Immunology AB_1144
Vrije Universiteit Amsterdam
2022
Rya Riedweg
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,Contents
Introduction ...................................................................................................................................................................... 4
Elements of the Immune System and Their Roles in Defense – Ch1/2 ............................................................................ 4
Components of the IS................................................................................................................................................ 4
Function of innate and adaptive IS ........................................................................................................................... 5
Complement.............................................................................................................................................................. 6
Innate Immunity - Induced response to infection: cells & receptors- Ch3 ....................................................................... 8
Macrophages............................................................................................................................................................. 8
Neutrophils ............................................................................................................................................................... 8
Receptors .................................................................................................................................................................. 9
Natural killer cells...................................................................................................................................................... 9
T Lymphocytes – Ch5/7 ................................................................................................................................................... 11
Antigen Recognition .................................................................................................................................................... 11
T cell receptor ......................................................................................................................................................... 11
Antigen processing and presentation for T helper cell activation .......................................................................... 11
Antigen processing and presentation for cytotoxic T cell activation ...................................................................... 12
Cross-presentation .................................................................................................................................................. 12
Development of T lymphocytes .................................................................................................................................. 13
The HLA system ....................................................................................................................................................... 13
Positive & negative selection .................................................................................................................................. 13
B cell immunology – Ch4 ................................................................................................................................................. 15
Intro and recap........................................................................................................................................................ 15
Structure of antibodies ........................................................................................................................................... 15
Generation of bcr and tcr diversity ......................................................................................................................... 17
Expression of isotypes ............................................................................................................................................. 18
Development of B lymphocytes – Ch6 ............................................................................................................................ 18
Recap ....................................................................................................................................................................... 18
Development of B cells in bone marrow................................................................................................................. 18
Negative and positive selection .............................................................................................................................. 19
Signaling via BCR ..................................................................................................................................................... 20
Induction of Immune responses ............................................................................................................................. 20
Immunity mediated by T cells and antibodies – Ch9 ...................................................................................................... 22
Induction of immune responses ............................................................................................................................. 22
Function of immunoglobulin isotypes .................................................................................................................... 23
Fc receptors............................................................................................................................................................. 24
T cell mediated immunity -Ch8 ....................................................................................................................................... 25
Dendritic cells and T cell activation......................................................................................................................... 25
T helper cell subsets ................................................................................................................................................ 26
The mucosal immune system – Ch10 ............................................................................................................................. 28
Mucosal tissues ....................................................................................................................................................... 28
Distinctive features of the mucosal immune system.............................................................................................. 28
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, Bacteria in the intestines ........................................................................................................................................ 30
Techniques in Immunology ............................................................................................................................................. 32
Immune cells in the blood....................................................................................................................................... 32
Antibodies and their application............................................................................................................................. 32
Detection of antigen specific T cells........................................................................................................................ 33
Immunological memory – Ch11 ...................................................................................................................................... 34
................................................................................................................................................................................. 34
Secondary infection ................................................................................................................................................ 34
Vaccines ...................................................................................................................................................................... 35
Types of vaccines .................................................................................................................................................... 36
Failure of body’s defences – Ch13/14............................................................................................................................. 38
Inherited or primary immunodeficiencies .............................................................................................................. 38
Acquired or secondary immunodeficiencies........................................................................................................... 38
Pathogen evasion and subvision of the IS .............................................................................................................. 39
IgE immunity and Allergy ............................................................................................................................................ 40
Ige, hygiene, allergy ................................................................................................................................................ 40
Allergic reaction ...................................................................................................................................................... 41
Allergy and therapy ................................................................................................................................................. 42
Autoimmunity - Ch16 ...................................................................................................................................................... 43
Mechanisms of tolerance induction ....................................................................................................................... 43
Antibody mediated autoimmune diseases ............................................................................................................. 44
Diabetes .................................................................................................................................................................. 44
T cell mediated disease ........................................................................................................................................... 45
The IS and cancer – Ch17 ................................................................................................................................................ 46
Immunosurveillance................................................................................................................................................ 46
Immune escape ....................................................................................................................................................... 47
Cancer immunotherapy .......................................................................................................................................... 47
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,Introduction
• IS ensures we stay healthy
• Definition: a diffuse, complex network of interacting cells, cell products and cell-forming tissues
o Protects the body from pathogens and other foreign substances
o Destroys infected and malignant cells
o Removes cellular debris
• Needs to discriminate between self & non-self and harmless & harmful
o Self harmless: tissue and organs
o Self harmful: cancer cells -> immune response
o Non-self harmful: pathogens -> immune response
o Non-self harmless : eg microbiom, polls
• There is a delicate balance in immune activation (inflammation) and inhibition (tolerance)
• A dysbalance in immunity can cause (severe) disease
o Immune response against self harmless -> auto immune disease
o No response against cancer cells -> cancer
▪ Treat with immunotherapy
o No response against non-self harmful -> infection
▪ Treat with vaccine
o Response against non-self harmless -> allergy
Elements of the Immune System and Their Roles in Defense – Ch1/2
Components of the IS
• IS includes: immune cells, complement, antibodies and lymphatics
Circulatory system
• In our blood we find multiple immunological components
o White blood cells: neutrophils, eosinophils, basophils, monocytes, lymphocyts
o Platelets
o Plasma: complement, antibodies
o Red blood cells
• Subdivided into two main immunological categories: innate vs adaptive immunity
o Innate: existing in one from birth, fast response (minutes, hours), local
▪ Granulocytes (neutro-, baso-, eosinophils & mast cells): can release granules immediately
▪ Monocytes (macrophages, dendritic cells)
▪ Lymphocyte: NK cells
o Adaptive: able to adapt, slow response (days, weeks), systemic
▪ B cells -> antibodies
▪ T cells
o Main difference: The innate is a general response and the adaptive is specifically tailored to the
pathogen
Hematopoesis
• Is the development of immune cells with two important common precursors
• 1 stem cells (pluripotent hematopoietic stem cell) -> common myeloid precursor or common lymphoid precursors
o Myeloid: granolycytes, APC (macrophages, dendritic cells), mast cells
▪ -> all innate cells except nk cells
▪ Macrophages can also develop from monocytes
o Lymphoid: lymphocytes (B cells, T cells, NK cells)
3 lines of defense
• After first time of infection: first innate, then adaptive
• The subdevision into 3 lines is based on the speed of activation upon danger
• First line of defense: Epithelial barriers -> To avoid initial entrance of pathogens and infection
o Mechanical: physical barriers (skin, mucous membranes (in gut, lungs, eyes/nore/oral cavity)),
movement of cilia
o Chemicals (eg low ph in gut, pulmonary surfactant, antimicrobial enzymes in tears etc)
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, o Microbiological: microbiota
• Second line of defense: innate immune cells & complement
• Third line: adaptive immune cells, antibodies
• -> the innate IS forms the first and second line of defense
Lymphatic system
• Lymphatic system is important for adaptive immunity
• Devided into primary and secondary lymphoid organs with different functions
• Primary: development of adaptive immune cells
o Bone marrow: b cells
o Thymus: t cells
• Secondary: activation of adaptive immune cells
o Lymph nodes
o Spleen
o Gut associated lymphoid tissues (GALT)
o Are highly structured with specific sites for T cell and B cell activation
▪ T cell zone, B cell follicle, germinal center
Function of innate and adaptive IS
• They differ in speed and specificity of inducing immunity
• Inntate: immediate & fast, equal in all of us
• Adaptive: adapted & slow, highly specific for each type of danger
Neutrophils and macrophages
• Are fast responders upon bacterial infection and induce inflammation
• Bacteria in the tissue activates macrophages to secrete cytokines
o Induce inflammation and recruit neutrophils
• Vasodilation increases permeability of capillary wall -> fluid and cells leave blood to enter tissue
• Cytokines: signaling molecules for activation
o Activates receptors on endothelial cells so that neutrophils come in
• Chemokines: signaling molecules for migration
o Neutrophils are recruited by macrophages from the bone marrow by chemokines
• Macrophages recruit neutrophils from the BM to collaborate and clear bacterial infection
o Neutrophils are stored in the BM and released on demand -> increase in number very fast
o Go to infected tissue and kill bacteria -> die -> degraded by macrophages
o They both eat up the bacteria in the tissue, they work together
• But they are unspecific -> can not keep up forever
o While pathogen load is high people are sick
o Without innate immune cells you get very sick very gast
o Without adaptive immune system you first have a normal increase in pathogens but
then later on you can not decrease it anymore -> eventually die from infection
o -> cooperation between innate and adaptive immunity for optimal pathogen clearance
Dendritic cells
• The dendritic cells also residue in the tissue and take up the pathogens
• While inflammation is ongoing dendritic cells carry particles of the pathogen into secondary lymphoid organs
-> activate adaptive immunity
Receptors
• Innate immune cells use pathogen recognition receptors to distinguish self from non-self and get activated
• There are different receptors on the surface of innate immune cells
o Are for activation or uptake of pathogens
o All the same cell sub-types express the same receptors
o Can differentiate between major pathogen species
▪ using associated molecular patterns
• pathogen associated: PAMPS
• danger associated (eg cancer or dead cell): DAMPS
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, o -> no specific response -> pathogens will win
• Adaptive immune cells use receptors to specifically detect danger and get activated
o Adaptive immune cell receptors used for activation and effector functions
▪ B cell: B cell receptor
• Becomes soluble: antibody -> Ab is a secreted b cell receptor
▪ T cells: T cell receptor
o Can differentiate within major pathogen species -> different responses for different pathogen
o Using antigens
▪ Highly specific for each pathogen
▪ Receptor is highly specific per cell -> one b cell recognizes corona, other b cell recognizes
other virus
• Antigens are specific for each pathogen and contain epitopes recognized by the
recepotrs of your adaptive immune system
o In the antigen we have specific parts that are actually bound by the b or t
cell receptors -> epitope
• After development every T and B cell expresses a receptor which will bind a different epitope -> have
different specificity
o They express multiple TCR or BCR but all with one specificity per cell
o Only the ones with a receptor specific for ongoing infection will be activated in secondary lymphoid
organs -> start proliferating = clonal expansion
▪ All clones have the same receptor specific for one epitope
▪ Takes ca a week -> therefore adaptive response is slow
▪ They remember infection
Difference b and t cell receptor
• TCR: bind processed antigen (epitopes)
o They activate other cells which present the epitopes ->
cellular response
• BCR bind epitopes on intact antigen/pathogen (antigen is still on the
pathogen)
o Differentiation into plasma cells
o Production of antibodies
o -> humoral response
• Antibodies:
o Produced during humoral response, have multiple functionalities against infection
o Broad range specific for the same pathogen
▪ Recognizing different epitopes between antibodies
o Recognizing one epitope per antibody
o Functions:
▪ Neutralization (counteract): bind toxin -> can no longer be toxic
• Finally also ingested over ab by phagocyte
▪ Opsonization (tagging): binding to pathogen -> red flag so other immune cells can detect it ->
eg macrophages can take up pathogen and destroy it
• Pathogens are then not neutralized!
▪ Complement activation
▪ Activation of innate cells via antibody-receptors interaction (Fc-FcR) -> enhanced
phagocytosis and activation of granulocytes & NK cells
Complement
• Complement system complements ongoing inflammation
• consists of plasma proteins with enzymatic activity
• Know C3 and C3a C3b
• C3 is inactive in the plasma -> cleaved by C3 convertase (enzymatic reaction) -> active
o C3a: anaphylatoxin
▪ enhances inflammation within minutes
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