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Transcript
Complement associated immune disorder Dr. Chen Hung Chen ( 陳 政 宏 ) Division of Rheumatology, Immunology and Allergy Department of Internal medicine Tri-Service General Hospital Introduction of Complement system: Definition: • A group of sequentially reacting proteins, which upon activation, mediate a number of biological reactions important to host defense Nomenclature: • • • • • “C”-designation for 11 of complement proteins( C1, C2, etc) “Factor”-designation for many alternative pathway components( factor B) Overbar-indicates an enzymatically active protein or complex Lower case letters-indicates a proteolytic cleavage fragments(C3a, C5a) “R”-designation for receptors in the complement system(CR1, CR2) Complement Biosynthetic Sites • • • • • • • • • Hepatocytes Monocyte/Macrophage Hematopoietic Fibroblasts Endothelial Reproductive Adipocytes Astrocytes Neurons Modular Structure of Complement Proteins • Enzymes-(Serine Protease Domain) C1s, C1r, C2, MASP 1/2,factor B, D, I • Collectins-(Collagen Stalk, Gobular Domain) C1q, MBL, Ficolin • Cytolytic-(C9/Perforin Domain) C6, C7, C8, C9 • Regulatory and Receptor (SCR Domain) DAF, MCP,C4BP,CR1 & factor H • “True” Complement Proteins C3,C4,C5 Protein of the Complement System Activation Serum Soluble Membrane Bound C1q, C1r, C1s, C2-C9, Factor B & D,MASP1/2 sMAP, ficolin Regulation Receptors C1-INH, C4BP Factor H & I Properdin,S protein(vitrone ctin), Sp40(clusterin) CR1,CD59, DAF(CD55), MCP(CD46) CR1-CR4 C3aR, C5aR C1qR Complement Activation • Classical PathwayAg-Ab complexes • Mannan-Binding Lectin PathwayMannose, N-acetylglucosamine • Alternative PathwayLPS, lipopolysaccharides Complement-fixing potential of Ab: IgM>IgG3>IgG1>IgG2>IgG4 Transmission EM of the C1q (left) and C1r-C1s complex (right) Properdin (C3aBbP) (C3bBbC3bP) (Potent chemotactant) Initiates the assembly of MAC “Classic doughnut hole formation” (C4b2a) (C4b2a3b) (Initiates by C3b5b) C3 convertases C5 convertases (C3bBbC3bP) (C3bBbC3bP) Complement regulatory proteins & primary location Fluid phase -C1-INH -Factor I, H, C4-bp, S protein (vitronectin), SP-40 (clusterin) -Carboxypeptidase Cell membrane -DAF (CD55) -MCP (CD46) -Protectin (CD59), membrane C3-proteinase Matrix -Decorin Complement Activation Regulation CLASSIC MBP ALTERNATIVE C4-bp:Cofactor for factor I C1-INH:inactivate C1r,C1s, MASPs Factor I: inactivate C3b, C4b Factor H: cofactor for Factor I DAF(CD55):Bind C3&C5convertase MCP(CD46): cofactor for factor I, bind C3& C5 convertase CR1(CD35): combine activities of factor H, C4bp,MCP & DAF C3a C3 C3b Vitronectin: Bind C5b67 & C9 to prevent membrane insertion Protectin(CD59): Bind C5b-8, C5b-9 to prevent pore formation Carboxypeptidas e:inactivate C3a & C5a C5a C5 C5b+C6-9(MAC) Clinical relevant biologic activities of complement Foreign organism, antigen RBC Tumor cells Blood vessels Heart Reproduction Lymphocyte Opsoniztion for phagocytosis by PMN, Monocyte, macrophage, lysis; in vivo trafficking Lysis( intavascular or extravascular) Immune complex trafficking Promotion of ADCC activity Promotion of NK activity Lysis Atherosclerosis Ischemia-reperfusion injury Antibody-mediated infertility, recurrent fetal loss Coactivation, antigen present Autoimmune and/or inflammatory disease Renal CNS Joints Platelets Blood vessels Skin Pulmonary Xenotransplantation Allotransplantation Mediates GN, proteinuria, stimulation of collagen & cytokine synthesis & cellular influx Demyelination in MS, Ab-mediated neuropathies Alzheimer’s disease Recruitment & activation of PMNs Activation of clotting pathway; Immune thrombocytopenia Immune complex vasculitis; neutrophil chemotaxis, binding and activation Ab-mediated inflammation ARDS by anaphylatoxin-mediated neutrophil activation Hyperacute rejection Chronic rejection Inflammatory Disorder associated with Complement Activation • Severe trauma, burn, sepsis • • Systemic inflammatory • reaction syndrome (SIRS) • • Adult respiratory distress syndrome (ARDS) • • Multiple organ dysfunction • syndrome (MODS) • • Ischemia reperfusion injury • • Angioedema, capillary leakage syndrome Hyperacute graft rejection Vasculitis, nephritis Autoimmune disorder, systemic lupus erythematosus Rheumatoid arthritis Multiple sclerosis Alzheimer’s disease Reaction to dialysis, apheresis, cardiopulmonary bypass Vasculitis & Immune complex disease • Local deposition of C3, C5b-9 and/or alternative pathway components. • Evidence of systemic depletion ( low C3, C4 or THC ) • Associated Disease: Immuneocomplexes disease, PAN, hypersensitivity vasculitis, vasculitis and GN in SLE HSP( alternative pathway activation:C3, properdin with IgA) except: Wegener’s or lymphomatoid granulomatosis: no local complement deposition or systemic depletion Rheumatoid arthritis Synovial fluid: ↓THC, ↑C3d, C3a, C5a, C5b-9 Pulmonary disease C3a and C5a induce neutrophils activationpulmonary injury MAC stimulating endothelial cell relieve thromboxanes increase adhesion molecule expression & pulmonary hypertensive change SLE with interstitial lung disease C1q, C3 with IgG, IgM deposition Renal disease Protective role: trafficking of ICs from kidney by binding to CR1 on RBC Detrimental role: complement activation without cell reflux (membranous), with cell reflux (membranoproliferative) e.g.: In MPGN, ↑C3 nephritic factor C5b-9 on cells increase collagen synthesis & thromboxanes and other proliferative molecules Platelet disease: ITP C5b-9 has potentially profound effects on its functionincrease thromboxane synthesis, activation of protein kinase C and myosin light-chain kinase Hemolytic anemia: Intravascular hemolytic anemia: alloimmunization during prior transfusions Extravascular hemolysis :in liver & spleen of opsonized cells by Fc & complement receptor HUS: 1/3 pts have hypocomplementemia & poor prognostic indicator Myocardial disease: ↑serum complement activation products in unstable angina ↑C3, C4, C5, C5b-9 & ↓CD59 & DAF in infracted zone reperfusion injury cause complement activation Atherosclerosis: C5b-9 & activated C3 found in lesion, ↑complement regulatory protein expression on Mac in lesion C5a promote peripheral vasoconstriction Cutaneous disease: SLE: C3 with Ig deposition(even in non-involved area) Evidence of complement activation: Autoimmune bullous disease(Pemphigus, bullous pemphigoid, epidermolysis bullosa) Acne: C3 in basement zones Psoriasis: C3a, C5a in lesion & complement activated products in serum Reproduction & pregnancy: Complement-fixing antibodies with specificity for paternal determinants on sperm mediate infertility High levels of complement regulatory protein on reproductive system prevent uncontrolled complement activation (e.g.: DAF, MCP,CD59) Myositis: DM : C5b-9 with IgG, IgM, C3 deposition in venules & arterioles PM: C5b-9 in muscle fiber Neurologic disease: Asceptic meningitis :↑in C3, C4: CSF/plasma index MS’s CSF: ↑C3a, C4a & ↓C9 SLE’s CSF :↑C5b-9 Alzheimer’s disease:↑C4d, C1q & C5b-9 in brain Xenotransplantation: Immediate hyperacute rejection: mediated by performed Abs and/or complement Chronic rejection: unclear Tumor resistance to complement: Increase complement regulatory protein level in some malignancies, e.g. MCP, DAF, CD59 provide tumor cells to escape the evasion of Ab or enhanced ADCC & NK activity mediated by C3b and/or C3bi bound to the tumor cell Disease in which complement inhibitors will probably be effective •Some forms of vasculitis •RA •ARDS •SLE •Many types of renal diseases •ITP •Hemolytic anemia •Myocardial infacion •Neurologic disease( possibly Alzheimer’s disease) •Ischemia-reperfusion injury •Antiphospholipid syndrome & recurrent fetal loss •Ab-mediated cutaneous disease •Xenotransplant rejection •Allotransplant rejection(? Accelerated atherosclerosis) Selected Complement Activation Inhibitors Under Development Product TPO10, TPO20 Description Actions Company sCR1 without(TPO10) or with sLe* Degrade C3b/C4b, decay Avant Immunotherapeutics TPO20 C3 & C5 convertase, TPO20 (Needham, MA) block selectin binding h5G1.1 Humanized, high-affinity anti-C5mAb Blcok cleavage of C5 to C5a & as single-chain Fv or intact mAb APT070 CAB-2 C1q RNA aptamers Amino-terminal 3 SCR of CR1 C5b by C5 convertase Alexion Pharmaceuticals (New Haven, CT) Inserts in cell membranes and AdProTech myristoylated at the carboxyl provides intrinsic protection (Royston, Herts, UK) terminus via CR1-like mechanisms Soluble recombinant chimera of Degrades C3b/C4b and Millenium Pharmaceuticals MCP & DAF decays C3 & C5 convertases (Cambridge, MA) Small molecule inhibitors of C1q Block C1q NeXstar Pharmaceuticals (Boulder, CO) C1q analogs Low-molecular-weight inhibitor of Block C1q Gliatech(Cleveland, OH) Inhibit AP activation BioCryst Pharmaceuticals beta-amyloid-induced activation of C1q Serine protease Low-molecular-weight inhibitors of factor D (Hoover, AL) Thanks for your attention!
