β Alzheimerrsquos disease

Hyaluronan Injury

Adjuvant Alum Th2 responses

Table 1 NLRP3 inflammasome activators Details of individual NLRP3 inflammasome activators are reviewed in (

Infections toxins amp environmental agents activate the inflammasome

Increased Th2 response

The inflammasome and alum-mediated adjuvanticitySuk-Jo Kang and Richard M Locksley

F1000 Biology Reports 2009 1 15 (doi 103410B1-15)

Figure 1 Alum-induced NLRP3 inflammasome activation

bull Phagocytosed alum-containing lysosomes rupture and release their components to the cytosol by an unknown mechanism The released contents and molecules generated during this process contribute to NLRP3ASCcaspase-1 inflammasome activation which in turn processes the proforms of IL-1 family members to active forms Either IL-1 family member cytokines or the products from NLRP3 inflammasome activation may elicit various immunostimulatory effects in vivo When and how potassium efflux and reactive oxygen species (ROS) play a role awaits further investigation DC dendritic cell MSU monosodium urate

2010 Science 327296The NLRP3 Inflammasome A Sensor for Metabolic DangerKate Schroder12 Rongbin Zhou1

Jurg Tschopp1

Activator class Activator Disease associations

Whole pathogen Candida albicans Infection

Saccharomyces

cerevisiae

Infection

Staphylococcus aureus Infection

Listeria monocytogenes Infection

Influenza virus Infection

Sendai virus Infection

Adenovirus Infection

Pathogen-associated

molecules

Bacterial porendashforming

toxins

Infection

Hemozoin Cerebral malaria

Environmental insults Silica Silicosis

Asbestos Asbestosis

Skin irritants Contact hypersensitivity

reactions

Ultraviolet light Sunburn

Endogenous danger

signals

ATP Injury or necrotic cell

death

Glucose Metabolic syndrome

MSU Gout

Calcium pyrophosphate

dihydrate (CPPD)

Pseudogout

Amyloid β Alzheimerrsquos disease

Hyaluronan Injury

Adjuvant Alum Th2 responses

Table 1 NLRP3 inflammasome activators Details of individual NLRP3 inflammasome activators are reviewed in (

Infections toxins amp environmental agents activate the inflammasome

Increased Th2 response

The inflammasome and alum-mediated adjuvanticitySuk-Jo Kang and Richard M Locksley

F1000 Biology Reports 2009 1 15 (doi 103410B1-15)

Figure 1 Alum-induced NLRP3 inflammasome activation

bull Phagocytosed alum-containing lysosomes rupture and release their components to the cytosol by an unknown mechanism The released contents and molecules generated during this process contribute to NLRP3ASCcaspase-1 inflammasome activation which in turn processes the proforms of IL-1 family members to active forms Either IL-1 family member cytokines or the products from NLRP3 inflammasome activation may elicit various immunostimulatory effects in vivo When and how potassium efflux and reactive oxygen species (ROS) play a role awaits further investigation DC dendritic cell MSU monosodium urate

Increased Th2 response

The inflammasome and alum-mediated adjuvanticitySuk-Jo Kang and Richard M Locksley

F1000 Biology Reports 2009 1 15 (doi 103410B1-15)

Figure 1 Alum-induced NLRP3 inflammasome activation

bull Phagocytosed alum-containing lysosomes rupture and release their components to the cytosol by an unknown mechanism The released contents and molecules generated during this process contribute to NLRP3ASCcaspase-1 inflammasome activation which in turn processes the proforms of IL-1 family members to active forms Either IL-1 family member cytokines or the products from NLRP3 inflammasome activation may elicit various immunostimulatory effects in vivo When and how potassium efflux and reactive oxygen species (ROS) play a role awaits further investigation DC dendritic cell MSU monosodium urate

The inflammasome and alum-mediated adjuvanticitySuk-Jo Kang and Richard M Locksley

F1000 Biology Reports 2009 1 15 (doi 103410B1-15)

Figure 1 Alum-induced NLRP3 inflammasome activation

bull Phagocytosed alum-containing lysosomes rupture and release their components to the cytosol by an unknown mechanism The released contents and molecules generated during this process contribute to NLRP3ASCcaspase-1 inflammasome activation which in turn processes the proforms of IL-1 family members to active forms Either IL-1 family member cytokines or the products from NLRP3 inflammasome activation may elicit various immunostimulatory effects in vivo When and how potassium efflux and reactive oxygen species (ROS) play a role awaits further investigation DC dendritic cell MSU monosodium urate

J Neuroimmune Pharmacol 2010 Jan 27El-Behi M Rostami A Ciric B

Th responses

IL-33

Fibrosis

DCM2wk CS exposure

250mgL 2hday M-FCVB3

Day 10pi

Myocarditis

Day 35-90pi

NSNV Smoke Virus Smoke+Virus

CS increases acute Pericarditis pericardial fibrosis amp MC degranulation

CS alone induces DCM by d35

Sex differences exist for all major chronic inflammatory diseases

Annual age-adjusted cancer incidence rates US 1975-2002

bullHeart disease (M)

bullCancer (M)

bullAutoimmune diseases (F)

bullAllergies amp Asthma (F)

Jemal et al 2006 Cancer Statistics 2006 Canc J Clin 56 106-130

Gender Differences in Asthma Prevalence

Arbes and Zeldin unpublished

Men 587000 annual deaths Women 427000 annual deaths

Heart disease US death rates 2000-2006 (CDC)

Copyright copy2008 American Heart Association

Rosamond W et al Circulation 2008117e25-e146

Incidence of CVD that does not include hypertensionby age and sex (FHS 1980ndash2003) Source NHLBI

Males develop DCM by day 35pi

Testosterone decreases heart function

Testosterone increases Inflammation

Testosterone increases inflammasomeactivation after infection

Synthesis of Vitamin D

Latitude correlates with CVD

bull75 GCM patients deficient or inadequatebull85 GCM patients ldquodeficientrdquo (lt30)bull5 GCM patients sufficient

bull20 LM patients deficient or inadequatebull45 LM patients ldquodeficientrdquo (lt30)bull55 LM patients sufficient

No apparent relationship between EF and VitD in LM patients

bullLow VitD is associated with poor EF in women with LM similar to GCM

bullSex Difference in LM patients

bullHigher VitD levels in men increase disease like found in our animal model

VDR increases Myocarditis in Males

VDR decreases Myocarditis in Females

Summary Inflammationbull Inflammation progresses from an innate immune response to

acute inflammation and then to either resolution of inflammation or chronic inflammationpathology

bull Immune mediators (ie cytokines) are responsible for redness swelling heat amp pain

bull Inflammation consists of immune cells infiltrating an organtissue

bull Inflammation is closely intertwined with the process of repair

bull Inflammation amp repair can both protect or damage tissues

bull Inflammation is a critical component of heart disease (CVD) cancer autoimmune diseases (ADs) like diabetes and chronic respiratory diseases like COPD

bull Inflammation is also a critical component of chronic diseases that are not the top causes of death such as allergies asthma obesity and ADs like lupus or multiple sclerosis

Main Pointsbull Acute inflammation leads to chronic disease in

susceptible individuals

bull Low doses of toxinschemicals amp injury can potentially launch a damaging immune response

bull Toxins and chemicals activate the Inflammasome driving a proinflammatory and profibrotic response (ie Th2 response)

bull Sex hormones regulate inflammation and the inflammasome

Fairweather Lab

Funding

R01 HL087033

P30 ES03819

Michael Coronado PhDJennifer OnyimbaErika Douglass MPHEunyong KimJessica Brandt

CS increases acute Pericarditis pericardial fibrosis amp MC degranulation

CS alone induces DCM by d35

Sex differences exist for all major chronic inflammatory diseases

Annual age-adjusted cancer incidence rates US 1975-2002

bullHeart disease (M)

bullCancer (M)

bullAutoimmune diseases (F)

bullAllergies amp Asthma (F)

Jemal et al 2006 Cancer Statistics 2006 Canc J Clin 56 106-130

Gender Differences in Asthma Prevalence

Arbes and Zeldin unpublished

Men 587000 annual deaths Women 427000 annual deaths

Heart disease US death rates 2000-2006 (CDC)

Copyright copy2008 American Heart Association

Rosamond W et al Circulation 2008117e25-e146

Incidence of CVD that does not include hypertensionby age and sex (FHS 1980ndash2003) Source NHLBI

Males develop DCM by day 35pi

Testosterone decreases heart function

Testosterone increases Inflammation

Testosterone increases inflammasomeactivation after infection

Synthesis of Vitamin D

Latitude correlates with CVD

bull75 GCM patients deficient or inadequatebull85 GCM patients ldquodeficientrdquo (lt30)bull5 GCM patients sufficient

bull20 LM patients deficient or inadequatebull45 LM patients ldquodeficientrdquo (lt30)bull55 LM patients sufficient

No apparent relationship between EF and VitD in LM patients

bullLow VitD is associated with poor EF in women with LM similar to GCM

bullSex Difference in LM patients

bullHigher VitD levels in men increase disease like found in our animal model

VDR increases Myocarditis in Males

VDR decreases Myocarditis in Females

Summary Inflammationbull Inflammation progresses from an innate immune response to

acute inflammation and then to either resolution of inflammation or chronic inflammationpathology

bull Immune mediators (ie cytokines) are responsible for redness swelling heat amp pain

bull Inflammation consists of immune cells infiltrating an organtissue

bull Inflammation is closely intertwined with the process of repair

bull Inflammation amp repair can both protect or damage tissues

bull Inflammation is a critical component of heart disease (CVD) cancer autoimmune diseases (ADs) like diabetes and chronic respiratory diseases like COPD

bull Inflammation is also a critical component of chronic diseases that are not the top causes of death such as allergies asthma obesity and ADs like lupus or multiple sclerosis

Main Pointsbull Acute inflammation leads to chronic disease in

susceptible individuals

bull Low doses of toxinschemicals amp injury can potentially launch a damaging immune response

bull Toxins and chemicals activate the Inflammasome driving a proinflammatory and profibrotic response (ie Th2 response)

bull Sex hormones regulate inflammation and the inflammasome

Fairweather Lab

Funding

R01 HL087033

P30 ES03819

Michael Coronado PhDJennifer OnyimbaErika Douglass MPHEunyong KimJessica Brandt

CS alone induces DCM by d35

Sex differences exist for all major chronic inflammatory diseases

Annual age-adjusted cancer incidence rates US 1975-2002

bullHeart disease (M)

bullCancer (M)

bullAutoimmune diseases (F)

bullAllergies amp Asthma (F)

Jemal et al 2006 Cancer Statistics 2006 Canc J Clin 56 106-130

Gender Differences in Asthma Prevalence

Arbes and Zeldin unpublished

Men 587000 annual deaths Women 427000 annual deaths

Heart disease US death rates 2000-2006 (CDC)

Copyright copy2008 American Heart Association

Rosamond W et al Circulation 2008117e25-e146

Incidence of CVD that does not include hypertensionby age and sex (FHS 1980ndash2003) Source NHLBI

Males develop DCM by day 35pi

Testosterone decreases heart function

Testosterone increases Inflammation

Testosterone increases inflammasomeactivation after infection

Synthesis of Vitamin D

Latitude correlates with CVD

bull75 GCM patients deficient or inadequatebull85 GCM patients ldquodeficientrdquo (lt30)bull5 GCM patients sufficient

bull20 LM patients deficient or inadequatebull45 LM patients ldquodeficientrdquo (lt30)bull55 LM patients sufficient

No apparent relationship between EF and VitD in LM patients

bullLow VitD is associated with poor EF in women with LM similar to GCM

bullSex Difference in LM patients

bullHigher VitD levels in men increase disease like found in our animal model

VDR increases Myocarditis in Males

VDR decreases Myocarditis in Females

Summary Inflammationbull Inflammation progresses from an innate immune response to

acute inflammation and then to either resolution of inflammation or chronic inflammationpathology

bull Immune mediators (ie cytokines) are responsible for redness swelling heat amp pain

bull Inflammation consists of immune cells infiltrating an organtissue

bull Inflammation is closely intertwined with the process of repair

bull Inflammation amp repair can both protect or damage tissues

bull Inflammation is a critical component of heart disease (CVD) cancer autoimmune diseases (ADs) like diabetes and chronic respiratory diseases like COPD

bull Inflammation is also a critical component of chronic diseases that are not the top causes of death such as allergies asthma obesity and ADs like lupus or multiple sclerosis

Main Pointsbull Acute inflammation leads to chronic disease in

susceptible individuals

bull Low doses of toxinschemicals amp injury can potentially launch a damaging immune response

bull Toxins and chemicals activate the Inflammasome driving a proinflammatory and profibrotic response (ie Th2 response)

bull Sex hormones regulate inflammation and the inflammasome

Fairweather Lab

Funding

R01 HL087033

P30 ES03819

Michael Coronado PhDJennifer OnyimbaErika Douglass MPHEunyong KimJessica Brandt

Sex differences exist for all major chronic inflammatory diseases

Annual age-adjusted cancer incidence rates US 1975-2002

bullHeart disease (M)

bullCancer (M)

bullAutoimmune diseases (F)

bullAllergies amp Asthma (F)

Jemal et al 2006 Cancer Statistics 2006 Canc J Clin 56 106-130

Gender Differences in Asthma Prevalence

Arbes and Zeldin unpublished

Men 587000 annual deaths Women 427000 annual deaths

Heart disease US death rates 2000-2006 (CDC)

Copyright copy2008 American Heart Association

Rosamond W et al Circulation 2008117e25-e146

Incidence of CVD that does not include hypertensionby age and sex (FHS 1980ndash2003) Source NHLBI

Males develop DCM by day 35pi

Testosterone decreases heart function

Testosterone increases Inflammation

Testosterone increases inflammasomeactivation after infection

Synthesis of Vitamin D

Latitude correlates with CVD

bull75 GCM patients deficient or inadequatebull85 GCM patients ldquodeficientrdquo (lt30)bull5 GCM patients sufficient

bull20 LM patients deficient or inadequatebull45 LM patients ldquodeficientrdquo (lt30)bull55 LM patients sufficient

No apparent relationship between EF and VitD in LM patients

bullLow VitD is associated with poor EF in women with LM similar to GCM

bullSex Difference in LM patients

bullHigher VitD levels in men increase disease like found in our animal model

VDR increases Myocarditis in Males

VDR decreases Myocarditis in Females

Summary Inflammationbull Inflammation progresses from an innate immune response to

acute inflammation and then to either resolution of inflammation or chronic inflammationpathology

bull Immune mediators (ie cytokines) are responsible for redness swelling heat amp pain

bull Inflammation consists of immune cells infiltrating an organtissue

bull Inflammation is closely intertwined with the process of repair

bull Inflammation amp repair can both protect or damage tissues

bull Inflammation is a critical component of heart disease (CVD) cancer autoimmune diseases (ADs) like diabetes and chronic respiratory diseases like COPD

bull Inflammation is also a critical component of chronic diseases that are not the top causes of death such as allergies asthma obesity and ADs like lupus or multiple sclerosis

Main Pointsbull Acute inflammation leads to chronic disease in

susceptible individuals

bull Low doses of toxinschemicals amp injury can potentially launch a damaging immune response

bull Toxins and chemicals activate the Inflammasome driving a proinflammatory and profibrotic response (ie Th2 response)

bull Sex hormones regulate inflammation and the inflammasome

Fairweather Lab

Funding

R01 HL087033

P30 ES03819

Michael Coronado PhDJennifer OnyimbaErika Douglass MPHEunyong KimJessica Brandt

Annual age-adjusted cancer incidence rates US 1975-2002

bullHeart disease (M)

bullCancer (M)

bullAutoimmune diseases (F)

bullAllergies amp Asthma (F)

Jemal et al 2006 Cancer Statistics 2006 Canc J Clin 56 106-130

Gender Differences in Asthma Prevalence

Arbes and Zeldin unpublished

Men 587000 annual deaths Women 427000 annual deaths

Heart disease US death rates 2000-2006 (CDC)

Copyright copy2008 American Heart Association

Rosamond W et al Circulation 2008117e25-e146

Incidence of CVD that does not include hypertensionby age and sex (FHS 1980ndash2003) Source NHLBI

Males develop DCM by day 35pi

Testosterone decreases heart function

Testosterone increases Inflammation

Testosterone increases inflammasomeactivation after infection

Synthesis of Vitamin D

Latitude correlates with CVD

bull75 GCM patients deficient or inadequatebull85 GCM patients ldquodeficientrdquo (lt30)bull5 GCM patients sufficient

bull20 LM patients deficient or inadequatebull45 LM patients ldquodeficientrdquo (lt30)bull55 LM patients sufficient

No apparent relationship between EF and VitD in LM patients

bullLow VitD is associated with poor EF in women with LM similar to GCM

bullSex Difference in LM patients

bullHigher VitD levels in men increase disease like found in our animal model

VDR increases Myocarditis in Males

VDR decreases Myocarditis in Females

Summary Inflammationbull Inflammation progresses from an innate immune response to

acute inflammation and then to either resolution of inflammation or chronic inflammationpathology

bull Immune mediators (ie cytokines) are responsible for redness swelling heat amp pain

bull Inflammation consists of immune cells infiltrating an organtissue

bull Inflammation is closely intertwined with the process of repair

bull Inflammation amp repair can both protect or damage tissues

bull Inflammation is a critical component of heart disease (CVD) cancer autoimmune diseases (ADs) like diabetes and chronic respiratory diseases like COPD

bull Inflammation is also a critical component of chronic diseases that are not the top causes of death such as allergies asthma obesity and ADs like lupus or multiple sclerosis

Main Pointsbull Acute inflammation leads to chronic disease in

susceptible individuals

bull Low doses of toxinschemicals amp injury can potentially launch a damaging immune response

bull Toxins and chemicals activate the Inflammasome driving a proinflammatory and profibrotic response (ie Th2 response)

bull Sex hormones regulate inflammation and the inflammasome

Fairweather Lab

Funding

R01 HL087033

P30 ES03819

Michael Coronado PhDJennifer OnyimbaErika Douglass MPHEunyong KimJessica Brandt

Gender Differences in Asthma Prevalence

Arbes and Zeldin unpublished

Men 587000 annual deaths Women 427000 annual deaths

Heart disease US death rates 2000-2006 (CDC)

Copyright copy2008 American Heart Association

Rosamond W et al Circulation 2008117e25-e146

Incidence of CVD that does not include hypertensionby age and sex (FHS 1980ndash2003) Source NHLBI

Males develop DCM by day 35pi

Testosterone decreases heart function

Testosterone increases Inflammation

Testosterone increases inflammasomeactivation after infection

Synthesis of Vitamin D

Latitude correlates with CVD

bull75 GCM patients deficient or inadequatebull85 GCM patients ldquodeficientrdquo (lt30)bull5 GCM patients sufficient

bull20 LM patients deficient or inadequatebull45 LM patients ldquodeficientrdquo (lt30)bull55 LM patients sufficient

No apparent relationship between EF and VitD in LM patients

bullLow VitD is associated with poor EF in women with LM similar to GCM

bullSex Difference in LM patients

bullHigher VitD levels in men increase disease like found in our animal model

VDR increases Myocarditis in Males

VDR decreases Myocarditis in Females

Summary Inflammationbull Inflammation progresses from an innate immune response to

acute inflammation and then to either resolution of inflammation or chronic inflammationpathology

bull Immune mediators (ie cytokines) are responsible for redness swelling heat amp pain

bull Inflammation consists of immune cells infiltrating an organtissue

bull Inflammation is closely intertwined with the process of repair

bull Inflammation amp repair can both protect or damage tissues

bull Inflammation is a critical component of heart disease (CVD) cancer autoimmune diseases (ADs) like diabetes and chronic respiratory diseases like COPD

bull Inflammation is also a critical component of chronic diseases that are not the top causes of death such as allergies asthma obesity and ADs like lupus or multiple sclerosis

Main Pointsbull Acute inflammation leads to chronic disease in

susceptible individuals

bull Low doses of toxinschemicals amp injury can potentially launch a damaging immune response

bull Toxins and chemicals activate the Inflammasome driving a proinflammatory and profibrotic response (ie Th2 response)

bull Sex hormones regulate inflammation and the inflammasome

Fairweather Lab

Funding

R01 HL087033

P30 ES03819

Michael Coronado PhDJennifer OnyimbaErika Douglass MPHEunyong KimJessica Brandt

Men 587000 annual deaths Women 427000 annual deaths

Heart disease US death rates 2000-2006 (CDC)

Copyright copy2008 American Heart Association

Rosamond W et al Circulation 2008117e25-e146

Incidence of CVD that does not include hypertensionby age and sex (FHS 1980ndash2003) Source NHLBI

Males develop DCM by day 35pi

Testosterone decreases heart function

Testosterone increases Inflammation

Testosterone increases inflammasomeactivation after infection

Synthesis of Vitamin D

Latitude correlates with CVD

bull75 GCM patients deficient or inadequatebull85 GCM patients ldquodeficientrdquo (lt30)bull5 GCM patients sufficient

bull20 LM patients deficient or inadequatebull45 LM patients ldquodeficientrdquo (lt30)bull55 LM patients sufficient

No apparent relationship between EF and VitD in LM patients

bullLow VitD is associated with poor EF in women with LM similar to GCM

bullSex Difference in LM patients

bullHigher VitD levels in men increase disease like found in our animal model

VDR increases Myocarditis in Males

VDR decreases Myocarditis in Females

Summary Inflammationbull Inflammation progresses from an innate immune response to

acute inflammation and then to either resolution of inflammation or chronic inflammationpathology

bull Immune mediators (ie cytokines) are responsible for redness swelling heat amp pain

bull Inflammation consists of immune cells infiltrating an organtissue

bull Inflammation is closely intertwined with the process of repair

bull Inflammation amp repair can both protect or damage tissues

bull Inflammation is a critical component of heart disease (CVD) cancer autoimmune diseases (ADs) like diabetes and chronic respiratory diseases like COPD

bull Inflammation is also a critical component of chronic diseases that are not the top causes of death such as allergies asthma obesity and ADs like lupus or multiple sclerosis

Main Pointsbull Acute inflammation leads to chronic disease in

susceptible individuals

bull Low doses of toxinschemicals amp injury can potentially launch a damaging immune response

bull Toxins and chemicals activate the Inflammasome driving a proinflammatory and profibrotic response (ie Th2 response)

bull Sex hormones regulate inflammation and the inflammasome

Fairweather Lab

Funding

R01 HL087033

P30 ES03819

Michael Coronado PhDJennifer OnyimbaErika Douglass MPHEunyong KimJessica Brandt

Copyright copy2008 American Heart Association

Rosamond W et al Circulation 2008117e25-e146

Incidence of CVD that does not include hypertensionby age and sex (FHS 1980ndash2003) Source NHLBI

Males develop DCM by day 35pi

Testosterone decreases heart function

Testosterone increases Inflammation

Testosterone increases inflammasomeactivation after infection

Synthesis of Vitamin D

Latitude correlates with CVD

bull75 GCM patients deficient or inadequatebull85 GCM patients ldquodeficientrdquo (lt30)bull5 GCM patients sufficient

bull20 LM patients deficient or inadequatebull45 LM patients ldquodeficientrdquo (lt30)bull55 LM patients sufficient

No apparent relationship between EF and VitD in LM patients

bullLow VitD is associated with poor EF in women with LM similar to GCM

bullSex Difference in LM patients

bullHigher VitD levels in men increase disease like found in our animal model

VDR increases Myocarditis in Males

VDR decreases Myocarditis in Females

Summary Inflammationbull Inflammation progresses from an innate immune response to

acute inflammation and then to either resolution of inflammation or chronic inflammationpathology

bull Immune mediators (ie cytokines) are responsible for redness swelling heat amp pain

bull Inflammation consists of immune cells infiltrating an organtissue

bull Inflammation is closely intertwined with the process of repair

bull Inflammation amp repair can both protect or damage tissues

bull Inflammation is a critical component of heart disease (CVD) cancer autoimmune diseases (ADs) like diabetes and chronic respiratory diseases like COPD

bull Inflammation is also a critical component of chronic diseases that are not the top causes of death such as allergies asthma obesity and ADs like lupus or multiple sclerosis

Main Pointsbull Acute inflammation leads to chronic disease in

susceptible individuals

bull Low doses of toxinschemicals amp injury can potentially launch a damaging immune response

bull Toxins and chemicals activate the Inflammasome driving a proinflammatory and profibrotic response (ie Th2 response)

bull Sex hormones regulate inflammation and the inflammasome

Fairweather Lab

Funding

R01 HL087033

P30 ES03819

Michael Coronado PhDJennifer OnyimbaErika Douglass MPHEunyong KimJessica Brandt

Males develop DCM by day 35pi

Testosterone decreases heart function

Testosterone increases Inflammation

Testosterone increases inflammasomeactivation after infection

Synthesis of Vitamin D

Latitude correlates with CVD

bull75 GCM patients deficient or inadequatebull85 GCM patients ldquodeficientrdquo (lt30)bull5 GCM patients sufficient

bull20 LM patients deficient or inadequatebull45 LM patients ldquodeficientrdquo (lt30)bull55 LM patients sufficient

No apparent relationship between EF and VitD in LM patients

bullLow VitD is associated with poor EF in women with LM similar to GCM

bullSex Difference in LM patients

bullHigher VitD levels in men increase disease like found in our animal model

VDR increases Myocarditis in Males

VDR decreases Myocarditis in Females

Summary Inflammationbull Inflammation progresses from an innate immune response to

acute inflammation and then to either resolution of inflammation or chronic inflammationpathology

bull Immune mediators (ie cytokines) are responsible for redness swelling heat amp pain

bull Inflammation consists of immune cells infiltrating an organtissue

bull Inflammation is closely intertwined with the process of repair

bull Inflammation amp repair can both protect or damage tissues

bull Inflammation is a critical component of heart disease (CVD) cancer autoimmune diseases (ADs) like diabetes and chronic respiratory diseases like COPD

bull Inflammation is also a critical component of chronic diseases that are not the top causes of death such as allergies asthma obesity and ADs like lupus or multiple sclerosis

Main Pointsbull Acute inflammation leads to chronic disease in

susceptible individuals

bull Low doses of toxinschemicals amp injury can potentially launch a damaging immune response

bull Toxins and chemicals activate the Inflammasome driving a proinflammatory and profibrotic response (ie Th2 response)

bull Sex hormones regulate inflammation and the inflammasome

Fairweather Lab

Funding

R01 HL087033

P30 ES03819

Michael Coronado PhDJennifer OnyimbaErika Douglass MPHEunyong KimJessica Brandt

Testosterone decreases heart function

Testosterone increases Inflammation

Testosterone increases inflammasomeactivation after infection

Synthesis of Vitamin D

Latitude correlates with CVD

bull75 GCM patients deficient or inadequatebull85 GCM patients ldquodeficientrdquo (lt30)bull5 GCM patients sufficient

bull20 LM patients deficient or inadequatebull45 LM patients ldquodeficientrdquo (lt30)bull55 LM patients sufficient

No apparent relationship between EF and VitD in LM patients

bullLow VitD is associated with poor EF in women with LM similar to GCM

bullSex Difference in LM patients

bullHigher VitD levels in men increase disease like found in our animal model

VDR increases Myocarditis in Males

VDR decreases Myocarditis in Females

Summary Inflammationbull Inflammation progresses from an innate immune response to

acute inflammation and then to either resolution of inflammation or chronic inflammationpathology

bull Immune mediators (ie cytokines) are responsible for redness swelling heat amp pain

bull Inflammation consists of immune cells infiltrating an organtissue

bull Inflammation is closely intertwined with the process of repair

bull Inflammation amp repair can both protect or damage tissues

bull Inflammation is a critical component of heart disease (CVD) cancer autoimmune diseases (ADs) like diabetes and chronic respiratory diseases like COPD

bull Inflammation is also a critical component of chronic diseases that are not the top causes of death such as allergies asthma obesity and ADs like lupus or multiple sclerosis

Main Pointsbull Acute inflammation leads to chronic disease in

susceptible individuals

bull Low doses of toxinschemicals amp injury can potentially launch a damaging immune response

bull Toxins and chemicals activate the Inflammasome driving a proinflammatory and profibrotic response (ie Th2 response)

bull Sex hormones regulate inflammation and the inflammasome

Fairweather Lab

Funding

R01 HL087033

P30 ES03819

Michael Coronado PhDJennifer OnyimbaErika Douglass MPHEunyong KimJessica Brandt

Testosterone increases Inflammation

Testosterone increases inflammasomeactivation after infection

Synthesis of Vitamin D

Latitude correlates with CVD

bull75 GCM patients deficient or inadequatebull85 GCM patients ldquodeficientrdquo (lt30)bull5 GCM patients sufficient

bull20 LM patients deficient or inadequatebull45 LM patients ldquodeficientrdquo (lt30)bull55 LM patients sufficient

No apparent relationship between EF and VitD in LM patients

bullLow VitD is associated with poor EF in women with LM similar to GCM

bullSex Difference in LM patients

bullHigher VitD levels in men increase disease like found in our animal model

VDR increases Myocarditis in Males

VDR decreases Myocarditis in Females

Summary Inflammationbull Inflammation progresses from an innate immune response to

acute inflammation and then to either resolution of inflammation or chronic inflammationpathology

bull Immune mediators (ie cytokines) are responsible for redness swelling heat amp pain

bull Inflammation consists of immune cells infiltrating an organtissue

bull Inflammation is closely intertwined with the process of repair

bull Inflammation amp repair can both protect or damage tissues

bull Inflammation is a critical component of heart disease (CVD) cancer autoimmune diseases (ADs) like diabetes and chronic respiratory diseases like COPD

bull Inflammation is also a critical component of chronic diseases that are not the top causes of death such as allergies asthma obesity and ADs like lupus or multiple sclerosis

Main Pointsbull Acute inflammation leads to chronic disease in

susceptible individuals

bull Low doses of toxinschemicals amp injury can potentially launch a damaging immune response

bull Toxins and chemicals activate the Inflammasome driving a proinflammatory and profibrotic response (ie Th2 response)

bull Sex hormones regulate inflammation and the inflammasome

Fairweather Lab

Funding

R01 HL087033

P30 ES03819

Michael Coronado PhDJennifer OnyimbaErika Douglass MPHEunyong KimJessica Brandt

Testosterone increases inflammasomeactivation after infection

Synthesis of Vitamin D

Latitude correlates with CVD

bull75 GCM patients deficient or inadequatebull85 GCM patients ldquodeficientrdquo (lt30)bull5 GCM patients sufficient

bull20 LM patients deficient or inadequatebull45 LM patients ldquodeficientrdquo (lt30)bull55 LM patients sufficient

No apparent relationship between EF and VitD in LM patients

bullLow VitD is associated with poor EF in women with LM similar to GCM

bullSex Difference in LM patients

bullHigher VitD levels in men increase disease like found in our animal model

VDR increases Myocarditis in Males

VDR decreases Myocarditis in Females

Summary Inflammationbull Inflammation progresses from an innate immune response to

acute inflammation and then to either resolution of inflammation or chronic inflammationpathology

bull Immune mediators (ie cytokines) are responsible for redness swelling heat amp pain

bull Inflammation consists of immune cells infiltrating an organtissue

bull Inflammation is closely intertwined with the process of repair

bull Inflammation amp repair can both protect or damage tissues

bull Inflammation is a critical component of heart disease (CVD) cancer autoimmune diseases (ADs) like diabetes and chronic respiratory diseases like COPD

bull Inflammation is also a critical component of chronic diseases that are not the top causes of death such as allergies asthma obesity and ADs like lupus or multiple sclerosis

Main Pointsbull Acute inflammation leads to chronic disease in

susceptible individuals

bull Low doses of toxinschemicals amp injury can potentially launch a damaging immune response

bull Toxins and chemicals activate the Inflammasome driving a proinflammatory and profibrotic response (ie Th2 response)

bull Sex hormones regulate inflammation and the inflammasome

Fairweather Lab

Funding

R01 HL087033

P30 ES03819

Michael Coronado PhDJennifer OnyimbaErika Douglass MPHEunyong KimJessica Brandt

Synthesis of Vitamin D

Latitude correlates with CVD

bull75 GCM patients deficient or inadequatebull85 GCM patients ldquodeficientrdquo (lt30)bull5 GCM patients sufficient

bull20 LM patients deficient or inadequatebull45 LM patients ldquodeficientrdquo (lt30)bull55 LM patients sufficient

No apparent relationship between EF and VitD in LM patients

bullLow VitD is associated with poor EF in women with LM similar to GCM

bullSex Difference in LM patients

bullHigher VitD levels in men increase disease like found in our animal model

VDR increases Myocarditis in Males

VDR decreases Myocarditis in Females

Summary Inflammationbull Inflammation progresses from an innate immune response to

acute inflammation and then to either resolution of inflammation or chronic inflammationpathology

bull Immune mediators (ie cytokines) are responsible for redness swelling heat amp pain

bull Inflammation consists of immune cells infiltrating an organtissue

bull Inflammation is closely intertwined with the process of repair

bull Inflammation amp repair can both protect or damage tissues

bull Inflammation is a critical component of heart disease (CVD) cancer autoimmune diseases (ADs) like diabetes and chronic respiratory diseases like COPD

bull Inflammation is also a critical component of chronic diseases that are not the top causes of death such as allergies asthma obesity and ADs like lupus or multiple sclerosis

Main Pointsbull Acute inflammation leads to chronic disease in

susceptible individuals

bull Low doses of toxinschemicals amp injury can potentially launch a damaging immune response

bull Toxins and chemicals activate the Inflammasome driving a proinflammatory and profibrotic response (ie Th2 response)

bull Sex hormones regulate inflammation and the inflammasome

Fairweather Lab

Funding

R01 HL087033

P30 ES03819

Michael Coronado PhDJennifer OnyimbaErika Douglass MPHEunyong KimJessica Brandt

Latitude correlates with CVD

bull75 GCM patients deficient or inadequatebull85 GCM patients ldquodeficientrdquo (lt30)bull5 GCM patients sufficient

bull20 LM patients deficient or inadequatebull45 LM patients ldquodeficientrdquo (lt30)bull55 LM patients sufficient

No apparent relationship between EF and VitD in LM patients

bullLow VitD is associated with poor EF in women with LM similar to GCM

bullSex Difference in LM patients

bullHigher VitD levels in men increase disease like found in our animal model

VDR increases Myocarditis in Males

VDR decreases Myocarditis in Females

Summary Inflammationbull Inflammation progresses from an innate immune response to

acute inflammation and then to either resolution of inflammation or chronic inflammationpathology

bull Immune mediators (ie cytokines) are responsible for redness swelling heat amp pain

bull Inflammation consists of immune cells infiltrating an organtissue

bull Inflammation is closely intertwined with the process of repair

bull Inflammation amp repair can both protect or damage tissues

bull Inflammation is a critical component of heart disease (CVD) cancer autoimmune diseases (ADs) like diabetes and chronic respiratory diseases like COPD

bull Inflammation is also a critical component of chronic diseases that are not the top causes of death such as allergies asthma obesity and ADs like lupus or multiple sclerosis

Main Pointsbull Acute inflammation leads to chronic disease in

susceptible individuals

bull Low doses of toxinschemicals amp injury can potentially launch a damaging immune response

bull Toxins and chemicals activate the Inflammasome driving a proinflammatory and profibrotic response (ie Th2 response)

bull Sex hormones regulate inflammation and the inflammasome

Fairweather Lab

Funding

R01 HL087033

P30 ES03819

Michael Coronado PhDJennifer OnyimbaErika Douglass MPHEunyong KimJessica Brandt

bull75 GCM patients deficient or inadequatebull85 GCM patients ldquodeficientrdquo (lt30)bull5 GCM patients sufficient

bull20 LM patients deficient or inadequatebull45 LM patients ldquodeficientrdquo (lt30)bull55 LM patients sufficient

No apparent relationship between EF and VitD in LM patients

bullLow VitD is associated with poor EF in women with LM similar to GCM

bullSex Difference in LM patients

bullHigher VitD levels in men increase disease like found in our animal model

VDR increases Myocarditis in Males

VDR decreases Myocarditis in Females

Summary Inflammationbull Inflammation progresses from an innate immune response to

acute inflammation and then to either resolution of inflammation or chronic inflammationpathology

bull Immune mediators (ie cytokines) are responsible for redness swelling heat amp pain

bull Inflammation consists of immune cells infiltrating an organtissue

bull Inflammation is closely intertwined with the process of repair

bull Inflammation amp repair can both protect or damage tissues

bull Inflammation is a critical component of heart disease (CVD) cancer autoimmune diseases (ADs) like diabetes and chronic respiratory diseases like COPD

bull Inflammation is also a critical component of chronic diseases that are not the top causes of death such as allergies asthma obesity and ADs like lupus or multiple sclerosis

Main Pointsbull Acute inflammation leads to chronic disease in

susceptible individuals

bull Low doses of toxinschemicals amp injury can potentially launch a damaging immune response

bull Toxins and chemicals activate the Inflammasome driving a proinflammatory and profibrotic response (ie Th2 response)

bull Sex hormones regulate inflammation and the inflammasome

Fairweather Lab

Funding

R01 HL087033

P30 ES03819

Michael Coronado PhDJennifer OnyimbaErika Douglass MPHEunyong KimJessica Brandt

No apparent relationship between EF and VitD in LM patients

bullLow VitD is associated with poor EF in women with LM similar to GCM

bullSex Difference in LM patients

bullHigher VitD levels in men increase disease like found in our animal model

VDR increases Myocarditis in Males

VDR decreases Myocarditis in Females

Summary Inflammationbull Inflammation progresses from an innate immune response to

acute inflammation and then to either resolution of inflammation or chronic inflammationpathology

bull Immune mediators (ie cytokines) are responsible for redness swelling heat amp pain

bull Inflammation consists of immune cells infiltrating an organtissue

bull Inflammation is closely intertwined with the process of repair

bull Inflammation amp repair can both protect or damage tissues

bull Inflammation is a critical component of heart disease (CVD) cancer autoimmune diseases (ADs) like diabetes and chronic respiratory diseases like COPD

bull Inflammation is also a critical component of chronic diseases that are not the top causes of death such as allergies asthma obesity and ADs like lupus or multiple sclerosis

Main Pointsbull Acute inflammation leads to chronic disease in

susceptible individuals

bull Low doses of toxinschemicals amp injury can potentially launch a damaging immune response

bull Toxins and chemicals activate the Inflammasome driving a proinflammatory and profibrotic response (ie Th2 response)

bull Sex hormones regulate inflammation and the inflammasome

Fairweather Lab

Funding

R01 HL087033

P30 ES03819

Michael Coronado PhDJennifer OnyimbaErika Douglass MPHEunyong KimJessica Brandt

bullLow VitD is associated with poor EF in women with LM similar to GCM

bullSex Difference in LM patients

bullHigher VitD levels in men increase disease like found in our animal model

VDR increases Myocarditis in Males

VDR decreases Myocarditis in Females

Summary Inflammationbull Inflammation progresses from an innate immune response to

acute inflammation and then to either resolution of inflammation or chronic inflammationpathology

bull Immune mediators (ie cytokines) are responsible for redness swelling heat amp pain

bull Inflammation consists of immune cells infiltrating an organtissue

bull Inflammation is closely intertwined with the process of repair

bull Inflammation amp repair can both protect or damage tissues

bull Inflammation is a critical component of heart disease (CVD) cancer autoimmune diseases (ADs) like diabetes and chronic respiratory diseases like COPD

bull Inflammation is also a critical component of chronic diseases that are not the top causes of death such as allergies asthma obesity and ADs like lupus or multiple sclerosis

Main Pointsbull Acute inflammation leads to chronic disease in

susceptible individuals

bull Low doses of toxinschemicals amp injury can potentially launch a damaging immune response

bull Toxins and chemicals activate the Inflammasome driving a proinflammatory and profibrotic response (ie Th2 response)

bull Sex hormones regulate inflammation and the inflammasome

Fairweather Lab

Funding

R01 HL087033

P30 ES03819

Michael Coronado PhDJennifer OnyimbaErika Douglass MPHEunyong KimJessica Brandt

VDR increases Myocarditis in Males

VDR decreases Myocarditis in Females

Summary Inflammationbull Inflammation progresses from an innate immune response to

acute inflammation and then to either resolution of inflammation or chronic inflammationpathology

bull Immune mediators (ie cytokines) are responsible for redness swelling heat amp pain

bull Inflammation consists of immune cells infiltrating an organtissue

bull Inflammation is closely intertwined with the process of repair

bull Inflammation amp repair can both protect or damage tissues

bull Inflammation is a critical component of heart disease (CVD) cancer autoimmune diseases (ADs) like diabetes and chronic respiratory diseases like COPD

bull Inflammation is also a critical component of chronic diseases that are not the top causes of death such as allergies asthma obesity and ADs like lupus or multiple sclerosis

Main Pointsbull Acute inflammation leads to chronic disease in

susceptible individuals

bull Low doses of toxinschemicals amp injury can potentially launch a damaging immune response

bull Toxins and chemicals activate the Inflammasome driving a proinflammatory and profibrotic response (ie Th2 response)

bull Sex hormones regulate inflammation and the inflammasome

Fairweather Lab

Funding

R01 HL087033

P30 ES03819

Michael Coronado PhDJennifer OnyimbaErika Douglass MPHEunyong KimJessica Brandt

VDR decreases Myocarditis in Females

Summary Inflammationbull Inflammation progresses from an innate immune response to

acute inflammation and then to either resolution of inflammation or chronic inflammationpathology

bull Immune mediators (ie cytokines) are responsible for redness swelling heat amp pain

bull Inflammation consists of immune cells infiltrating an organtissue

bull Inflammation is closely intertwined with the process of repair

bull Inflammation amp repair can both protect or damage tissues

bull Inflammation is a critical component of heart disease (CVD) cancer autoimmune diseases (ADs) like diabetes and chronic respiratory diseases like COPD

bull Inflammation is also a critical component of chronic diseases that are not the top causes of death such as allergies asthma obesity and ADs like lupus or multiple sclerosis

Main Pointsbull Acute inflammation leads to chronic disease in

susceptible individuals

bull Low doses of toxinschemicals amp injury can potentially launch a damaging immune response

bull Toxins and chemicals activate the Inflammasome driving a proinflammatory and profibrotic response (ie Th2 response)

bull Sex hormones regulate inflammation and the inflammasome

Fairweather Lab

Funding

R01 HL087033

P30 ES03819

Michael Coronado PhDJennifer OnyimbaErika Douglass MPHEunyong KimJessica Brandt

Summary Inflammationbull Inflammation progresses from an innate immune response to

acute inflammation and then to either resolution of inflammation or chronic inflammationpathology

bull Immune mediators (ie cytokines) are responsible for redness swelling heat amp pain

bull Inflammation consists of immune cells infiltrating an organtissue

bull Inflammation is closely intertwined with the process of repair

bull Inflammation amp repair can both protect or damage tissues

bull Inflammation is a critical component of heart disease (CVD) cancer autoimmune diseases (ADs) like diabetes and chronic respiratory diseases like COPD

bull Inflammation is also a critical component of chronic diseases that are not the top causes of death such as allergies asthma obesity and ADs like lupus or multiple sclerosis

Main Pointsbull Acute inflammation leads to chronic disease in

susceptible individuals

bull Low doses of toxinschemicals amp injury can potentially launch a damaging immune response

bull Toxins and chemicals activate the Inflammasome driving a proinflammatory and profibrotic response (ie Th2 response)

bull Sex hormones regulate inflammation and the inflammasome

Fairweather Lab

Funding

R01 HL087033

P30 ES03819

Michael Coronado PhDJennifer OnyimbaErika Douglass MPHEunyong KimJessica Brandt

Main Pointsbull Acute inflammation leads to chronic disease in

susceptible individuals

bull Low doses of toxinschemicals amp injury can potentially launch a damaging immune response

bull Toxins and chemicals activate the Inflammasome driving a proinflammatory and profibrotic response (ie Th2 response)

bull Sex hormones regulate inflammation and the inflammasome

Fairweather Lab

Funding

R01 HL087033

P30 ES03819

Michael Coronado PhDJennifer OnyimbaErika Douglass MPHEunyong KimJessica Brandt

Fairweather Lab

Funding

R01 HL087033

P30 ES03819

Michael Coronado PhDJennifer OnyimbaErika Douglass MPHEunyong KimJessica Brandt