Autoimmunity to the alpha 3 chain of type IV collagen in glomerulonephritis is triggered by 'autoantigen complementarity'
Preston, Gloria A.
Pressler, Barrak M.
Jennette, J. Charles
Cook, H. Terence
Falk, Ronald J.
Pusey, Charles D.
AffiliationImperial College London
University of North Carolina at Chapel Hill
University of Bedfordshire
MetadataShow full item record
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.
CitationReynolds J, Preston GA, Pressler BM, Hewins P, Brown M, Roth A, Alderman E, Bunch D, Jennette JC, Cook HT, Falk RJ, Pusey CD (2015) 'Autoimmunity to the alpha 3 chain of type IV collagen in glomerulonephritis is triggered by 'autoantigen complementarity'', Journal of Autoimmunity, 59 (), pp.8-18.
JournalJournal of Autoimmunity
PubMed Central IDPMC4459745
- Identification of a nephritogenic immunodominant B and T cell epitope in experimental autoimmune glomerulonephritis.
- Authors: Reynolds J, Haxby J, Juggapah JK, Evans DJ, Pusey CD
- Issue date: 2009 Feb
- T-cell epitope of alpha3 chain of type IV collagen induces severe glomerulonephritis.
- Authors: Wu J, Borillo J, Glass WF, Hicks J, Ou CN, Lou YH
- Issue date: 2003 Oct
- Epitope spreading and autoimmune glomerulonephritis in rats induced by a T cell epitope of Goodpasture's antigen.
- Authors: Bolton WK, Chen L, Hellmark T, Wieslander J, Fox JW
- Issue date: 2005 Sep
- The pathogenicity of T cell epitopes on human Goodpasture antigen and its critical amino acid motif.
- Authors: Hu SY, Gu QH, Wang J, Wang M, Jia XY, Cui Z, Zhao MH
- Issue date: 2017 Sep
- Point mutations of single amino acids abolish ability of alpha3 NC1 domain to elicit experimental autoimmune glomerulonephritis in rats.
- Authors: Hellmark T, Chen L, Ohlsson S, Wieslander J, Bolton WK
- Issue date: 2003 Nov 21