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Immunologie2020

• Prof. Martin GUILLIAMS, • Laboratory of Myeloid Cell Ontogeny and Functional Specialization VIB, 

Technologiepark, Zwijnaarde. Martin.guilliams@UGent.be• Sources:

– Slides made available on Minerva– Janeway’s– Immunobiology 9th edition, Kenneth Murphy and Casey Weaver, 

Garland Science. 2017, ISBN  978‐0‐8153‐4505‐3• Practical course: Integrated practicum “Advanced Biotechnology part 2”, 

Monday 04/03 – Friday 08/03

• Optional Ma2 course:Experimental Molecular Immunology, Prof. M. Guilliams 1

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Amazon or Bol.com

(40€ ‐ 70€)

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Lessen• 25/02 = Chapter 1• Practicum from 02/03 till 06/03• 10/03 = Chapter 2• 17/03 = Chapter 3• 24/03 = Chapter 4• 31/03 = Chapter 5• Easter break• 21/04 = Chapter 6• 28/04 = Chapter 7• 05/05 = Chapter 8 

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• If you can find the 8th edition from a previous student it should be ok, but the 9th edition will be better.

• I will update the course with recent news and technological developments.

• I will do my best to use examples of UGent research. 

• Textbooks are very rapidly outdated. The data remain the same, but the interpretation can change rapidly.

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Mouse Human

www.immgen.orgProfiling mouse liver Myeloid Cells

Invited for theLiver Cell Atlas

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www.immgen.orgProfiling mouse liver Myeloid Cells

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Elon Musk

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Aviv Regev Sarah Teichmann

Mark Zuckerberg and Priscilla Chan

Course overview

I. Historical perspective and concepts II. Inventory of immune effectorsIII. Antigen recognition by B and T lymphocytesIV. Selection of B and T lymphocyte receptors V. Antigen presentation to T lymphocytesVI. The adaptive immune response – initiation of T cell

responsesVII. The adaptive immune response – T and B cell

effector functionsImmune diseases

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Introduction

Historical perspective and concepts

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Immune Free of consequence

Infection Free of disease

The immune system

System Vital

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Immune Free of consequence

Infection Free of disease

Suboptimal immune defense (immune deficiency)

Recovery from infection with no lasting damage

Immune disease

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SCIDSevere Combined Immune Deficiency

Outgrowth of Candida albicans in the mouth

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Malignant transformationCancer

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Immune Free of consequence

Infection Free of disease

Suboptimal immune defense (immune deficiency) • SCID (Severe Combined Immune Deficiency)• HIV AIDS (Acquired Immune Deficiency Syndrome)• Immune suppressive drugs (tissue transplantation)• Cancer

Recovery from infection with no lasting damage

Immune disease

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Immune Free of consequence

Infection Free of disease

Suboptimal immune defense (immune deficiency)

Recovery from infection with no lasting damage

Immune disease

Responsiveness to innocent antigens

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Allergy

Airborne allergens•Birch pollen

•Grass pollen

•Domestic animals

•House dust mite

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Bach JF. NEJM 2002; 347:911

Epidemic increase in chronic inflammatory diseases

1 in 3 children is allergic1/12 children is asthmatic

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Hay fever (rhinitis) and asthma

Antibody (IgE) mediated

Allergen

Saline

Histamine

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Contact allergy

Cell (T-lymphocyte) mediated

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Anaphylactic Shock

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IgE mediated

You need prior allergy, high release of histamine   Epipen (adrenaline)

Low blood pressure ‐ from fluid loss from blood into tissues Lungs filling with fluid Airways spasmingThroat swellingSwelling all over the bodyFlushing: redUltimately collapse; death, if not treated 

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(Adrenaline)

Immune Free of consequence

Infection Free of disease

Suboptimal immune defense (immune deficiency)

Recovery from infection with no lasting damage

Immune disease

Responsiveness to innocent antigens • Allergic hyperreactivity responses• Asthma• Anaphylactic shock

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Immune Free of consequence

Infection Free of disease

Suboptimal immune defense (immune deficiency)

Recovery from infection with no lasting damage

Immune disease

Responsiveness to innocent antigens

Responsiveness to self antigens

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Butterfly-like skin rash

Systemic Lupus Erythematosus (SLE)

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Rheumatoid arthritis

Psoriasis

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Inflammatory Bowel Disease (IBD)

Crohn’s disease30

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Vaccination

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Historical perspective

VACCINATION at the basis of ‘Immunology’ awareness

Smallpox • Variola virus• Single segment dsDNA virus• Poxviridae

Epidemiology• Old disease (Egyptian mummies)• Large and recurrent epidemics

worldwide devastating effects on native population in New World 18th century: 400 000 European casualties annually• Mortality: ~ 25%• Morbidity and permanent disfigurement/scars

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“Pokken” in Dutch.

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The Intangible Value of Vaccination

Vaccination is a major life safer !!!• Prevents > 3 million deaths annualy • Total eradication of a pathogen is possible IF no animal reservoir!!!!

Eradication of smallpox Global programs for eradication of polio and measles

Only two things increased life expectancy significantly: Antibiotics & Vaccinations

“Mazelen” in Dutch.“Polio” in Dutch.

The Economist 2019

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Vaccination• Edward JennerMilkmaids were resistent to smallpox after a cowpox infection

Deliberately infecting people with cowpox (1796)

Vaccination ~ vacca = cow

• 19th century

Cowpox replaced by vaccinia (poxviridaea)

• cross-protective antibodies• 1967 WHO global smallpox eradication program

• 1979 TOTAL ERADICATION of smallpox

Eureka!!!!!

Historical perspective

VACCINATION at the basis of ‘Immunology’ awareness

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Louis PasteurMicro-organisms as causative agents of disease

Chicken cholera vaccine = ‘lucky shot?’ Chicken inoculated with old culture of cholera were resistent against infectionwith fresh cholera bacteria = ‘attenuation’

Attenuation= weakening pathogen so it can induce immunity but only causes mild or subclinical disease anthrax vaccines: culturing anthrax bacteria at 42°C

rabies vaccine

Historical perspective

VACCINATION at the basis of ‘Immunology’ awareness

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• Edward Jenner (1798) discovers VACCINATION– Vacca  = cow, Vaccinia = cowpox

• Inoculation with cowpox protects again smallpox

– BUT relation between infectious agents and disease still unknown

• Robert Koch and others show that disease is caused by microorganisms (19th century)

• Louis Pasteur develops successful vaccines against cholera and rabies (1880)

• E. von Behring (1890) discovers in serum of immune animals– Serum antitoxic activity = ‘antibody’

• Antibody‐eliciting structure = ‘antigen’

• Underlying mechanism  birth of the science of Immunology

Historical timeline

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Successful vaccination campaigns against infectious diseases

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Subacute sclerosingpanencephalitis (SSPE) is a progressive, disabling, and deadly brain disorder related to measles infection

NEW SLIDE

Immune defense major challenges to meet

Non-infectious antigens

Self antigens Non-self antigens

Infectious antigens

Viruses Bacteria Parasites

Nano Micro Macro 42

Intracellular Intra‐ or Extracellular Extracellular

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MTB: Tuberculosis bacterium  inside macrophages

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Pseudomonas aeruginosa: Gram Negative Extracellular bacterium

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Eosinophil attacking a worm

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The golden age of immunology

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The golden age of immunology

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This is just the beginning…• You can compare this to the discovery of Penicillin by Fleming. That was just the first antibody.

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There are many more immunoregulatory receptors on different types of cells.

CTLA‐4 and PD1 on T cells is just the beginning.

Combinatory therapies, many additional types of immune cells.

Take a break here

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Immune defense major challenges to meet

Fast onsetSterilization of the infected tissue

Tissue damage

Clearance of

infection

Tissue repair Tissue remodelingImmune homeostasis

Memory of the infection57

Misdirected response• Autoimmune inflammatory diseases • Allergic diseasesMisdirected tolerance• Hyporesponsiveness to infection, vaccines• Cancer

Immune defense is made up of two branches immune pathology

Excessive/chronic activation• Irreversible tissue damage • Shock

• Septic shock• Anaphylactic shock• Traumatic shock

Innate immunity Adaptive immunity

Fast onsetLocal leucocytes

Elicited leucocytes

Delayed onsetCirculating T-

lymphocytes and antibodies

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Innate immunity Adaptive immunity

Both immune branches are strongly interconnected

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Macrophage:‐ Phagocytosis‐ Cytokine: TNF, …‐ Nitric Oxide: toxic for bacteria

TNF

Neutrophil:PhagocytosisCytokine: TNFNetosis: trap in NETsReactive Oxygen Species: toxic for bacteria

NK Cell:‐ Kills infected/stressed cells‐ Cytokine: IFN‐ activates macrophages

IFN‐

INNATE IMMUNE RESPONSE:Fast (hours!): which cells calls which other cell?Cells recognize stressed cells: what are the signals?Cells recognize general bacterial building blocks: what are the receptors?No strain specificityNo memory

Epithelium

Endothelium

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Macrophage

IFN‐ stronger macrophage activation  pathogen elimination

ADAPTIVE IMMUNE RESPONSE:Specific responseMuch stronger response to specific threatMemoryBut… takes multiple days to set‐up

MHC Antigen

TCR

Effector T cell‐ Scan the body to find pathogen‐ Are antigen SPECIFIC‐ Memory T cells‐ Basis of vaccines

TEff cell = TH1

LN

Chapter I:The different type of 

Immune cells

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Immune cells

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CLP CMP GMP MEP

Guilliams et al. Immunity 2018

2017

2007

2013

20092018

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2017

2017

The different type of Immune cells:

Myeloid Cells

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Dendritic cell =Unique capacityTo migrate to the 

Lymph Nodes

Death by NETOSISto trap extracellular 

bacteria

Myeloid Cells

Fight wormsAllergies!

Monocytes• Classical Monocytes: precursors of inflammatory macrophages• Patrolling Monocytes: patrol blood vessels looking for damage

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Macrophages = Big Eaters

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Other Receptors are needed for the first encounter!

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Induced by IFN‐ activation

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Eosinophils

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Granules contain:‐ Neurotoxins‐ Peroxidases: form Reactive Oxygen Species (ROS)‐ IL‐4 (less than basophils)  Activate Mast Cells and Basophils

‐ Fight parasitic worms

‐ Drive allergies: ROS, toxins,  tissue damage

Basophils

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‐ Fight worms, induce diarrhea (expulsing the worm)

‐ Drive allergies: release of Histamine

Granules contain:‐ Histamine  dilatation of blood vessels (recruitment of cells and serum components)‐ Cytokines: IL4, IL13  important for TH2 induction (anti‐parasite T cell response)

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Mast Cells

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‐ Fight worms, induce diarrhea (expulsing the worm)

‐ Drive allergies: release of Histamine, Prostaglandines that induce mucus production

Granules contain:• Histamine• Cytokines: IL4, IL13

(less than Basophil)• Prostaglandines

(more than Basophil)

Neutrophils

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Neutrophils release:‐ Cytokines = IL1, TNF: activate other immune cells‐ Reactive Oxygen Species (ROS): toxic for bacteria‐ NETs to trap bacteria

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Neutrophil NETOSIS

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Dendritic Cells

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The different type of Immune cells:

Lymphoid Cells

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Lymphoid Cells

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Innate Lymphoid Cells:one for each type of pathogen

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Production of Defensins by Epithelial CellsActivation of Neutrophils (NETOSIS,…)

intra

extra 

NK Cells

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• Primary function: killing of ‘aberrant’body cells:

– Stressed– Virus infected

• Secondary function: activation of macrophages and enabling of adaptive immune responses through the production of the instructive cytokine IFN-.

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3 types of adaptive immune cells:

• B-lymphocytes: Primary function production of antibodies.

• CD4 T-lymphocytes: Provide help to B-lymphocytes and innate cells by the production of cytokines ( TH)

• CD8 T-lymphocytes: Cytotoxic cells ( CTL)

TN = TNaive

TEff = TEffector = TH (CD4+ TEff) or CTL (CD8+ TEff) 

TH = THelper = TH1, TH2, TH17

CTL = Cytotoxic T Lymphocyte

T Cells and B cells

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intra

extra 

KILLINGCTL =

CD8 T cell

KILLING

NK cell

HELPCD4 T cell

HELPILC

IFN‐Granzyme

intra

extra 

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T cells: T cell Receptor (TCR)

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The antigen receptor on T lymphocytes (TCR) recognizes a linear peptide sequence within a protein antigen

The peptide is presented to the TCR by a second set of cell surface receptors for peptide, namely the Major Histocompatibility Complex (MHC) molecules

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MHCI for intracellular cytosolic antigens

CD8 TN

TEff = CTL

Endogenous antigen in

Cytosol

MHC I

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CD4 TN

TEff = TH1 = HELP

Engulfed antigen in Endosome

MHC II

Helps macrophages to kill ingested pathogens (endosome) = TH1

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TH1 = against intracellular bacteriaActivates macrophages for killing

TH2 = against parasitic worms Activates Mast Cells and EosinophilsActivates macrophages for tissue repair

TH17 = against extracellular bacteria, Activates Neutrophils for killing/hunting

Helps B-lymphocytes to produce antibodies

Opsonins for mast cells/eosinophils

Opsonins for Macrophages

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CD4 TN

TEff = TFH = HELP to B cells

Engulfed antigen in Endosome

MHC II

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B cells: B cell Receptor (BCR)

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Heavy chain

Light chain

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