Download Notes on Cytokines

CYTOKINES
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IFN-α and IFN-β:
Released by phagocytes in response to TLR-3 binding viral dsRNA
o Protects uninfected cells (inhibits translation of viral mRNA)
o Activates NK cells (kill virus infected cells)
o Increase expression of MHC class I (promote killing by Tc cells)
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IFN-γ:
Produced by TH1 cells
o Activates macrophages and NK cells
o Upregulates MHC class II
o Induces B cells to produce IgG3 (complement)
o Inhibits formation of TH2 and TH17 cells
Involved in class switching
Inhibited by cyclosporine and tacrolimus
Produced by NK cells (Kong’s Tumor Immunity lecture)
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IL-1:
PROINFLAMMATORY
Released by activated macrophages; released by dendritic cells in response to uptake of infectious agents
o Local: activates endothelium and lymphocytes
o Systemic: induces fever and stimulates IL-6 production
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IL-2:
Growth factor for T cells (CD4, CD8) and NK cells
Produced by CD4+ cells (TH1) and SOME CD8+ cells
o Discrepancy between Kong and Sundick’s notes
o Sundick’s response: some CD8+ T cells produce IL-2 and therefore do not need CD4 to provide it I
Interaction of CD28 (T cells) and B7 (APCs) stimulates T cell and its production of IL2
o B7 interaction:
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Increases transcription of IL-2 mRNA
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Increases half-life of IL-2 mRNA
Production decreased by interaction of CTLA4 and B7
Inhibited by cyclosporine and tacrolimus
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IL-3:
Macrophage differentiation in the bone marrow (similar to GM-CSF)
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IL-4:
Parasitic worms and allergens stimulate synthesis of IL-4, promoting formation of TH2 cells
TH2 cells release IL-4
o Induces B cells to produce IgE and IgG4 (along with IL-13)
o Prevents development of TH1 and TH17 cells
Involved in class switching
IL4 gene cluster possibly involved in genetic component of allergy
Released as a preformed substance from mast cells during type I hypersensitivity
Inhibited by cyclosporine and tacrolimus
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IL-5:
Released by TH2 cells
o Growth factor for eosinophils
Released as a preformed substance by mast cells during type I hypersensitivity
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IL-6:
PROINFLAMMATORY
Released by activated macrophages
o Local: activates lymphocytes and increases Ab production
o Systemic: induces fever; induces liver to produce acute phase proteins (CRP, MBL, SPA, SPB-opsonize
bacteria, activate complement)
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IL-7:
Required for development of B cells from stem cells (along with stromal cells)
Required for development of T cells in the thymus (along with contact from dendritic and epithelial cells)
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IL-8:
Released by activated macrophages
o Chemokine that attracts PMNs, basophils and T cells
Released as a preformed substance in mast cell granules during Type I hypersensitivity
o Chemokine that attracts PMNs
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IL-10:
Release of IL-10 + TGF-β by Treg cells suppresses the formation of TH1, TH2 and TH17 cells
Activated TH2 cells released TGF-β, IL-4 and IL-10 [discrepancy between Kong and Sundick]
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IL-12:
Released by activated macrophages; released by dendritic cells in response to uptake of infectious agents
o Activates NK cells (kill virus infected and tumor cells; cells that are deficient in MHC I)
o Induces CD4+ TH0 cells to become TH1 cells
Produced by NK cells (Kong’s Tumor Immunity lecture)
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IL-13:
Released by TH2 cells
o Induces B cells to produce IgE and IgG4 (along with IL-4)
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IL-17 + IL-22:
Released by TH17 cells
o Recruit and activate PMNs
o Induce epithelial cells to produce proinflammatory cytokines (IL1, IL6, TNFα)
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IL-21:
Release of IL-21 + TGF-β by dendritic cells leads to formation of TH17 cells
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TGF-β:
Release of IL-21 + TGF-β by dendritic cells leads to formation of TH17 cells
Release of TGF-β alone by dendritic cells leads to formation of Treg cells
Treg cells release TGF-β + IL-10 to suppress the formation of TH1, TH2, and TH17 cells
Activated TH2 cells released TGF-β, IL-4 and IL-10 [discrepancy between Kong and Sundick]
Can be secreted by tumor cells in tumor-induced immunosuppression (suppress T cell function)
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TNF-α:
PROINFLAMMATORY
Released by activated macrophages; released by dendritic cells in response to uptake of infectious agents
o Local: activates vascular endothelium by inducing adhesion molecules- selectins (E), ICAMs (E),
integrins (L); induce permeability (promotes diapedesis)
o Systemic: fever and shock
Produced by NK cells (Kong’s Tumor Immunity lecture)
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TNF-β (Lymphotoxin):
Promotes diapedesis of fresh macrophages to site of infection
Released by activated TH1 cells in delayed-type hypersensitivity reaction against tissue grafts (cytotoxic to graft)
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GM-CSF:
Released as a preformed substance by mast cells during type I hypersensitivity
Macrophage differentiation in bone marrow
OTHER MOLECULES:
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C5a: chemotactic factor for PMNs; vasoactive; activate mast cells
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C3a: vasoactive; activate mast cells
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C2b: buildup causes swelling (as seen in C1 inhibitor deficiency- hereditary angioneurotic edema)
ECF: eosinophilic chemotactic factor; preformed substance in mast cells
Thromboxanes/Prostaglandins: chemotactic for PMNs and eosinophils
CELL MARKERS:
T Cells:
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TCR Complex:
o TCR: heterodimer Ag-specific receptor (first signal necessary to activate T cells)
o CD3: pan T cell marker; signal transduction, transports TCR to cytoplasmic membrane; invariant
o Zeta chains (2): signal transduction; invariant
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CD2: pan T cell marker; lymphocyte adherence and signaling
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Integrins (LFA-1 and VLA-4): adherence to APC and endothelial cell
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CD62L/L-Selectin: homing molecule that binds addressins on the endothelium; facilitates migration of T cell into LN
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ICOS: interacts with ICOSL on B cell; facilitates germinal center formation in LNs and other lymphoid tissue
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CD4: on Th cells; stabilizes binding and involved in signaling
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CD8: on Tc cells; stabilizes binding and involved in signaling
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CD28: binds B7 on APC (required for activation of T cell)
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CTLA4/CD154: upregulated in activated T cells; interaction with B7 on APC shuts down T cell
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Class I MHC: on all nucleated cells
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FasL: on CD8+ T cells; allows for killing of Fas+ cells
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CCL2 (MCP-1): allows for migration of TH1 cells to site of infection
B Cells:
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BCR: Ig + Igα and Igβ (signal transduction molecules associated with the Ig H chain)
B-Cell Co-Receptor:
CD21: binds C3dg (cleavage product of C3b) on bacteria to increase Ag signaling 100x; also a receptor for the
Epstein Barr Virus
CD19
CD81
CD22: downregulate B cell activity
CD32: downregulate B cell activity (bind Ag-Ab complexes)
CD5: on the surface of B-1 cells
B7: interacts with CD280 (stimulation) or CTLA4 (inhibition) on T cells
CD40: interacts with CD40L on T cells to allow for Ab class switching
FcR: receptor for Fc portion of Igs (one for each class); delivers signal to B cell
Class I MHC: on all nucleated cells
3 loci (A,B,C) encode alpha chain only
Alpha chain combines with invariant beta-2 microglobulin
Alpha3 domain interacts with CD8 on T cells
Alpha1 and 2 domains form CLOSED peptide binding groove (8-9 aa)
Class II MHC: on APCs
3 loci (DP, DQ, DR) encode both alpha and beta chains
Beta2 domain interacts with CD4 on T cells
Alpha1 and Beta1 domains form OPEN peptide binding groove (12-20 aa)
Phagocytes:
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Mannose-Binding Lectin Receptor: binds MBL bound to mannose on bacterial surface (increases binding affinity)
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Mannose Receptor: binds mannose on surface of bacteria
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Surfactant Protein A and D Receptors: binds SPA/SPD bound to bacteria (increases binding affinity)
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Scavenger Receptors: react with lipoproteins
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fMet-Leu-Phe (N-formylated peptides) Receptor: receptor for these peptides, which are chemotactic factors for
phagocytes
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Toll-Like Receptors:
o TLR-4: binds bacterial LPS and triggers activation of NFkB (genes transcribed to fight bacteria)
o TLR-3: binds viral dsRNA triggering synthesis of IFN alpha and beta
o TLR-5: bacterial flagellin
o TLR-9: unmethylated CpG DNA
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TLR1:TLR2 heterodimer: peptidoglycan and zymosan
Leukocytes (General):
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Integrins: bind ICAMs on endothelium and APC (strong binding)
HYPERSENSITIVITY REACTION EXAMPLES:
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Type I:
Systemic anaphylaxis
Allergic rhinitis
Asthma
Food allergies
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Type II:
ABO/Rh incompatability reaction
Myastenia gravis
Grave’s Disease
Penicillin drug allergy (can also be IgE mediated-type I)
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Type III:
Serum sickness
Arthus reaction
SLE
Rhematoid arthritis
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Type IV:
Posion ivy (contact dermatitis)
Tuberculin rejection
Graft rejection
Hashimoto’s Thyroiditis
Multiple Sclerosis
IDDM