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CYTOKINES AND RECEPTORS DR SANJITA DAS

Learn about cytokines, low molecular weight proteins that regulate immune responses. Understand their actions, categories, receptors, and role in innate and adaptive immunity.

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CYTOKINES AND RECEPTORS DR SANJITA DAS

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  1. CYTOKINES AND RECEPTORSDR SANJITA DAS

  2. What Is A Cytokine? • Low molecular weight proteins (30 KDa) • Bind receptors, alter gene expression • Can bind the secreting cell (autocrine) • Can bind another cell close by (paracrine) • Few cases bind another cell far away (endocrine) • Very low Kd receptors (10-10-10-12 M) • Cytokines regulate immune responses

  3. Cytokines • Cytokines can activate many cells • Ex. Cytokines secreted by TH can affect B-cells, CTLs, M, NK • A cytokine can be pleiotropic (different effect on different cells) • Synergism, redundancy, antagonism • Interleukins, monokines, lymphokines, chemokines, term CYTOKINE includes all of them

  4. Innate and adaptive Immunity

  5. Autocrineaction act on cytokine-producing cell itself Paracrine action act on a nearby cell circulation Endocrine action act at a distance from the site of infection Cytokine actions may be local and systemic

  6. Cytokine Categories • 4 Categories • TNF family • Chemokine family • Interferon family • Hematopoietin family • Hematopoietin family • -helical structure prevalence • Little or no -sheet • Ex. IL-2 and IL-4 • Amino acid sequences vary considerably

  7. Cells That Make Cytokines And Their Function • A Variety Of Cells Are Capable Of Making Cytokines • However The Biggest Producers: M and TH • Cytokines Are Involved In • Hematopoiesis • Adaptive Immunity • Innate Immunity • Inflammation • See Appendix For Complete List And Function • Activities Established Thru Recombinant Cytokines (Simplistic Approach), In Vivo Function Can Vary

  8. Cytokines Are Non-Specific • How Does Immune Specificity Fit With Non-Specific Cytokines • Answer 1: Thru Receptors • Receptors Expressed On Antigen Activated Cells • Answer 2: Close Proximity To Cytokine Secreting Cells. • Ex. APC-TH • Cytokine Concentrations (TH) Are High Locally • Only Interacting APC Gets Activated • Answer 3: Short Half Life • Short ½ Life Ensures Local Activity

  9. Cytokine Receptors • 5 Major Families • Immunoglobulin Superfamily • Hematopoietin Receptor Family (Class I) • Interferon Receptor Family (Class II) • TNF Receptor Family • Chemokine Receptor Family • Class I and II (Majority Of Receptors) • Multimeric • Upon Receptor Engagement, Tyrosine Phosphorylation

  10. Hematopoietin Receptor Family (Class I)

  11. Receptor Signalling (IFNR) • Ligand Binds  Subunit • Ligand Binding Causes Dimerization of Receptor • JAKs Get Activated • Phosphorylation of tyrosine residues on receptor • Phosphorylation of JAKs themselves • STATS Dock Receptor • Phosphorylation of STATs by JAKs • Dimerized STATs Translocate To Nucleus • Gene Expression

  12. Cytokine Antagonists • Antagonists Exist In 2 Forms • Receptor Antagonists (Bind Receptor, No Activation) • Bind Cytokine (Prevent Cytokine From Binding Receptor) • Well Studied Example: IL1Ra • In Many Cases Antagonist Is A Soluble Receptor • Derived From Proteolytic Cleavage Of Extracellular Domain Of Particular Receptor • IL-2, IL-4, IFN, IFN • Viruses Produce Cytokine Mimics Or Cytokine Binding Proteins • Ex. Poxviruses Produce IL-1-Binding Protein And TNF-binding-protein • These Agents Offer Viruses An Advantage

  13. Microbes Antigen presentation Activation Macrophage Dendriticcell Naïve CD4+T cell CD40 CD40L IL-12 CD8+ T cell NK cell NK cell TH1 cell IFN- Increased cytolytic activity Macrophage activation;killing of phagocytosed microbes Killing of infected cell

  14. 0 1 3 6 Hours after LPS injection Roles of cytokines in innate immunity and inflammation

  15. TH1 vs TH2 • CD4+ TH Cells Secret A Variety Of Cytokines • Evidence For 2 Subsets • TH1 • TH2 • Distinction Is Based On Cytokine Secretion • Cytokine Environment Determines Which Subset Will Develop • IFN for TH1 (IL-12 and IL-18 from M,DCs) • IL-4 for TH2

  16. Transcription Factors TH1 And TH2 • T-bet Expression Results In TH1 • T-bet Suppresses TH2 • GATA-3 Results In TH2 • GATA-3 Suppresses TH1 • IFN- Regulates Expression of T-bet (Stat 1) • IL-4 Regulates Expression of GATA-3 (Stat 6)

  17. Active recruitment of the cells to the sites of infectionrecognition of microbes phagocytosis destruction

  18. TNF Low quantities (plasma conc.<10-9M) Moderate quantities High quantities (plasma conc.10-7M) Systemic effects Septic shock Local inflammation Leukocyte Fever Low output Activation Thrombus Adhesion molecule IL-1,chemokines Endothelial cell Hypoglycemia

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