Autoimmunity to the alpha 3 chain of type IV collagen in glomerulonephritis is triggered by 'autoantigen complementarity'

作者：Reynolds John^*; Preston Gloria A; Pressler Barrak M; Hewins Peter; Brown Michael; Roth Aleeza; Alderman Elizabeth; Bunch Donna; Jennette J Charles; Cook H Terence; Falk Ronald J; Pusey Charles D

来源：Journal of Autoimmunity, 2015, 59: 8-18.

DOI：10.1016/j.jaut.2015.01.003

• Glomerular basement membrane
• Anti-GBM disease
• Autoantigen complementarity

'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 alpha 3 chain of type IV collagen. In this study, WKY rats were immunized with a complementary alpha 3 peptide (c-alpha 3-Gly) comprised of amino acids that 'complement' the well characterized epitope on alpha 3(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-alpha 3-Gly-immunized animals were shown to be specific for alpha 3 protein, binding in a region containing sense pCol(24-38) sequence. Interestingly, anti-complementary alpha 3 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.

• 出版日期2015-5