医学免疫学课件：Complement and system lupus erythematosus

1、Complement and system lupus erythematosusIntroductionComplement systemSystemic lupus erythematosus(SLE)C1q deficiency & SLEC2&C4 deficiency & SLEMechanisms & HypothesisThe activation pathways and regulation of complement systemThe functions of complement systemOpsonizationClearance of ICsConnection

2、of innate immunity and adaptive immunityComplement dependent cytotoxicitySLEManifestations & Features:Autoantibodies: anti-nuclear antibodies, anti-phospholipid antibodies, etc.Injury to the skin, joints, kidney, and serosal membranes is prominent.Every other organ in the body may also be affexted.F

3、airly common, 1 in 2500 in certain populations.Predominantly affects women, 1 in 700 among women of childbearing age. SLEPathogenesis:Genetic factors:Higher rate of concordance(20%)in monozygotic twinswhen compared with dizygotic twins(1% to 3%).Inherited deficiencies of early complement components,

4、such as C2, C4, or C1q. SLEPathogenesis:Immunologic factors:Failure of self-tolerance in B cellsCD4+ helper T cells specific for nucleosomal antigens also escape tolerance and contribute to the production of high-affinity pathogenic autoantibodies. SLEPathogenesis:Environmental factors:Exposure to u

5、ltraviolet(UV) lightSex hormones(gender bias)Drugs, such as hydralazine, procainamide, and D-penicillamine can include and SLE-like response in humans. Complement Deficiencies in Systemic Lupus Erythematosus.Angela R. Bryan & Eveline Y. Wu Springer Science+Business Media New York 10 May 2014Compleme

6、nt Deficiencies in Systemic Lupus ErythematosusClinical presentation of human C1q deficiency: How much of a lupus? Mihaela Stegert a, Merete Bock a, Marten Trendelenburg Molecular Immunology 67 (2015) 311C1q deficiencySchejbel, L., Skattum, L., Hagelberg, S., Ahlin, A., Schiller, B., Berg, S., Genel

7、, F., Trueds- son, L., Garred, P., 2011.Molecular basis of hereditary C1q deficiency revisited: identification of several novel disease-causing mutations. Genes Immun. 12, 626634. C1q deficiencyLewis MJ, Botto M. Complement deficiencies in humans and animals: links to autoimmunity. Autoimmunity. 200

8、6;39(5):36778.Jonsson G et al. Rheumatological manifestations, organ damage and autoimmunity in hereditary C2 deficiency. Rheumatology (Oxford). 2007;46(7):11339.C2 deficiencyJonsson G et al. Rheumatological manifestations, organ damage and autoimmunity in hereditary C2 deficiency. Rheumatology (Oxf

9、ord). 2007;46(7):11339.C2 deficiencyJonsson G et al. Rheumatological manifestations, organ damage and autoimmunity in hereditary C2 deficiency. Rheumatology (Oxford). 2007;46(7):11339.C2 deficiencyC4 deficiencyYang Y, Chung EK, Wu YL, et al. Gene copy-number variation and associated polymorphisms of

10、 complement component C4 in human systemic lupus erythematosus (SLE): low copy number is a risk factor for and high copy number is a protective factor against SLE susceptibility in European Americans. Am J Hum Genet 2007;80:103754.Yang Y, Chung EK, Wu YL, et al. Gene copy-number variation and associ

11、ated polymorphisms of complement component C4 in human systemic lupus erythematosus (SLE): low copy number is a risk factor for and high copy number is a protective factor against SLE susceptibility in European Americans. Am J Hum Genet 2007;80:103754.FC : female unrelated controlsFF : female first-

12、degree relativesFP : female patients with SLE0: 6.5% in FP;1.3% in FC1: 26% in FP; 18.2% in FC2,3,4: 15.3% in FP; 23.8% in FCOverall, the pattern of C4A GCN distribution in female patients with SLE was significantly different from that in unrelated healthy controls(x2=25.1;df=5;P=0.00014)No signific

13、ant differences in C4B GCN distribution patternsWere observed among FP, FF, and FC.Mechanisms & Hypothesis:Waste Disposal HypothesisDisruption of Tolerance InductionDysregulation of Cytokines Lewis MJ, Botto M. Complement deficiencies in humans and animals: links to autoimmunity. Autoimmunity. 2006;

14、39(5):36778.Disruption of Tolerance InductionA protective role for innate immunity in systemic lupus erythematosusMichael C. CarrollDysregulation of cytokinesLood C et al. C1q inhibits immune complex-induced interferon- alpha production in plasmacytoid dendritic cells: a novel link between C1q defic

15、iency and systemic lupus erythematosus patho- genesis. Arthritis Rheum.2009;60(10):308190. Reference1.Complement Deficiencies in Systemic Lupus Erythematosus.Angela R. Bryan & Eveline Y. Wu Springer Science+Business Media New York 10 May 20142.Urowitz MB, Gladman DD, Ibanez D, et al. Evolution of di

16、sease burden over fiveyears in a multicenter inception systemic lupus erythematosus cohort. Arthrit CareRes 2012;64:1327.3.Clinical presentation of human C1q deficiency: How much of a lupus? Mihaela Stegert a, Merete Bock a, Marten Trendelenburg Molecular Immunology 67 (2015) 3114. Arkwright PD, Ril

17、ey P, Hughes SM, et al. Successful cure of C1q deficiency in human subjects treated with hematopoietic stem cell transplantation. J Allergy Clin Immunol 2014;133:2657.5.Schejbel, L., Skattum, L., Hagelberg, S., Ahlin, A., Schiller, B., Berg, S., Genel, F., Trueds- son, L., Garred, P., 2011.Molecular

18、 basis of hereditary C1q deficiency revisited: identification of several novel disease-causing mutations. Genes Immun. 12, 626634. 6. Toller-Kawahisa JE, Vigato-Ferreira IC, Pancoto JA, et al. The variant of CD11b,rs1143679 within ITGAM, is associated with systemic lupus erythematosus andclinical ma

19、nifestations in Brazilian patients. Hum Immunol 2014;75:11923.Reference7.Lewis MJ, Botto M. Complement deficiencies in humans and animals: links to autoimmunity. Autoimmunity. 2006;39(5):36778.8. Angela R. Bryan & Eveline Y. WuComplement Deficiencies in Systemic Lupus ErythematosusCurr Allergy Asthma Rep (2014) 14:448；9.Jonsson G et al. Rheumatological manifestations, organ damage and autoimmunity in hereditary C2 deficiency. Rheumatology (Oxford). 2007;46(7):11339.10.Yang Y, Chung EK, Wu YL, et al. Ge