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Lecture 3

Lecture 3. ORIGINS AND MEANS OF THE IMMUNE RESPONSE Jan Żeromski 2013/2014. 1. Points to be discussed. Rationale and phases of the immune response The role of inflammation and tissue injury Cytokines and chemokines Cell adhesion molecules Leucocyte-endothelial cell interactions

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Lecture 3

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  1. Lecture 3 ORIGINS AND MEANS OF THE IMMUNE RESPONSE Jan Żeromski 2013/2014 1

  2. Points to be discussed • Rationale and phases of the immune response • The role of inflammation and tissue injury • Cytokines and chemokines • Cell adhesion molecules • Leucocyte-endothelial cell interactions • Origin and subsets of T and B cells • CD (Cluster Determinants) classification • Intracellular biochemical events following Ag recognition • Patterns and mechanisms of cell migration • Immunoglobulins and generation of diversity 2

  3. Rationale of immune response • Recognition of foreign structure or organism • Detection of its pathogenicity • Prevention of its unwanted effects • Destruction of invader • Elimination it from the body

  4. Phases of the immune response • Induction phase – recognition of antigen • Central (activation) phase – cell proliferation and differentiation into various subsets, • Effector phase – engagement of various mechanisms and cells

  5. Factors participating in particular phases of the immune response • Induction phase: PRRs, MHC antigens, T and B cell receptors, • Central ph: adhesion molecules, cytokines, antigen-presenting cells (APCs), macrophages • Effector ph: cytotoxic T lymphocytes (CTLs), immunoglobulins, activ. macrophages, NK cells

  6. The role of inflammation • Inflammatory agent leads to activation of PRRs and results in tissue injury • Injury induces chemotaxis of various cells to the site of damage, such neutrophils, macrophages, APCs • APCs ingest foreign antigens, process them to peptides suitable for the presentation to T cells • Cytokines released by neutrophils, macrophages and other cells activate APCs and enhance them to migration to lymph nodes. Cytokines secreted by APC activate T cells responding to given antigen

  7. Main properties of some interleukins • IL-1 – proinflammatory, pleotropic • IL-2 – growth factor for T, B and NK cells • IL-4 –maturation and differentiation of B cells • IL-5 – as above but of eosinophils • IL-6 – proinflammatory, differentiating agent for B cells, • IL-7 – lymphocyte development in primarylymph organs , • IL-10 – immunosuppressive • IL-12 – strong activator of cellular immune response • IL-15 – maturation of NK cells in bone marrow • IL-17 – proinflammatory, pleotropic • IL-18 – production of interferon gamma przez T and NK cells 7

  8. CELL ADHESION MOLECULES (CAM) Integrins: adhesion to endothelium and extracellular matrix (VLA-1 to 6, LFA-1) CAM of the immunoglobulin supergene family: various (ICAM-1-3, VCAM-1, PECAM-1, NCAM, CEA) Selectins: molecules on leucocytes and endothelium which bind to carbohydrate (E, P, L-selectins, ) 8

  9. CELL ADHESION MOLECULES (CAM)-2 Cadherins: bind to catenins, cytoskeleton elements in calcium dependent manner (E, N,T-cadherins) CD44 and it variants: cell hyaluronate receptor involved in cell-to-cell and cell-to-matrix interactions 9

  10. LEUCOCYTE-ENDOTHELIAL CELL INTERACTIONS • Leucocytes interact with the vessel wall in multistep fashion, using several leucocyte surface molecules that recognize their counter-receptors on endothelial cells • The rolling and tethering of leucocytes on vessel wall is mediated by selectins (a subtype of cell adhesion molecules) 10

  11. LEUCOCYTE-ENDOTHELIAL CELL INTERACTIONS -2 • Chemokines and their receptors are needed to activate leucocyte integrins • Only activated integrins are able to mediate firm adhesion between leucocytes and endothelium • The transmigration of leucocytes into the tissues requires proteinases and repair mechanisms 11

  12. Subdivision of T lymphocytes • T helper (CD4+) • Th1 • Th2 • Treg (CD25, Foxp3) • Th17 • T cytotoxic(CD8+) • Tc1 • Tc2 12

  13. CD (CLUSTER DETERMINANTS) CLASSIFICATION • Based on the identification of single epitopes by monoclonal antibodies • Involves mainly differentiation antigens of cells and cell receptors, but also various proteins, enzymes • Most, but not all, CD markers are at cell surface • Actual number of CD markers is above360. 13

  14. EXAMPLES OF CD MARKERS • CD3 TCR signalling complex: T cells • CD4 MHC class II receptor: T cells • CD8 MHC class I receptor: T cells • CD10 neutral endopeptidase: ALL cells • CD19 co-receptor subunit: B cells • CD45 LCA (tyrosine phosphatase): leukocytes • CD62L L-selectin: T cells, mono-, granulocytes • CD247 zeta chain of TCR : T cells, NK cells 14

  15. CD4 Th1 and Th2 T cells:profile of produced cytokines Th1Th2 IL-2IL-4 IFN-gammaIL-5 TNF-beta IL-6 IL-10 IL-13 15

  16. T CELL ACTIVATION-EARLY STEPS • Formation of immunological synapse – lymphocyte polarization, adhesion to APC, maturation of synapse • Microdomains (lipid rafts) – regions of cell membranes rich in lipids: contain several proteins able for fast signal transduction, kinases from Src family, and other 16

  17. T CELL ACTIVATION-EARLY STEPS-2 • Lymphocyte activation leads to microdomain grouping- so called supramolecular activation clusters-SMAC • First (Ag-TCR) and second signal (CD28-CD80, CD86, CD58-CD2) concept; naive lymphocytes need 2 signals, activated cells – only the first one 17

  18. INTRACELLULAR SIGNALING IN T CELL ACTIVATION • Involves transduction of signals from both T cell receptor and CD28 • CD4 bound lck kinases become activated by CD45 phosphatase • ITAM (Immunoreceptor Tyrosine-based Activation Motif) domains of CD3 (zeta chains) become phosphorylated by lck 18

  19. INTRACELLULAR SIGNALING IN T CELL ACTIVATION • ITAMs associate with other kinases such as ZAP-70 and fyn • Fyn activates phopholipase C (PLC) which cause release of intracellular calcium (calcium flux) • Calcium binds to calcineurin and activates transcription factors (NF-AT, NF-kappa B, AP-1) 19

  20. LAT signaling pathology (LSP) • LAT - Linker for activation of T cells • Functional defect of Lat gene results in – • Lymphoproliferative syndrome – LSP • It is manifested by polyclonal proliferation of CD4+ T cells, secreting chronically in excess cytokines typical for Th2 response 20

  21. SIGNALING IN B CELL ACTIVATION • Tyrosine kinases lck, lyn ,fyn become activated via Ig and Ig of B cell receptor • They phosphorylate BCR ITAM domains • These can then bind Syk, another kinase, which activates phospholipase C (PLC-) 21

  22. WHAT ARE TRANSCRIPTION FACTORS? • Answer: transcription factors are complex protein molecules residing in cytoplasm, which after stimulation and assembly are able to enter cell nucleus and induce several genes transcription. • The most common: NF-κB, NF-AT, AP-1 22

  23. LYMPHOCYTE RECIRCULATION • Lymphocytes recirculate continuously between blood and lymphoid organs • 80% of lymphocytes enter the lymph nodes via specialized vessels called high endothelial venules (HEV) • The remaining lymphocytes enter the lymph nodes together with dendritic cells and antigens via afferent lymphatics 23

  24. LYMPHOCYTE RECIRCULATION - 2 • Lymphocytes leave the lymph nodes via efferent lymphatics • Lymphocyte recirculation allows the lymphocytes to meet their cognate antigens and other leukocyte subsets to evoke an efficient immune response 24

  25. IMMUNOGLOBULINS KEY CONCEPTS • Isotype: antigenic differences between classes, subclasses and types • Allotype: antigenic differences between Ig constant domains of various individuals • Idiotype: antigenic differences within variable domains reflecting antigen binding site 25

  26. IMMUNOGLOBULINS KEY CONCEPTS - 2 • Isotype (class)switching: the change of produced Ig (from IgM to other Ig), usually in secondaryimmune response • Polyclonal Ig: a mixture of Igs having either kappa or lambda chains (3:1 ratio in humans) • Monoclonal Ig: either kappa or lambda light chain – incidence in tumors such as myeloma, or produced in vitro (monoclonal Abs) 26

  27. Main Immunoglobulin Classes • IgG – the most abundant Ig. Exists in 4 subclasses (IgG1, IgG2, IgG3, IgG4) • IgA – exists as serum and secretory Ig present on mucosal surfaces, 2 subclasses (IgA1 and IgA2). • IgM – present in bloodstream is composed of 5 molecules forming pentamer. Protects from sepsis. Produced mainly in spleen. 27

  28. Immunoglobulin classes - 2 • IgD –with IgM forms antigen receptor on B cells. In serum in trace amounts. • IgE – anti-parasitic. Participates in allergic reactions. Very short lifetime when free, but stable when bound to cell surface such as mast cells. 28

  29. FEATURES OF IMMUNOGLOBULIN SUPERFAMILY • Large family of ancestrally related genes-probably >100 (MHC molecules, TCRs, some cytokine receptors etc.) • Most products involved in immune system function or other cell – cell interactions 29

  30. THANK YOU!Sorry for a huge amount of difficult new data and terms! 30

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