医学免疫学课件：补体与免疫性身边

1、Complement System and Autoimmune Renal DiseasesOutlineIntroduction of the Complement SystemComplement and Primary Autoimmune Renal DiseasesMembranous NephropathyIgA NephropathyLupus NephritisC3 Glomerulopathy Treatment Introduction of the Complement SystemComplement System: Activation and Regulation

2、BIRMINGHAM D J, HEBERT L A. Semin Nephrol, 2015, 35(5): 444-54.Complement andAutoimmune Kidney DiseasesComplement and Autoimmune Kidney DiseasesAntibody-Initiated Activation of ComplementMembranous NephropathyIgA NephropathyLupus NephritisImpaired Complement RegulationC3 GlomerulopathyMembranous Nep

3、hropathy: IntroductionMajor cause of Nephritic Syndrome2nd or 3th leading cause of end-stage renal diseasePresenting in older demographic groupCharacteristicsThickening of the glomerular capillary walls on light microscopyImmune deposits on the glomerular basement membraneMembranous Nephropathy: Imm

4、une ComplexBeck LH Jr et al. N Engl J Med 2009;361:11-21.Target antigen: M-Type Phospholipase A2 ReceptorAntibody subclass：IgG4Complement components in immune deposits and urine:Membranous Nephropathy: Complement ActivationMBL pathwayMBL can bind N-linked sugars on IgG that do not have terminal gala

5、ctoseAge , hypogalactosylated IgG Alternative Pathway: Loss of HS chains from the GBMBIRMINGHAM D J, HEBERT L A. Semin Nephrol, 2015, 35(5): 444-54.BORZA D-B. Frontiers in Immunology, 2016, 7(157)IgA Nephropathy: IntroductionLeading form of primary glomerulonephritisRecurred in 9-61% of transplanted

6、 patientsCharacteristicsMicroscopic hematuria and proteinuriaMesangial cell proliferation with IgA depositionMAGISTRONI R et al. Kidney international, 2015, 88(5): 974-89.IgA Nephropathy: PathogenesisMAGISTRONI R et al. Kidney international, 2015, 88(5): 974-89.ROBERT T et al. Trends in molecular me

7、dicine, 2015, 21(12): 762-75IgA Nephropathy: Complement ComponentsBIRMINGHAM D J, HEBERT L A. 2015, 35(5): 444-54.IgA Nephropathy: Complement ActivationAlternative pathwayComplement regulator: factor H and factor H related proteins (CFHR)Genetic variants: CFH, CFHR3, CFHR1MBL pathwayAberrant O-linke

8、d glycosylation of IgA1Associated with MALT: SIgA co-localized with MBLMore severeLi Zhu et al. JASN 2015;26:1195-1204Lupus Nephritis: IntroductionAssociated with systemic lupus erythematosus (SLE)60% of adults with SLEMost important predictor of mortality in patients with SLEEncompassed various pat

9、terns of renal diseasesglomerular pathologytubulointerstitial pathologyLupus Nephritis: Contradictory roles of complementComplement-mediated protectionClassic pathway: clearance of cellular debris, deficiency is the strongest genetic factor for SLEMake immune complex smaller: less pathogenicErythroc

10、yte CR1: immune adherence, preventing abnormal deposition of immune complexLupus Nephritis: Contradictory roles of complementComplement-mediated renal injuriesClassical pathwayExcess immune complex formationAnti-C1q: enhancing activationAlternative pathwayLower C3 levels: marker of flareProteinuria

11、cause activation with the tubular lumen: MAC on brush borderBIRMINGHAM D J, HEBERT L A. Semin Nephrol, 2015, 35(5): 444-54.C3 Glomerulopathy: IntroductionComplement-mediated Membranoproliferative Glomerulonephritis1-2 case per million inhabitantsCharacteristicsGlomerular C3 stainingabsent immunoglob

12、ulinsNORIS M, REMUZZI G. Am J Kidney Dis, 2015, 66(2): 359-75.C3 Glomerulopathy: Alternative Pathway OveractivationZIPFEL P F et al. Mol Immunol, 2015, 67(1): 21-30.BIRMINGHAM D J, HEBERT L A. 2015, 35(5): 444-54.TreatmentTreatmentInhibit Complement ActivationAnti-C5 antibody: EcuilizumabAnti-factor

13、 B monoclonal antibodiesCorrect dysregulationBinding complement inhibitor to the sites of activation: CR2-fHProviding factor H：infusion of fresh frozen plasmaConclusionImmune ComplexComplement Pathway OveractionComplement Regulatoractivatefail to inhibitRenal InjuriesReferencesBIRMINGHAM D J, HEBERT

14、 L A. The Complement System in Lupus Nephritis J. Semin Nephrol, 2015, 35(5): 444-54.RONCO P, DEBIEC H. Pathophysiological advances in membranous nephropathy: time for a shift in patients care J. Lancet (London, England), 2015, 385(9981): 1983-92.MATHERN D R, HEEGER P S. Molecules Great and Small: T

15、he Complement System J. Clinical journal of the American Society of Nephrology : CJASN, 2015, 10(9): 1636-50.BORZA D-B. Alternative Pathway Dysregulation and the Conundrum of Complement Activation by IgG4 Immune Complexes in Membranous Nephropathy J. Frontiers in Immunology, 2016, 7(157)MA H, SANDOR

16、 D G, BECK L H, JR. The role of complement in membranous nephropathy J. Semin Nephrol, 2013, 33(6): 531-42.ROBERT T, BERTHELOT L, CAMBIER A, et al. Molecular Insights into the Pathogenesis of IgA Nephropathy J. Trends in molecular medicine, 2015, 21(12): 762-75GHARAVI A G, KIRYLUK K, CHOI M, et al.

17、Genome-wide association study identifies susceptibility loci for IgA nephropathy J. Nat Genet, 2011, 43(4): 321-7.MAGISTRONI R, DAGATI V D, APPEL G B, et al. New developments in the genetics, pathogenesis, and therapy of IgA nephropathy J. Kidney international, 2015, 88(5): 974-89.ZHU L, ZHAI Y L, W

18、ANG F M, et al. Variants in Complement Factor H and Complement Factor H-Related Protein Genes, CFHR3 and CFHR1, Affect Complement Activation in IgA Nephropathy J. J Am Soc Nephrol, 2015, 26(5): 1195-204.WYATT R J, JULIAN B A. IgA nephropathy J. The New England journal of medicine, 2013, 368(25): 240

19、2-14.GHARAVI A G, KIRYLUK K, CHOI M, et al. Genome-wide association study identifies susceptibility loci for IgA nephropathy J. Nat Genet, 2011, 43(4): 321-7.DAHA M R, VAN KOOTEN C. Role of complement in IgA nephropathy J. J Nephrol, 2016, 29(1): 1-4.ROOS A, RASTALDI M P, CALVARESI N, et al. Glomerular activation of the lectin pathway of complement in IgA nephropathy is associated with more severe renal disease J. J Am Soc Nephrol, 2006, 17(6): 1724-34.ESPINOSA M, ORTEGA R, SANCHEZ M, et al. Association of C4d deposition with clinical outcomes in IgA nephropathy J. Clinical journal of the A