Ahmad Shihada Silmi Hematologist & Immunologist IUG Cytokines Ahmad Shihada Silmi Hematologist & Immunologist IUG

General Characteristics Mediate and regulate the immune system Secretion is brief and self-limited Individual cytokines are produced by multiple cell types Act of multiple cell types-pleiotrophic (PLEITROPISM): one type of cytokine may act on several different cell types.

General Characteristics Actions are redundant (REDUNDANCY): different cytokines may have the same effect.

General Characteristics Effect synthesis and actions of other cytokines. (SYNERGY): two or more different cytokines may have a greater than additive effect. (ANTAGONISM): one type of cytokine may the action of another type of cytokine.

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 Activities Established Thru Recombinant Cytokines (Simplistic Approach), In Vivo Function Can Vary

General Functions 1- Mediators of natural/innate immunity Produced mainly by mononuclear phagocytes in response to infectious agents. Act on endothelial cells ( production of adhesion molecules for B-cells and T-cells to bind to and or leukocyte activation ); main members of this group are: TNF ( tumor necrosis factor): Causes endothelial cells to produce adhesion molecules for lymphocytes and secret chemokines ( guide leukocytes to the site of inflammation “chemotaxis “ ). Causes fever. B. IL-7: similar / same effect as TNF. C. IL-6 D. IL-8 E. INF-γ: causes activation of macrophage.

General Function II- MEDIATORS & REGULATORS OFADAPTIVE IMMUNITY Produced mainly by T-lymphocytes in response to specific regulation of antigen. Act on lymphocyte to induce growth & differentiation during the activation phase at T-cell dependent immune response. Also act on EFFECTOR CELLS (such as mononuclear phagocytes, neutrophil and eosinophils) in the effector phase of adaptive immune response. These are divided into:

A- ACTIVATORS OF CYTOTOXIC RESPONSE: Induction of macrophage cytotoxic T cell & NK cell activation. Main members of the group: IL-2:causes exponential proliferation of T cells after recognition of antigen IL-3 INF-γ: similar effect to IL-2 LT ( lymphotoxin): similar effect to TNF, thus as a link between T-cell activation & inflammation.

B- ACTIVATORS OF HUMORAL RESPONSE: Induction of B-cell activation Main members of the group: IL-2: is produced by T-cells, thus have similar gene effect on B-cells IL-3 IL-4: similar/ same effect as IL-2, and also cause isotype switch to IgE. IL-5: causes isotype switch to IgA IL-6: causes B-cells differentation to plasma cells TGF-B (Transforming Growth Factor- β): causes isotype switch towards IgA INF-γ: cause isotype switch towards IgG

General Function III- Activators of inflammatory cells Type II IFN IFN-g

General Functions VI- Stimulators of hematopoiesis Produced by BONE MARROW STROMA CELL & leukocyte to stimulate growth & differentation of immature leukocytes. Main members of the group. A. IL-3: causes induction of all principal hematocytes. B. IL-7: induction of B- and T- lymphocytes. C. CSF (STEM CELL FACTOR ) :induction of all principal hematocytes. D. GM-CSF (granulocyte –monocytes –CSF. E. M-CSF (MONOCYTE-CSF ). F. G-CSF (GRANULOCYTES-CSF ).

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

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

Hematopoietin Receptor Family (Class I)

Th17 and Treg Cells Treg (CD4+, Foxp3+) Th17 (CD4+, FoxP3-) IL-17 is a pro-inflammatory cytokine Promotes secretion of pro-inflammatory cytokines (IL-6) from fibroblasts, epithelial and endothelial cells. Th17 cells are critical to anti-bacterial immunity. Over expression of IL-17 is associated with rheumatoid arthritis, SLE, MS and asthma Treg (CD4+, Foxp3+) Natural (develop in the thymus) Prevent effector T cell development in LN Induced (develop in the periphery) Develop under the influence of TGF-ß Inhibit effector T cell function in periphery.

Regulation of Cytokines Chromatin Structure (Regulation of expression)

Cytokine Therapies Suppression of TH-cell poliferation and TC-cell activation