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Immunology of the Lung
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NEUTROPHILS and TISSUE
MACROPHAGES
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Neutrophil and macrophagedefense against infection
• Diapedesis
• Ameboid motion
• Chemotaxis
•
Phagocytosis
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Monocyte-macrophage system
(Reticuloendothelial system )
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generalized phagocytic system speciallyabundant in most exposed areas of the
body such as1.Skin
2.Lymph nodes
3.Lungs
4.Liver
5.Spleen and bone marrow
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Name of cell Location
Dust cells/Alveolar macrophages pulmonary alveolus of lungs
Histiocytes connective tissue
Kupffer cells liver
Microglia neural tissue
Epithelioid cells granulomas
Osteoclasts bone
Sinusoidal lining cells spleen
Giant cells Connective Tissue
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Disease Entity Type of the immune
reaction
Major Features
Asthma I type IgE mediated
Drug-induced lung
diseases & reactions
Cytotoxic type II
CMI
The drug is a hapten
Ab or sens. Ly
Hypersensitive
pneumonitis
ABPA
Type III immune
complexes & CMI
Type I & Type III
Exposure to exogenous
allergen
Lung Tuberculosis CMI
SarcoidosisCMI Granulomatous
inflammation
Autoimmune-Mediated
Diseases
Immune Complexes
type III
Multiple pathogenesis
Pulmonary Vasculitis
Syndromes
Autoimmune,
type II & type III
Different lung
involvement
AntiphospholipidSyndrome
ACA & other types APL- antibodies
Rare are diagnosed at time
Idiopathic Pulmonary
Fibrosis
Unknown etiology Primary or end - stage
of the inflammation in
the lung
Pulmonary EosinophilicSyndromes
Elevated Eo in blood andin situ Eo>1500/mm3 Pulmonary infiltrates9 clinical forms 2
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Respiratory AllergiesHypersensitivity
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Hypersensitivity
Hypersensitivity refers to undesirable
reactions produced by the normal
immune system, including allergies and
autoimmunity
These reactions may be damaging,
uncomfortable, or occasionally fatal.
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Classification
Type I – Immediate, Atopic,
Anaphylactic
Type II – Antibody DependentType III – Immune Complex
Type IV – Cell Mediated / Delayed
Type Of Hypersensitivity
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TYPE I. Immediate OR Anaphylactic
Hypersensitivity
Type I hypersensitivity is also known as
immediate or anaphylactic hypersensitivity.
The reaction may involve skin (urticaria andeczema), eyes (conjunctivitis), nasopharynx
(rhinorrhea, rhinitis), bronchopulmonary
tissues (asthma) and gastrointestinal tract(gastroenteritis).
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Mediated by IgE antibody to specific
antigens
The primary cellular component in this
hypersensitivity is the mast cell or basophil.
The reaction is amplified and/or modified
by platelets, neutrophils and eosinophils.
Mast cells stimulated and release histamine.
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Most of the IgE in the body is bound withhigh affinity receptors (Fc epsilonRI), found
on mast cells and basophils.
The cells are activated by cross-linking of
Fc epsilonRI receptors via antigen binding
to the bound IgE molecules.
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Such cross-linking leads to rapid
degranulation of the mast cells and therelease of primary inflammatorymediators stored in the granules.
Mast cell activation via Fc epsilonRI alsoleads to the production of two other typesof mediators. These secondary
mediators.
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Molecules SOME SPACES Effects
Primary mediators
Histamine Vascular permeability,
sm contraction
Serotonin vascular permeability,
sm contraction
Secondary mediators
Leukotrienes vascular permeability,
sm contraction
Prostaglandins
vasodilation, sm
contraction, platelet
activation
Bradykinin vascular permeability,
sm contraction
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Type II Hypersensitivity
The second class of damaging reactions iscaused by specific antibody binding to cellsor tissue antigens.
The antibodies are of the IgM or IgG classes
and cause cell destruction.It involves binding of antibodies (IgG or IgM)
to cell surface antigen or extracellularmatrix molecules.
Antibody directed to cell surface antigenscan activate complement to damage thecells.
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Red Blood cell
with Ag on cell
membrane
IgG binds to Ag on
membraneMembrane attack
complex of
compliment lysis red
cell (cell death)
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The result may be complement mediated
lysis as occurs in
Haemolytic Anemia
ABO Transfusion Reactions.
Pencillin allergy also belong to this class.
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Type III (Immune-Complex Mediated)
Hypersensitivity
Due to the formation of antigen-antibody
complexes, also called immune-complexes.
Type III hypersensitivity is mediated byimmune complexes essentially of IgGantibodies.
When antibody combines with specific
antigen, immune complexes are formed.Normally they are promptly removed by
reticulo-endothelial system.
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Occasionally, they persist and deposit in
tissues resulting in disorders.
In persistent microbial or viral infections,
immune complexes may be deposited in
organs eg. Kidneys - resulting in dysfunction,
in joints – arthirits, in BV – Vasculitis.
Wherever the immune complexes are
deposited, they cause inflammation and
tissue injury.
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Type IV Hypersensitivity
This is the only class of hypersensitivereactions to be triggered by antigen -specific
T lymphocyte cells (not antibodies).
Cell mediated hypersensivity is inducedmainly in skin.When skin again comes in contact with
those agents, the sensitized person develops
erythema, itching, eczema or necrosis within12 – 48 hours.
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The Langerhans cell in the epidermisinteracts with CD4 T cells to cause contact
sensitivity.
It occurs after sensitisation with simplechemicals, (e.g nickel & formaldehyde), plant
materials (Ivy poison, Oak poison), topically
applied drugs (sulfonamides & neomycin),some cosmetics and soaps.
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(a) In the sensitization phase after initialcontact with antigen (e.g., peptides derived
from intracellular bacteria), TH cells
proliferate and differentiate into TH1 cells.Cytokines secreted by these T cells are
indicated by the dark blue balls.
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(b) In the effector phase after subsequentexposure of sensitized TH1 cells to antigen,
the TH1 cells secrete a variety of cytokines
and chemokines. These factors attract and
activate macrophages and other nonspecific
inflammatory cells. Activated macrophages
are more effective in presenting antigen, thus
perpetuating the DTH response, andfunction as the primary effector cells in this
reaction.
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A prolonged DTH response can lead toformation of a granuloma, a nodule-like
mass. Lytic enzymes released from
activated macrophages in a granuloma cancause extensive tissue damage.
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ExamplesTuberculin response
Allergic contact dermatitis
Graft rejection
Corticosteroids and other immunosuppressive
agents are used in treatment.
Comparison of Different Types of hypersensitivity
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Comparison of Different Types of hypersensitivity
characteris
tics
type-I
anaphylactic
type-II
(cytotoxic)
type-III
(immune
complex)
type-IV
(delayed type)
antibody IgE IgG, IgM IgG, IgM None
antigen exogenous cell surface soluble tissues & organs
response
time15-30 minutes minutes-hours 3-8 hours 48-72 hours
histologybasophils and
eosinophil
antibody and
complement
complement and
neutrophils
monocytes and
lymphocytes
transferred
with antibody antibody antibody T-cells
examplesallergic asthma,
hay fever
erythroblastosis
fetalis,
Goodpasture's
nephritis
SLE, farmer's lung
disease
tuberculin test,
poison ivy,
granuloma
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Respiratory Allergies
(Allergic Asthma)
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Asthma
Asthma is a condition characterized by
reversible bronchospasm and chronic
inflammation of airway passages.
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Individuals with asthma appear to producelarge amounts of the Antibody IgE that
attach to the mast cells present in many
tissues.Exposure to a trigger such as pollen
will result in the allergen-binding mast cell-
bound IgE, which in turn causes the releaseof inflammatory mediators such as
Histamine and Leukotrienes.
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The response of a patient with asthma to
these triggers can be divided into an
―early phase‖ and a ―late phase.‖
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Early Phase of Asthma
The early phase of asthma is characterized by:a. Marked constriction of bronchial airways
(bronchospasm)
b. Difficulty in breathing
c. Production of excess mucus.
The bronchospasm that occurs may be the result of
the increased release of certain inflammatory
mediators such as histamine, prostaglandins andbradykinin that, in the early stages of asthmatic
response, promote bronchoconstriction rather
than inflammation.
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Allerg
en
Antigen-
presenting
cell
Processed
allergen
Plasma Cells IgE antibodies
E l L t
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Early
Phase
Late
Phase
Allergen
IgE antibodies Inflammation
Complications
Cellular
Infiltration
Glands
NervesBlood
vessels
Sneezing
Itching
Rhinorrhea
Congestion
Mediator
release Eosinophils
Basophils
Monocytes
Lymphocytes
Mast
cell
Irreversible
Disease?Priming
Hyper-
responsiveness
Late-phase
reaction
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Late Phase of Asthma
The late phase of asthma can occur several hours after theinitial onset of symptoms and manifests mainly as an
inflammatory response.
The primary mediators of inflammation during the
asthmatic response are the white blood cells Eosinophils that stimulate mast cell degranulation and release
substances that attract other white cells to the area.
Subsequent infiltration of the airway tissues with white
blood cells such as Neutrophils and lymphocytes alsocontributes to the overall inflammatory response of the
late phase of asthma.
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Some Potential Asthma Triggers..
Allergens — Pollen, pet dander, fungi, dust
mites
Perfumes
Pollutants
Cigarette smoke
Respiratory tract infections
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Sign and Symptoms
Early Phase:
Shortness of breath
Cough
Chest tightness and pain
Wheezing
Cyanosis
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Late Phase:
Mucosal odema
Severe bronchoconstrictionEpithelial damage
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M. Tuberculosis
and
immune responses
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Outline : TB history
TB epidemiology M TB bacteriology
TB clinical features
- symptoms and signs
- transmission- active vs. latent TB
Experimental models
Immune response against TB
- Innate immune defense- Adaptive immune defense
HIV and TB
Difficulties and advantages in TB research
Risk factors
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Outline : TB history
TB epidemiology M TB bacteriology
TB clinical features
- symptoms and signs
- transmission- active vs. latent TB
Experimental models
Immune response against TB
- Innate immune defense- Adaptive immune defense
HIV and TB
Difficulties and advantages in TB reaserch
Risk factors
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The pathogen structure:
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Outline : TB history
TB epidemiology M TB bacteriology
TB clinical features
- symptoms and signs
- transmission- active vs. latent TB
Experimental models
Immune response against TB
- Innate immune defense- Adaptive immune defense
HIV and TB
Difficulties and advantages in TB reaserch
Risk factors
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M. Tuberculosis Characteristics
Slow-growing
Facultative Intracellular
Gram-positive
Non Spore Forming
Aerobic
Acid-fast bacilli
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O l
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Outline : TB history
TB epidemiology M TB bacteriology
TB clinical features
- symptoms and signs
- transmission- active vs. latent TB
Experimental models
Immune response against TB
- Innate immune defense- Adaptive immune defense
HIV and TB
Difficulties and advantages in TB reaserch
Risk factors
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Spine TB :
Nemhotep,Priest of Amun died about 1000 BCE
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Brain TB :
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TB Meningitis :
Meningitis TB
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O li
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Outline : TB history
TB epidemiology M TB bacteriology
TB clinical features
- symptoms and signs
- transmission- active vs. latent TB
Experimental models
Immune response against TB
- Innate immune defense- Adaptive immune defense
HIV and TB
Difficulties and advantages in TB reaserch
Risk factors
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O tli
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Outline : TB history
TB epidemiology M TB bacteriology
TB clinical features
- symptoms and signs
- transmission- active vs. latent TB
Experimental models
Immune response against TB
- Innate immune defense- Adaptive immune defense
HIV and TB
Difficulties and advantages in TB reaserch
Risk factors
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Outline :
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Outline : TB history
TB epidemiology M TB bacteriology
TB clinical features
- symptoms and signs
- transmission- active vs. latent TB
Experimental models
Immune response against TB
- Innate immune defense- Adaptive immune defense
HIV and TB
Difficulties and advantages in TB research
Risk factors
Active vs. latent
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Active vs. latent
TB :
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Active TB :
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Active TB:
Two Forms :1. Primary-progressive TB (more common
in children) :Progress rapidly to active disease
2. Post-primary TB: present after an interval of
many years following exposure
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Differences :
I. Clinical presentations
II. Different temporal pathogenesis
III. Host genetic susceptibilities
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Latent TB :
L TB
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Latent TB :
Most infected individuals areasymptomatic
5 – 10% of latent individuals will develop
active TB during their lifetime individuals who are immunosuppressed,
particularly those with HIV coinfection
are in Higher risk
Outline :
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Outline : TB history
TB epidemiology M TB bacteriology
TB clinical features
- symptoms and signs
- transmission- active vs. latent TB
Experimental models
Immune response against TB
- Innate immune defense- Adaptive immune defense
HIV and TB
Difficulties and advantages in TB research
Risk factors
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R d i f i f i
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Route and site of infection
Mycobacterium tuberculosis is an obligatory aerobic,intracellular pathogen, which has a predilection forthe lung tissue rich in oxygen supply.
The tubercle bacilli enter the body via the respiratoryroute.
The bacilli spread from the site of initial infection inthe lung through the lymphatics or blood to otherparts of the body,the apex of the lung and theregional lymph node being favoured sites.
Extrapulmonary TB of the pleura, lymphatics, bone,
genito-urinary system,meninges, peritoneum, or skinoccurs in about 15 percent of TB patients.
E f ll i f b illi
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Events following entry of bacilli
Stage1: Phagocytosis of M.Tb by Alveolar macrophage
Destruction of M.Tb,but some evade destruction& continue to multiply inside them & infect
Bystander macrophagesStage 2:
Influx of PMN’s,recruitment ofMonocytes,differentiate into Macrophage,but fail
to eliminate completely Logarithmic growth of bacilli,little tissue
destruction
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Stage 3: Ag specific T-cells are recruited to the site
that activate monocytoid cells &
differentiate into two types of Giant cells EPITHELIOID,LANGHANS’ GIANT
CELL
Walling off infection from rest of the body& prevent dissemination of bacilli.
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Stage 4: Stage of Latency (Granuloma) disrupts
under conditions of failing immune
surveillance & leads to ENDOGENOUSRE ACTIVATION of dormant foci
Characterised by CASEATION
NECROSIS
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Binding of M. tuberculosis to
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g f
monocytes /macrophages
Complement receptors (CR1, CR2,CR3 and CR4), mannosereceptors (MR) and other cell surface receptor molecules play animportant role in binding of the organisms to the phagocytes.
The interaction between MR on phagocytic cells andmycobacteria seems to be mediated through the mycobacterial
surface glycoprotein lipoarabinomannan (LAM). Prostaglandin E2 (PGE2) and interleukin (IL)-4, a Th2-type
cytokine,upregulate CR and MR receptor expression and function
interferon-g (IFN-g) decreases the receptor expression, resultingin diminished ability of the mycobacteria to adhere to
macrophages. There is also a role for surfactant protein receptors, CD14
receptor7 and the scavenger receptors in mediating bacterialbinding.
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BA
Ph l f i
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Phagolysosome fusion
Phagocytosed microorganisms are subject todegradation by intralysosomal acidic hydrolases uponphagolysosome fusion.
This highly regulated event constitutes a significantantimicrobial mechanism of phagocytes.
Prevention of phagolysosomal fusion is a mechanism bywhich M. tuberculosis survives inside macrophages.
mycobacterial sulphatides,derivatives of multiacylatedtrehalose 2-sulphate,have the ability to inhibit
phagolysosomal fusion. studies demonstrated that M. tuberculosis generates
copious amounts of ammonia in cultures,which isthought to be responsible for the inhibitory Effect.
F t f lf d M Tb
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Fate of engulfed M.Tb
Anti mycobacterial effector functionsROI
RNI
Other mechanisms (IFN-γ ,TNF-α)MACROPHAGE APOPTOSIS
FIG
MACROPHAGE ACTIVATION
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MACROPHAGE ACTIVATION
IFN ,TNF (Th1 cells) Most welldocumented
Vitamin D
SLC11A1 (formerly Nramp1)
Reacti e o e i te ediates (ROI)
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Reactive oxygen intermediates (ROI)
Hydrogen peroxide (H2O2), one of the ROIgenerated by macrophages via the oxidative burst,was the first identified effector molecule thatmediated mycobactericidal effects of mononuclearphagocytes.
M.tuberculosis infection induces the accumulation ofmacrophages in the lung and also H2O2 production.
Similar local immune response in tuberculous asciticfluid has also been demonstrated.
Increased production of hydrogen peroxide by
alveolar macrophages is not specific for TB. Moreover, the alveolar macrophages produced less
H2O2 than the corresponding blood monocytes
Reactive nitrogen intermediates (RNI)
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Reactive nitrogen intermediates (RNI)
Phagocytes upon activation by IFN andTNF generate NO & related RNI via
iNOS2
1,25 dihydroxy Vit D3 reported to inducethe expression of NOS2
High level expression of NOS 2 detected
immunohistochemically in macrophagesobtained by BAL in individuals with active
PTB
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Other mechanisms of growth
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g
inhibition/killing
IFN and TNF mediated antimycobacterialeffects
VIT D3 alone or in combination with IFN
and TNF able to activate macrophage toinhibit/kill M.Tb
Macrophage apoptosis
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Macrophage apoptosis
potential mechanism involved in macrophage defenseagainst M. tuberculosis is apoptosis or programmedcell death.
apoptosis associated with TB is mediated through a
downregulation of bcl-2, an inhibitor of apoptosis Within the granuloma, apoptosis is prominent in the
epithelioid cells as demonstrated by condensedchromatin viewed by light microscopy or with the in
situ terminal transferase mediated nick end labeling(TUNEL)
Results in reduced viability of M.Tb
Evasion of host immune response by
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p
M.tuberculosis Modulation of antigen presentation to avoid elimination
by T cells. Protein secreted by m. Tuberculosis such as superoxide
dismutase and catalase are antagonistic to ROI.
Mycobacterial components such as sulphatides, LAM andPHENOLIC- GLYCOLIPID I (PGLI) are potent oxygen
radical scavengers. M.Tuberculosis-infected macrophages appear to be
diminished in their ability to present antigens toCD4+T cells, which leads to persistent infection.
Another mechanism by which antigen presenting cells(APCS) contribute to defective T cell proliferation andfunction is by the production of cytokines, including TGF-Β,IL-10 OR IL-6.
Virulent mycobacteria were able to escape from fusedphagosomes and multiply
Host immune mechanisms in
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TB
Innate immune response Acquired immune response
Humoral
Cell mediatedCD 8
CD 4
Th1
Th2
Immune response in TB :
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Immune response in TB :
1. Formation of Granulomas2. Initials events
3. MQ apoptosis
4. Role of PMN(Neu)
Formation of
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Granulomas
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The classical feature of human TBgranulomas:
The presence of a necrotic caseous corethat is thought to be secondary to cell lysis
that results in a central hypoxic
environment .
Caseation necrosis :
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Caseation necrosis :
Granuloma in active & latent TB :
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Granuloma in active & latent TB :
In latent TB the bacilli reside in thecentral hypoxic zone in a metabolically
altered state
In active TB they can replicate inperipheral oxygenated areas.
Are they purely protective for the
host or do they promote infection? The pathogen may be able to
engineer a supportive environment
in the granuloma
Granuloma classification in active
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TB:
1. The classical caseous granuloma :central eosinophilic debris surrounded bymacrophages and a layer of lymphocytes
2. The non-necrotizing granuloma:internal core of macrophages and someneutrophils surrounded by a lymphocytelayer
3. The suppurative granuloma: centralcore of degenerative neutrophils
surrounded by macrophages andmultinucleated giant cells and an outerenvelope of lymphocytes
First line of defence
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First line of defence
Influx of phagocytic cells including :1. primarily resident alveolar MQ
2. recruited neutrophils and DCs
Escape : TB prevents phagolysosomal fusionand persist in the phagosome
Immune defense: Opsonization of the bacilli
prior to infection inhibits this blockade ofphagolysosomal fusion
Role of MQ :
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Role of MQ :
Infection of MQ with M.TB can induce:1. necrotic death: allows exit from MQ
and therefore cell-to-cell spread of the
bacilli
2. Apoptotic death : is associated with
diminished pathogen viability andenhanced immunity
Efferocytosis
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Efferocytosis
TB – infected MQ are themselves rapidlyengulfed by uninfected MQ through a
process called efferocytosis , generally
regarded as a constitutive housekeepingfunction of macrophages.
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The type of cell death is regulated by :
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The lipid mediators include :
1. (proapoptotics): eicosanoids , prostaglandin E2(PGE2)
2. (pronecrotic): lipoxin A4 (LXA4)
Virulent strains of TB evade innate defensemechanisms of the host by inducing LXA4 andinhibiting PGE2 production
They lead to MQ necrosis and inhibition of MQapoptosis, ultimately resulting in mycobacterialspread.
Role of Neutrophils
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Role of Neutrophils Lung Neu facilitate activation of naive antigen-specificCD4+
Tcells during M .TB infection. IT promote an anti – M.TB adaptive immune response by
delivering the bacilli to DCs in a form that makes DCsmore effective initiators of CD4+ T cell activation.
Neu have a protective or detrimental effect during animmune response to TB infection may be determined by:
1. The genetics of the pathogen as well as by the genetics ofthe host
2. The stage of TB disease3. Tissue environment
4. Network of cytokines
Detrimental role of Neu :
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Detrimental role of Neu :
Neutrophils are dominant producers of IL-10
in the lung .
Depletion of neutrophils reduces the lung
bacterial load while enhancing IL-6 and IL-17,
but not IFN-γ, responses
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Outline :
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TB history
TB epidemiology M TB bacteriology
TB clinical features
- symptoms and signs
- transmission- active vs. latent TB
Experimental models
Immune response against TB- Innate immune defense
- Adaptive immune defense
HIV and TB
Difficulties and advantages in TB research
Risk factors
Innate immune response
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Innate immune response
The phagocytosis and the subsequent secretion of IL-12 are processes initiated in the absence of priorexposure to the antigen and form a component ofinnate immunity.
The other components of innate immunity arenatural resistance associated macrophageprotein (Nramp),neutrophils, natural killercells (NK) .
PLASMA LYSOZYME and other enzymes may playan important role in the first line defense, of innateimmunity to M. tuberculosis.
The role of CD-1 restricted CD8+ T cells andnon-MHC restricted T cells(γ/δ cell) have beenimplicated but incompletely understood.
Nramp
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Nramp
Nramp(SLC11A1) is crucial intransporting nitrite from intracellularcompartments such as the cytosol to moreacidic environments like phagolysosome,where it can be converted to NO.
Integral membrane protein,ion transporterfamily esp Feᶧᶧ
Defects in Nramp production increasesusceptibility to mycobacteria.
NRAMP1 gene might not be associated withthe susceptibility to pulmonary and spinal TBin the Indian population
NEUTROPHILS
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NEUTROPHILS
Increased accumulation of neutrophil in the granuloma and
increased chemotaxis has suggested a role for neutrophils. At the site of multiplication of bacilli, neutrophils are the
first cells to arrive followed by NK cells, γ/δ cells andα/β cells.
There is evidence to show that granulocytemacrophage-
colony stimulating factor (GM-CSF) enhances phagocytosis ofbacteria by neutrophils
Human studies have demonstrated that neutrophils provideagents such as defensins, which is lacking for macrophage-mediated killing.
neutrophils can bring about killing of M. tuberculosis in thepresence of calcium under in vivo conditions.
NK CELL Effector cells of innate immunity.
Directly lyse the pathogens or can lyse infected
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Directly lyse the pathogens or can lyse infected
monocytes.
Culture with live m. Tuberculosis brought about theexpansion of NK cells
During early infection, NK cells are capable of activating
phagocytic cells at the site of infection.
A significant reduction in nk activity is associated withmultidrug resistant tb (MDR-TB).
Nk activity in BAL has revealed that different types of
pulmonary tb are accompanied by varying degrees of
depression Apoptosis is a likely mechanism of NK cytotoxicity. NK
cells produce IFN-g and can lyse mycobacterium pulsed
target cells.
Lowered NK activity during TB infection is probably the
TOLL LIKE RECEPTOR
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TOLL LIKE RECEPTOR
Phylogenetically conserved mediators ofinnate immunity essential for microbialrecognition on macrophages & dendriticcells
M. tuberculosis can immunologically activatecells via either TLR2 or TLR4 in a CD 14-independent, ligand-specific manner
TLR 2 – LAM
TLR 4 – Heat labile factor
TLR 9 – cpg DINUCLEOTIDES
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TLR binds to target Coupling of IRAK -1 signalling molecules
& MyD88 (myeloid differentiation) gene
Translocation of NF κB (transcriptionfactor) from cytosol to nucleus
Cytokine production
Innate immune factors :
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1. TNF2. Inflammation
3. Pattern recognition receptors ,Adaptor
proteins
TNF
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Role :
1. Formation and maintenance of the integrity ofthe granuloma
2. Boosting the intracellular killing of bacilli
Granuloma formation could occur even in theabsence of TNF signaling, but these granulomaswere :
Delayed More necrotic
With higher bacillary numbers.
Inflammation :
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1. Eicosanoids
2. Matrix metalloproteinases :
MMP-1 and MMP-9 : key collagenase upregulated
in patients with TB and associated with increasedlung pathology in transgenic mice
3. Vitamin D
a pro-hormone that in kidney converts to itsactive form .Conversion can also occur in
granulomatous tissue.
V D3 h l d fl
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Vit D3 has regulatory and anti-inflammatory
immune effects ,therefore continues to be ofpotential therapeutic interest.
Historically ,sunlight exposure and vitamin D
were used as treatments for TB.
Pattern recognition receptors
d Ad t t i
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and Adaptor proteins :
Pattern-recognition receptors (PRRs):
1. Toll-like receptors (TLRs)
2. C-type lectin receptors (CLRs)includingdectin-1, mannose receptor, and DC-SIGN
3. Nod-like receptors (NLRs)
MyD88 and CARD9 :
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MyD88 and CARD9 :
- master adaptors of TLR
- critical for protective immunity to M.TB in
mouse models
TLR2, TLR4, and TLR9 play a role in host
recognition of M.TB
Outline :
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TB history
TB epidemiology M TB bacteriology
TB clinical features
- symptoms and signs
- transmission- active vs. latent TB
Experimental models
Immune response against TB- Innate immune defense
- Adaptive immune defense
HIV and TB
Difficulties and advantages in TB research
Risk factors
Acquired immune response
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q p
Humoral immune response: Since M. tuberculosis is an intracellular
pathogen, the serum components may notget access and may not play any
protective role. Although many researchers have
dismissed a role for B cells or antibody in
protection against TB, recent studiessuggest that these may contribute to theresponse to TB.
Adaptive immune response :
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p p
1. T cells2. DC cells
3. CD-1 restricted response
4. B cell5. Cytokines
DC cell
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DCs in lymph nodes from patients with M.TB may themselvescontain M.TB
Depletion of CD11c+ cells in mice before intravenous infection
with M.TB delays the development of CD4+ T cell responses
T cells
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The most important T cells is CD4+ T cells
CD8+ T cells also contribute to anti-TBimmunity by:
1. Secreting IFNγ To Activate MQ to ControlInfection2. Secreting products that can directly kill The
TB bacilli.
However, CD8+ T cells clearly can notcompensate for a lack of CD4+ T cells.
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Cellular immune response
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p
T CELLS M.TB is a classic example of pathogen
with a protective response relying on CMI
Activated T cells migrate to site ofinfection and interact with APC’s.
Tuberculous Granulomas contain both
CD4 & CD 8 T cells & helps to containthe infection within Granuloma and
prevent reactivation.
CD4 T CELLS
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Most important cells in protectiveresponse against M.Tb
Primary effector function - production of
IFN γ & other cytokines to activateMacrophage
Also related to NOS2 expression
Other unknown functions(protective)which are IFN & NOS2 independent
Target for vaccine design
CD 8 T CELLS
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Play in regulating Th1/Th2 balance Studies: TB with slow regression was
associated with an ↑ CD 8 T cell in BAL F
Capable of secreting IFN & IL 4 (Mφ
activation) Lysis of infected human dendritic cells & Mφ
By CD8 T cells specific for M.Tb Ag reducesintracellular bacterial numbers(CTL)
o Killing : Perforin/Granulysin pathway
Attractive vaccine candidate
T cell APOPTOSIS
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Attenuation of CMI by inducing T CELLapoptosis in M.Tb
Leads to diminished M.Tb stimulated IFNγ
& IL 2 production TB infection leads to CD 95 mediated
Th1 depletion
Non classically restricted CD 8 T
cell
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cell
CD 1 restricted T cells (NK T cells)γ/δ T cells
T reg CELLS
γ/δ T cells
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Large granular lymphocytes with dendriticmorphology in lymphoid tissue
Non MHC restricted
Function as cytotoxic T cells formonocytes pulsed with mycobacterial
antigen.
Secrete cytokines involved in granulomaformation.
NK T CELLS
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CD 1 molecules are antigen presentingmolecules that present lipids or
glycolipids to T cells.
Usually found on dendritic cells present inthe lungs.
Stimulate CD 1 restricted T(NK T cells)
in the granuloma that can have abystander effect on infected Mφ.
T reg cells
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T cells with suppressing (other T cells) capability
CD4 cells expressing CD 25 FOXp3,transcription factor essential for development of T
reg cells (also MARKER)
CTLA4 expressed on T reg induce negative signalling(contact dependent CD80/CD86))
It secrete IL 10,TGF β which supress activated T cells It requires
Expansion & recruitment(CCR1,CCR4) at pathologic sites forthe above actions
Express TLR2,TLR 4 On its surface
TLR2 engagement –ELIMINATION → Th1 response TLR 4 engagement – EXPANSION →immunosuppression
Th1/Th2 dichotomy
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Th1 secrete IL2, IFNγ
Protective role in intracellular infections. Th2 secrete IL4, IL5, IL10.
Exert a negative influence on the immune response
IL 12 induce Th1 type responseTh1 type response relate directly to the clinical
manifestations of the disease
Limited TB: alveolar lymphocytosis with high levels ofIFNγ.
Far advanced / cavitary disease : no Th1 response.
Proinflammatory Cytokines TNF Alfa (Stimulation of monocytes, macrophages, and dendritic cells withm c bacteria r m c bacterial r d cts ind ces the r d cti n f TNF a
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mycobacteria or mycobacterial products induces the production of TNF-, aprototype proinflammatory cytokine)
TNFα plays a key role in granuloma formation, induces macrophageactivation, and has immunoregulatory properties.
In tuberculosis patients, TNF- production is present at the site ofdisease.
Systemic spill over of TNF- may account for unwanted
inflammatory effects like fever and wasting. (double edged sword)
Clinical deterioration early in treatment is associated with aselective increase of TNFα in plasma , and quick recovery isassociated with a rapid decrease of TNFα in plasma .
To limit the deleterious effects of TNF α, systemic production ofTNF- is downregulated and soluble TNF- receptors which blockTNF- activity are increased .
In line with this, the use of potent monoclonal anti-TNF-antibodies in Crohn’s disease and rheumatoid arthritis has been
associated with increased reactivation of tuberculosis (including
IL-1β
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produced by monocytes, macrophages,and dendritic cells .
In tuberculosis patients, IL-1β is
expressed in Excess and at the site ofdisease.
Acute phase response
Fever & cachexia
IL-6
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IL-6, which has both pro- and anti-inflammatory properties , is produced earlyduring mycobacterial infection and at the siteof infection.
Role :inflammation,hematpoeisis,differentiation ofT cells
IL-6 may be harmful in mycobacterial
infections, as it inhibits the production ofTNF- and IL-1.
IL 12
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IL-12 is a key player in host defense against M. tuberculosis.
IL-12 is produced mainly by phagocytic cells(Mφ,DC) IL-12 has a crucial role in the induction of IFN-γ
production.
In tuberculosis, IL-12 has been detected in lung infiltrates, in
pleurisy, in granulomas , and in lymphadenitis. The expression of IL-12 receptors is also increased at the site
of disease.
In humans suffering from recurrent nontuberculousmycobacterial infections, deleterious genetic mutations in the
genes encoding IL-12p and IL-12R have been identified.Thesepatients display a reduced capacity to produce IFN- γ.
IL-12 is a regulatory cytokine which connects the innate andadaptive host response to mycobacteria and which exerts itsprotective effects mainly through the induction of IFN-γ
IL-18 and IL-15
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IL-18, a novel proinflammatory cytokine which shares many
features with IL-1, was initially discovered as an IFN--inducing factor, synergistic with IL-12.
IL-18 also stimulates the production of otherproinflammatory cytokines, chemokines, and transcriptionfactors .
Also, M. tuberculosis-mediated production of IL-18 byperipheral blood mononuclear cells is reduced intuberculosis patients, and this reduction may be responsiblefor reduced IFN-γ production .
IL-15 resembles IL-2 in its biologic activities, stimulating T-cell and NK-cell proliferation and activation .
Unlike IL-2, however, IL-15 is primarily synthesized bymonocytes and macrophages
IL 2
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Pivotal in generating immune response Induce expansion of pool of lymphocytes
Secreted by CD4 Th1 subtype
lymphocytes Influence the course of Tuberculosis
IFNγ
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The protective role of IFN- in tuberculosis is well
established, primarily in the context of antigen-specific T-cell immunity.
Produced by both CD4,CD8 T cells & NK cells
Augment antigen presentation leading to recruitmentof Lymphocytes
potent activator of infected macrophage resulting inlytic mechanisms
can be used as a surrogate marker of infection with M. tuberculosis
Ability of cells to respond to this cytokine is morepredictive than the amount.
Severely depressed in far advanced cases of TB
Anti-Inflammatory Cytokines
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The proinflammatory response which isinitiated by M. tuberculosis is antagonized
by anti-inflammatory mechanisms
IL-4, IL-10, and transforming growthfactor beta (TGF β)
IL 10
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Produced by Mφ after phagocytosis ofM.Tb
Downregulation of IFN γ,TNFα ,IL 12
Macrophage deactivation Directly inhibits CD4 T cell by inhibiting
APC function of M.Tb infected cells
M.Tb induced IL 10 suppresses aneffective immune response
TGF β
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Produced by monocytes and dendriticcells after stimulation with M.Tb or LAM
Inhibits IFN γ production andproliferation
In Mφ,it antagonises antigenpresentation,proinflammatory cytokineproduction & cellular activation
Involved in TISSSUE DAMAGE & FIBROSISby promoting macrophage collagenasesand deposition of collagen matrix
IL 4
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Deleterious effects of IL 4 in intracellularinfections including TB ascribed tosuppression of IFN γ & macrophageactivation
Progressive disease & reactivation were asso
with an ↑ IL 4 Overexpression of IL 4 intensified tissue
damage
Conversely,Inhibition of IL 4 didn’t seem to
promote cellular immunity So, IL 4 in TB is subject of controversy !
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CD1-Restricted Responses
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TB contains glycolipid Ag that arepresented by The CD1 family molecules
Glycolipid-reactive T cells play a role in an
effective response to TB
They proliferate and produce IFN-γ in
response to TB glycolipids
B cells
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Follicle-like B cell have been observed inthe lungs of M.TB patients and in the
granulomas of infected mice
Role :
1. moderate inflammatory progression
2. modulating immune activation andsusceptibility to infection by induction of
IL-10
IFNγ
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The most invariably detected cytokine atthe sites of human TB infection in :
- Lung (most )
- bronchoalveolar lavage (BAL) fluid- pleuritis fluid
- lymph nodes
IFN-γ-Mediated Killing
in MQ :
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IFN-γ-
inducible molecules include: iNOS , LRG-47, an IFN inducible GTP-
binding protein
IFN-γ is also important for endosome
maturation and the induction of
antimicrobial peptide
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Control of Inflammation and CD4+
T Cells
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various mechanisms are in place to preventimmunopathology, including:
1. Foxp3+ regulatory T cells
2. IL-103. PD1 ( expressed by T cells from TB patients)
PD-L1 is overly abundant in the whole blood of
active TB patients
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PD1 binded to PDl1---> negative signal
chronic infection
PD1 deletion ---- > increase of M.TB-specificCD4+ T cell --- > active TB
This finding demonstrated the importance of afinely regulated immune response to control
disease.
IL-17 :
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Both IFN-γ and IL-17-producing T cells areinduced during mycobacterial infection
IFN-γ serves to limit the IL-17-producing T cell
population IL-17 can also be produced by γδ T cells and a
non-CD4+ CD8+ population .
Role :- Granuloma formation
- Th1 enhancement
FOLLOWING BCG VACCINATION WITH AMYCOBACTERIAL PEPTIDE:
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IL-17 is required for theaccelerated recruitment of
IFN-γ-producing cells to
the lung as a result ofincreased concentrations of
the chemokines CXCL9, 10,
and 11, which recruit cells
to sites of inflammation
IL 23
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Essential for the IL-17 response during TB
Dispensable for protection and antigen-
specific IFN-γ responses if IL-12p70 is
available
The double-edged sword ofsuppressive
cytokines in tuberculosis
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cytokines in tuberculosis
IL10
TH2 cytokine
Type1 IFN
IL10
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An immunosuppressive cytokine induced by TB
for immune evasion
If overproduced, IL-10 can contribute to
chronic infection
IL-10 was elevated in the lungs , BAL fluid ,
sputum and serum of active TB patients
Activation of TLR4 (but not of TLR2) will
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induce higher levels of IL-10 production by
MQ
Bone marrow – derived Neu infected in vitro or
Neu isolated from the lungs of mice challenged
with TB produce significant levels of IL-10
Th2 Cytokines
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Chronic worm infection of mice reducesimmunogenicity to M.TB and reduce Th1
responses.
Generally ,Helminthes reduce protective
immune responses to M.TB infection.
Type I IFNs
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The type I IFN family of cytokines havepleiotropic effects on the broader immuneresponse
Role :
1. Increases susceptibility to M.TB 2. Suppresses production of host-protective
cytokines including IL-1 and IL-12 followingM.TB infection in MQ
3. Induction of the immunosuppressivecytokine IL-10
Outline : TB history
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y
TB epidemiology
M TB bacteriology
TB clinical features
- symptoms and signs
- transmission
- active vs. latent TB
Experimental models
Immune response against TB- Innate immune defense
- Adaptive immune defense
HIV and TB
Difficulties and advantages in TB research
Risk factors
HIV and TB :
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TB is the most common opportunisticinfection worldwide in HIV-1-infectedpersons
Antiretroviral therapy (ART) for HIV-1infection improves immune resistance to TB
Vitamin D reportedly inhibits HIV-1 and TBinfection in MQ through the induction ofautophagy.
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TB-IRIS
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HIV+ patient ---> immunosuppressed--->ART
----> decreased viral load and increased
CD4+ T cells ---> sudden over activation of
immune system ----> rapid recognition of
pathogens in body (like TB ) ----> causes
severe systemic inflammatory disease
Outline : M TB history
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y
M TB epidemiology
M TB bacteriology
TB clinical feature
- symptoms
- transmission
- active vs. latent TB
Experimental models
Immune response against TB- Innate immune defense
- Adaptive immune defense
HIV and TB
Difficulties and advantages in TB research
Risk factors
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Outline : M TB history
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M TB epidemiology
M TB bacteriology
TB clinical feature
- symptoms
- transmission
- active vs. latent TB
Experimental models
Immune response against TB- Innate immune defense
- Adaptive immune defense
HIV and TB
Difficulties and advantages in studying
Risk factors
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Epidemiology of Interstitial Lung
Diseases
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Idiopathic pulmonary fibrosis
Occupational/environmental
Post inflammatory pulmonary fibrosis Sarcoidosis
Connective tissue disease
Hypersensitivity pneumonitis Drugs and radiation
3
Pulmonary Immunobiology and InflammationConsensus 2000
“adopted” pathways of immune control in processing
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foreign antigens
mucociliary clearance
1010 particles per day
5x108 alveoli / 100m2 area upper & lower respiratory
tracts - ciliated epithelium
lymphatic tissues - NALT,
BALT, draining lymph nodes secretory IgA - immobilizes Ag
AM - poor APC, but “excellentcleaners” without initiating aninflammation - preventing thealveolar capil. membrane
T-cells - residual T - cells
CD4 - /CD8 - T cells
CD4+ & CD8+ - hyporesponsive
B- cells - high % in interstitium
4
Pulmonary Immunobiology and InflammationConsensus 2000
pulmonary inflammatory events
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Neutrophils - under normal conditions the lung is designed toexclude Neu from alveolar capillary membrane;
- transendothelium trafficking via CAM
- phagocytic defence - ingesting and clearing damaged epithelium
Eos, Ba, Mast cells – transvessels migration, role in Asthma,
Eosinophilic Pneumonia, Lung Fibrosis, Lung parasitic diseases
Oxidative stress - reactive oxygen and NO intermediates
tissue injury; antioxidants - glutathione (100x) higher than in other
tissues, extracellular superoxide dismutase (alveolar type II cells)
5
Pulmonary Immunobiology and InflammationConsensus 2000
unique immune characteristics
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type II alveolar cells – secreting and dividing cells
(Surfactant, SOD3, IL-8, MCP-1, MIP12, RANTES)
bronchiolar epithelial serous cells (Clara cells) - secretingand dividing cells (stem cells for ciliated/not ciliated bronch. epith.)
(lactoferrin, - defensin, cathelicidins, SP, cyt-p450)
type II alveolar cells and Clara cells - a potent source ofcytokines and variety peptide/protein antibiotics - LL37/ hCAP18,PhosphoLipase - A2, Clara Cell 26kDa protein
unique immune characteristics
6
Immunologic Methods for Diagnosisin Lung Diseases
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blood ( serology ) – C3, C4, C1-IHN, Ig (G, A, M), IgE, CRP, 1-AT, autoantibodies, infections diseases
blood ( cells ) - CMI - CD3, CD4, CD8, CD19, NK, adhesion
molecules CD62L, CD11b, CD54, CD25, CD86
cutaneous tests – test for type 1 allergic reaction; MULTITEST®
CMI (Skin Test Antigens for Cell-Mediated Immunity); Mantu test
invasive methods - bronchoscopy, pleural punction - respiratory cells
profile in BALF and PF biopsy - histological examination, immunohistochemial staining
7
parameter blood % BALF %
BALF normal respiratory cells profile
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Ma 77 - 87
Lymphocytes 28 - 39 7 - 14.7
Neutrophils 1.2 - 2.8
Eosinophils 0.2 - 0.4
CD3 78 3 74 1.5
CD4 42 3 44 2.5
CD8 36
2.3 31
3.5
CD4+/CD25+ 7 1.6 4.3 0.3
CD19 11 - 16 <5
NK 10 - 19 6 - 8
Тh/Тs 0.9 - 1.5 1.1 - 1.7 8
Pleural Fluid normal respiratory cells profile
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parameter Nonsmokers % Smokers %
Ma 64 - 80 69 - 81
lymphocytes 18 - 36 12 - 28
neutrophils 0 - 1 1 - 2
eosinophils 0 0
Mesotelial cells 0 - 2 0 -2
Тh/Тs 0.75 (0.6 - 1) 0.72 (0.4 - 1.4)
9
Autoimmune - Mediated Lung Disease
Connective tissue disease SLE RA SS PSS DM
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Connective tissue disease - SLE, RA, SS, PSS, DM
Antiphospholipid Syndrome (APS)
Pulmonary Vasculitis Syndromes
systemic necrotizing vasculitis ( Polyarteritis Nodosa, Allergic
granulomatosis of Churg & Strauss )Wegener’s Granulomatosis, Henoch-Schonlein Purpura,
Behcet’s Disease
Goodpasture’s Syndrome - pulmonary-renal involvement
Post inflammatory Pulmonary Fibrosis
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Connective Tissue Diseases
clinical features – polyserositis
SLE - pleuritis 30%; chest pain 50%; atypical pneumonia - lupus
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pneumonitis - 71%; pulmonary hypertension.; DAH;
pneumothorax, hemothorax, vasculitis
RA - interstitial lupus pneumonitis
PSS - dyspnea, chr. cough, pleuritis, fibrosis, pulm. hypertension
immunologic diagnosis - serology immunologic diagnosis - cytology – BALF, PF
Neu - 41%, Eos - 24%
with clinical picture - worse baseline fibrosis
Ly - 24% asymptomatic
in 56% of the cases- BALF cytology is the once way for the right
diagnosis and for monitoring the treatment response
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Autoimmune - Mediated Lung Disease in conclusion
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serology - autoantibodies immunologic diagnosis - BALF - hemorrhagic alveolitis - over
80% of the cells are activated, peripheral blood neutrophils
immunofluorescence - linear or granular deposition of immune
complexes along glomerular / alveolar basement membrane, pulmonary arteries, veins
treatment - immune suppression (corticosteroid,
cyclophosphamide), plasmapheresis
37
References
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Demedts M et al. Eur Respir J Suppl.2001, 32, 2-16.
Crapo JD et al. Am J Respir Crit Care Med, 2000, 162 (5), 1983-6.
Statement on Sarcoidosis. Am J Respir Crit Care Med, 1999, 160, 2, 736-755.
Statement on Sarcoidosis. Am Fam Physician, 2001, 15, 6, 553-556.
Andreeva H. et al. Allergy & Asthma, 6, 2001, 25-30.
Israel-Assayag E et al. Am J Respir Crit Care Med, 1999, 159,1830- 34. Mittoo S et al. Respir Med, 2009, 103 (8): 1152-8.
Meltzer EB&Noble PW. Orph J Rare Dis, 2008, 26, 3-8.
Marchand E&Cordier J-F. Orph J Rare Dis, 2006, 1, 1-11.
BAL Cooperative Group. Am Rev Respir Dis, 1990, 141:169.
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REFERENCES
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TUBERCULOSIS–
WILLIAMROM,STUART GARAY
TUBERCULOSIS – SURENDRA
SHARMA,ALLADIMOHAN
IMMUNOLOGY OF TUBERCULOSIS-
IJMRDr.ALAMELA RAJU,TRC,CHENNAI
IMMUNOLOGY OF TUBERCULOSIS:
FROM BENCH TO BEDSIDE
Reference :
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