title: Autoimmunity to the alpha 3 chain of type IV collagen in glomerulonephritis is triggered by 'autoantigen complementarity'.
abstract: 'Autoantigen complementarity' is a theory proposing that the initiator of an autoimmune response is not necessarily the autoantigen or its molecular mimic, but may instead be a peptide that is 'antisense/complementary' to the autoantigen. We investigated whether such complementary proteins play a role in the immunopathogenesis of autoimmune glomerulonephritis. Experimental autoimmune glomerulonephritis, a model of anti-glomerular basement membrane (GBM) disease, can be induced in Wistar Kyoto (WKY) rats by immunization with the α3 chain of type IV collagen. In this study, WKY rats were immunized with a complementary α3 peptide (c-α3-Gly) comprised of amino acids that 'complement' the well characterized epitope on α3(IV)NC1, pCol(24-38). Within 8 weeks post-immunization, these animals developed cresentic glomerulonephritis, similar to pCol(24-38)-immunized rats, while animals immunized with scrambled peptide were normal. Anti-idiotypic antibodies to epitopes from c-α3-Gly-immunized animals were shown to be specific for α3 protein, binding in a region containing sense pCol(24-38) sequence. Interestingly, anti-complementary α3 antibodies were identified in sera from patients with anti-GBM disease, suggesting a role for 'autoantigen complementarity' in immunopathogenesis of the human disease. This work supports the idea that autoimmune glomerulonephritis can be initiated through an immune response against a peptide that is anti-sense or complementary to the autoantigen. The implications of this discovery may be far reaching, and other autoimmune diseases could be due to responses to these once unsuspected 'complementary' antigens.
authors.affiliation: Renal Section, Department of Medicine, Imperial College London, Hammersmith Campus, London, UK; Institute of Biomedical and Environmental Science and Technology, Department of Life Sciences, University of Bedfordshire, Luton, UK. Electronic address: john.reynolds@beds.ac.uk.
authors.forename: John
authors.initials: J
authors.lastname: Reynolds
authors.affiliation: UNC Kidney Center, Department of Medicine, Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Gloria A
authors.initials: GA
authors.lastname: Preston
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Barrak M
authors.initials: BM
authors.lastname: Pressler
authors.affiliation: UNC Kidney Center, Department of Medicine, Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Hewins
authors.affiliation: UNC Kidney Center, Department of Medicine, Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Brown
authors.affiliation: UNC Kidney Center, Department of Medicine, Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Aleeza
authors.initials: A
authors.lastname: Roth
authors.affiliation: UNC Kidney Center, Department of Medicine, Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Alderman
authors.affiliation: UNC Kidney Center, Department of Medicine, Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Donna
authors.initials: D
authors.lastname: Bunch
authors.affiliation: UNC Kidney Center, Department of Medicine, Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: J Charles
authors.initials: JC
authors.lastname: Jennette
authors.affiliation: Renal Section, Department of Medicine, Imperial College London, Hammersmith Campus, London, UK.
authors.forename: H Terence
authors.initials: HT
authors.lastname: Cook
authors.affiliation: UNC Kidney Center, Department of Medicine, Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Falk
authors.affiliation: Renal Section, Department of Medicine, Imperial College London, Hammersmith Campus, London, UK.
authors.forename: Charles D
authors.initials: CD
authors.lastname: Pusey
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000276:immunology*; D000888:Antibodies, Anti-Idiotypic / Q000378:metabolism; D001324:Autoantigens / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D001327:Autoimmune Diseases / Q000139:chemically induced / Q000276:immunology*; D024141:Collagen Type IV / Q000008:administration & dosage / Q000235:genetics; D004195:Disease Models, Animal; D050533:Glomerular Basement Membrane / Q000276:immunology*; D005921:Glomerulonephritis / Q000139:chemically induced / Q000276:immunology*; D006801:Humans; D008297:Male; D018448:Models, Immunological; D010446:Peptide Fragments / Q000008:administration & dosage / Q000235:genetics; D011485:Protein Binding; D016372:RNA, Antisense / Q000235:genetics; D051381:Rats; D011921:Rats, Inbred WKY
chemical_list: D000888:Antibodies, Anti-Idiotypic; D001324:Autoantigens; D024141:Collagen Type IV; D010446:Peptide Fragments; D016372:RNA, Antisense; C057112:type IV collagen alpha3 chain
keywords: Anti-GBM disease; Autoantigen complementarity; Glomerular basement membrane
references.citation: Semin Nephrol. 2011 Jul;31(4):361-8
references.pmid: 21839369
references.citation: J Am Soc Nephrol. 2011 Oct;22(10):1946-52
references.pmid: 21868497
references.citation: Am J Pathol. 2012 May;180(5):1843-51
references.pmid: 22445570
references.citation: J Clin Invest. 1992 Feb;89(2):592-601
references.pmid: 1737849
references.citation: Kidney Int. 1993 Aug;44(2):307-12
references.pmid: 8377374
references.citation: J Immunol. 1996 Jul 1;157(1):198-206
references.pmid: 8683115
references.citation: J Leukoc Biol. 2001 Dec;70(6):849-60
references.pmid: 11739546
references.citation: J Neuroimmunol. 2002 May;126(1-2):25-36
references.pmid: 12020954
references.citation: Vet Microbiol. 2002 Sep 24;88(4):325-38
references.pmid: 12220808
references.citation: Exp Nephrol. 2002;10(5-6):402-7
references.pmid: 12381925
references.citation: Mol Med. 2002 Jun;8(6):293-305
references.pmid: 12428060
references.citation: J Pathol. 2003 May;200(1):118-29
references.pmid: 12692850
references.citation: FASEB J. 2003 May;17(8):860-8
references.pmid: 12724345
references.citation: J Autoimmun. 2003 Aug;21(1):17-26
references.pmid: 12892732
references.citation: Kidney Int. 2003 Oct;64(4):1292-301
references.pmid: 12969147
references.citation: Kidney Int. 1997 Jan;51(1):222-9
references.pmid: 8995737
references.citation: J Clin Invest. 1997 Nov 1;100(9):2263-75
references.pmid: 9410904
references.citation: Nephrol Dial Transplant. 1998 Jan;13(1):44-52
references.pmid: 9481714
references.citation: Kidney Int. 1998 Mar;53(3):664-71
references.pmid: 9507212
references.citation: Clin Exp Immunol. 1998 Jul;113(1):17-27
references.pmid: 9697978
references.citation: Kidney Int. 1999 Mar;55(3):936-44
references.pmid: 10027930
references.citation: J Biol Chem. 1999 Apr 16;274(16):11267-74
references.pmid: 10196215
references.citation: J Mol Med (Berl). 2005 Jan;83(1):12-25
references.pmid: 15592920
references.citation: Transplantation. 1999 Nov 15;68(9):1393-401
references.pmid: 10573081
references.citation: Nephrol Dial Transplant. 2001 Feb;16(2):253-61
references.pmid: 11158397
references.citation: Lancet. 2001 Sep 15;358(9285):917-20
references.pmid: 11567730
references.citation: N Engl J Med. 2003 Oct 16;349(16):1526-33
references.pmid: 14561795
references.citation: J Biol Chem. 2003 Nov 21;278(47):46516-22
references.pmid: 12970356
references.citation: Nat Med. 2004 Jan;10(1):72-9
references.pmid: 14661018
references.citation: Biofizika. 1969 Jul-Aug;14(4):581-4
references.pmid: 5396298
references.citation: Oncology. 1973;27(3):286-8
references.pmid: 4704740
references.citation: Immunology. 1981 May;43(1):101-10
references.pmid: 7251045
references.citation: J Mol Biol. 1982 May 5;157(1):105-32
references.pmid: 7108955
references.citation: Mol Immunol. 1983 Feb;20(2):169-77
references.pmid: 6188949
references.citation: Lancet. 1983 Oct 8;2(8354):824-6
references.pmid: 6137652
references.citation: Biochem Biophys Res Commun. 1984 May 31;121(1):203-7
references.pmid: 6547339
references.citation: J Clin Lab Immunol. 1984 Dec;15(4):199-204
references.pmid: 6527375
references.citation: J Biol Chem. 1988 Sep 15;263(26):13374-80
references.pmid: 3417661
references.citation: J Am Soc Nephrol. 2005 May;16(5):1350-9
references.pmid: 15814836
references.citation: J Am Soc Nephrol. 2005 Sep;16(9):2657-66
references.pmid: 16049074
references.citation: J Immunol. 2006 Jan 15;176(2):1252-8
references.pmid: 16394016
references.citation: Nature. 2006 Feb 16;439(7078):851-5
references.pmid: 16482158
references.citation: Clin Dev Immunol. 2006 Mar;13(1):49-65
references.pmid: 16603444
references.citation: J Am Soc Nephrol. 2006 Nov;17(11):3076-81
references.pmid: 17005930
references.citation: Clin Immunol. 2007 Aug;124(2):207-12
references.pmid: 17556023
references.citation: Nat Genet. 2008 May;40(5):553-9
references.pmid: 18443593
references.citation: Kidney Int. 2008 Nov;74(9):1159-69
references.pmid: 18596726
references.citation: J Am Soc Nephrol. 2008 Dec;19(12):2421-9
references.pmid: 18701607
references.citation: Clin Exp Immunol. 2009 Feb;155(2):311-9
references.pmid: 19040602
references.citation: Am J Pathol. 2009 Jun;174(6):2202-10
references.pmid: 19406992
references.citation: N Engl J Med. 2010 Jul 22;363(4):343-54
references.pmid: 20660402
references.citation: Kidney Int. 2010 Sep;78(6):590-7
references.pmid: 20592714
references.citation: J Autoimmun. 2010 Nov;35(3):256-64
references.pmid: 20643529
references.citation: Autoimmunity. 2011 Mar;44(2):98-106
references.pmid: 20712431
references.citation: J Am Soc Nephrol. 2011 Jun;22(6):1161-7
references.pmid: 21617122