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CYTOKINES NETWORK

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  1. CYTOKINES NETWORK • Cytokines are: - Soluble regulators for the immune system (development, function) of effector cells. - Regulate function of other cells in human body (e.g. nervous system cells, endothelial….) - Cells regulated by cytokines must express a receptor for that cytokine. - One cytokine can effect more than one type of cells, (IL-2) can effect the proliferation of T-cells and also effect induce the differentiation of osteoplasts, whereas TNF- inhibits the differentiation of osteoplasts (Pleiotropic properties). - Cytokines act like hormones (synergistic or additive or antagonistic effect). - Cytokines found in blood serum at very low concentrations 10-9-10-12 mg/ml.

  2. CYTOKINES NETWORK Cytokines are proteins with short half life. - Some expressed as membrane-associated (TNF-α,β). - Their action maybe local (autocrine) or can be on other cells (paracrine). - Their effect take place when cytokine binds to its specific receptor on the effected cell. Responded cell may up-regulate or down regulate other IL-receptors (IL-Rs). IL-1 up regulates IL-2R, IFN- up-regulates MHC-I, IL-10 inhibits production of other cytokines. - One cell can secretes many cytokines, same cell may targeted by more than one cytokine. - Cytokines interactions during immune response referred to it as cytokine cascade.

  3. CYTOKINES NETWORK Sources and activities of regulatory cytokines: • CD4 T-cell is the main source of cytokines. Other immune cells and non-immune cells also secrete cytokines. • Ag and resulted cytokine cascade control T-cell differentiation (TH1 or TH2). • TcR binding affinity (weak TH2, strong TH1) may also play a role in T-cell differentiation. FUNCTIONAL CATEGORIES OF CYTOKINES: Cytokines of innate immunity: • Proinflammatory cytokines which include: • IL-1α, IL-6, TNF α (IL-8) • Pro-inflammatory involved in systemic acute phase response.

  4. CYTOKINES NETWORK • Acute phase response characterised by the production of acute phase proteins (CRP) C-reactive proteins. • CRP bind phosphorylcholin on bacteria surface and act as OPSONIN (fix complement). • MBL (mannan binding lectin) another acute phase protein (fix complement-lectin). • IL-1 and IL-6 increase neutrophils circulation in blood. • Pro-inflammatory. Cytokines responsible of Inflammatory responses (swelling, redness, pain) acute inflammation. • Interferons (, and ) play an important role during viral infections. IFN-  and  up regulate MHC-I molecules. Cytokines that affect leukocytes movement: - Chemotactics belong to one family, have amino acids residues responsible for attracting monocytes, neutrophils and lymphocytes.

  5. CYTOKINES NETWORK • Chemotactics include subfamilies e.g. CXC, CC, CX3C, C.. Cytokines that stimulate haematopoiesis: • Cytokines effect the differentiation pathway of pluripotent stem cells. • CSFs (M-CSF,G-CSF and GM-CSF). • IL-3. • IL-7 in bone marrow. Cytokines that regulate adaptive immune response: During T and B cell activation due to Ag-stimulation. Cytokines play +ve or –ve on cell proliferation, differentiation or development. • Mechanism of action involve specific receptors. • Another mechanism involve (cell to cell interact) without activation of antigen non-specific immune response T and B cells, termed (cognate).

  6. CYTOKINES NETWORK Cytokines receptors: • Immunoglobulin superfamily receptors: IL-1 M-CSF. • Class I cytokine receptors: IL-2, IL-3, IL-4, IL-6, IL-13, IL-15, GM-CSF, G-CSF. • Class II cytokine receptors: INFs α,β, and IL-10. • TNF superfamily: TNF-α,β, CD154. TNF receptor-associated factors. • Chemokine receptors (G protein- coupled receptor): IL-8

  7. Complement system • Made up of many circulating proteins. • Complement proteins are important in both innate and acquired immunity (antibody-mediated immunity). • Complement proteins function involve: - Production of opsonins. - Production of anaphylatoxins. - Direct killing of bacteria. - Homeostasis. • Complement proteins synthesised in liver and immune cells like macrophages. • Complement factors or proteins activation can takes place by three pathways. The activation is a sequential activation.

  8. Complement system THE CLASSICAL PATHWAY: • Complement proteins activation initiated by the formation of Ag/Ab complex. Other substances like drugs, venoms and components of bacterial surfaces. C1 binds Ab bound to Ag. ( C1q, C1r and C1s), C1q binds the Ab (Fc region) cause activation to the C1r and C1s. Active form of C1 called C1s esterase. C1s esterase binds C4 and cause splitting of the molecule to C4a and C4b. C4b binds the surface of the Ag. C4a stay in unattached and called anaphylatoxin. C4b binds C2a (C4b2a), C2 activated by C1s esterase by splitting it to C2a and C2b. C2b is anaphylatoxin. C4b2a known as C3 convertase.

  9. Complement system C4b2a will activates C3 into C3a and C3b. C3a is anaphylatoxin and C3b should bind C4b2a3b. THIS STEP IS THE MOST IMPORTANT STEP IN COMPLEMENT ACTIVATION. C4b2a3b also called C5 convertase. C4b2a3b should activates C5 and cause splitting for C5 to C5a and C5b. C5a is anaphylatoxin, C5b should binds the surface of the bacteria. C6 should then binds C5b bound to the surface of the bacteria to form C5b6, C7 comes then to form C5b67 and then comes C8 to complete the construction of C5b678 which acts as a receptor for C9. One C9 binds the complex C5b678 and form C5b6789 more C9 molecules binds the complex to form polymerization for C9. Polymerization of C9 cause channels whitin the membrane of the bacteria causing disturbance in the osmotic equilibrium and finally death. C5b6789 called Membrane Attack Complex (MAC).

  10. Complement system THE LECTIN PATHWAY: • This pathway is activated by the presence of mannose residues (a complex of protein and polysaccharide) found on the surface of many bacteria and funji. • Mannose residues binds a serum complex mannose-binding lectin (MBL) • MBL structurally similar to C1q (found in classical pathway). • Binding of MPL to the pathogen results in the association of two serine proteases MASP-1 and MASP-2 (mannose- associated serine protease), MASPs are similar to C1r, C1s. • The formation of MASP-2 lead to the cleavage of C4 into C4a and C4b which formed during the classical pathway. • C4b then binds C2 to form C4b2 which activated to C4b2a.

  11. Complement system THE ALTERNATIVE PATHWAY: • This pathway activated by most foreign Ag but mostly LPS. • C3 is the first factor to be activated during the alternative pathway. • C3b is spontaneously formed in the circulation by C3 cleavage. C3b can deposit on surface of sells. • C3b formed by any activator and attach to the surface of the Ag (bacteria). • Blood factor B binds C3b to form C3bB. Another blood factor (D) cleaves factor B to become C3bBb. • C3bBb also acts as C3 convertase, it is called the alternative pathway C3 convertase.

  12. Complement system • C3bBb is unstable molecule but stabilised by binding to properdin (factor P). • C3 convertase formation activates more C3b formation. • The pathway then continues as it does in the classical pathway. REGULATION OF COMPLEMENT ACTIVATION: • Uncontrolled complement activation can be catastrophic. • The formation of anaphylatoxins C4a, C2b, C3a and C5a is not favourable due to their actions. • Presence of normal body regulators inhibits continuous activation of complement system. C1 esterase inhibitor (C1INH), binds C1r and C1s and prevent the activation of C4.

  13. Complement system • C1INH also can binds C3bBb formed from alternative pathway. Also inhibits MASP-1 and MASP-2 in lectin pathway. • C4b-bindig protein (C4BP) is another inhibitory regulator. • DAF (decay accelerating factor CD55) is also important in regulating the complement activity. • Membrane cofactor protein (MCP) and complement receptor CR1 (CD35) are all cofactors. • Factor -I which cleaves C4b in to C4c and C4d. C4BP, MCP and CR1 work as cofactors for factor-I (BUT NOT DAF). • Factor H regulates the alternative pathway by binding to C3b and prevent factor B binding. Factor H favours binding human cells because they have sialic acid, whereas bacterial membrane lack sialic acid so factor B is the favourable in this case to bind C3b.

  14. Complement system • Factor H also has another function and this involves binding C3b so factor I can then binds the C3b to form iC3b (inactive) then cleave it to C3c and C3d. In this case factor H as a cofactor for factor I. • Normal cell surface protein associate CD59 prevents lyses of normal cells in case of C5b678 bind its surface. CD59 binds the complex C5b6789 complex and prevent C9 from polymerisation. • Fluid phase protein SP-40 prevents C5b6, C5b67-9 from binding to cell surface.

  15. Complement system BIOLOGICAL ACTIVITIES OF COMPLENT: Production of opsonins: • C3b and C4b are major opsonins, iC3b also shows some opsonic activity (but does not activates complement system). Production of anaphylatoxins: • C3a, C4a and C5a all are anaphylatoxins (C5a most potent), these small fragment play an important role in inflammatory responses. • They increase the permeability of blood vessels and C5a plays a chemotactic role. C5a is a strong chemotactic for neutrophils. Lysis of cells: • It’s a vital activity for killing pathogens.

  16. Complement system Enhansing B-cell responses to Agntigens. Removing immune complexes: Removing dead cells from the body: Responses to viruses: C1 binging to viruses