title: T cell epitope mimicry in antiglomerular basement membrane disease.
abstract: Antiglomerular basement membrane (GBM) disease or Goodpasture's syndrome is among the earliest recognized human autoimmune diseases. Although collagen 4alpha3 NC1 (Col4alpha3NC1) has been identified as the responsible autoantigen, it remains unknown how autoimmunity to this autoantigen is provoked. We have demonstrated in our rat model that a single nephritogenic T cell epitope pCol28-40 of Col4alpha3NC1 induces glomerulonephritis. We hypothesized that microbial peptides that mimic this T cell epitope could induce the disease. Based on the critical residue motif (xxtTxNPsxx) of pCol28-40, seven peptides derived from human infection-related microbes were chosen through GenBank search and synthesized. All peptides showed cross-reactivity with pCol28-40-specific T cells at various levels. Only four peptides induced transient proteinuria and minor glomerular injury. However, the other three peptides induced severe proteinuria and modest to severe glomerulonephritis in 16-25% of the immunized rats. Unexpectedly, the most nephritogenic peptide, pCB, derived from Clostridium botulinum, also induced modest (25%) to severe (25%) pulmonary hemorrhage, another important feature of anti-GBM disease; this was not correlated with the severity of glomerulonephritis. This finding suggests that subtle variations in T cell epitope specificity may lead to different clinical manifestations of anti-GBM disease. In summary, our study raises the possibility that a single T cell epitope mimicry by microbial Ag may be sufficient to induce the anti-GBM disease.
authors.affiliation: Department of Diagnostic Science, Dental Branch, University of Texas Health Science Center, Houston, TX 77030, USA.
authors.forename: Jon
authors.initials: J
authors.lastname: Arends
authors.forename: Jean
authors.initials: J
authors.lastname: Wu
authors.forename: Jason
authors.initials: J
authors.lastname: Borillo
authors.forename: Luan
authors.initials: L
authors.lastname: Troung
authors.forename: Cindy
authors.initials: C
authors.lastname: Zhou
authors.forename: Nadarajah
authors.initials: N
authors.lastname: Vigneswaran
authors.forename: Ya-Huan
authors.initials: YH
authors.lastname: Lou
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000209:etiology / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D000942:Antigens, Bacterial / Q000737:chemistry / Q000235:genetics; D000956:Antigens, Viral / Q000737:chemistry / Q000235:genetics; D001323:Autoantibodies / Q000096:biosynthesis; D001324:Autoantigens / Q000737:chemistry / Q000235:genetics; D024141:Collagen Type IV / Q000737:chemistry / Q000235:genetics; D003429:Cross Reactions; D004195:Disease Models, Animal; D000939:Epitopes / Q000737:chemistry / Q000235:genetics; D005260:Female; D006470:Hemorrhage / Q000209:etiology / Q000473:pathology; D006801:Humans; D007114:Immunization; D008171:Lung Diseases / Q000209:etiology / Q000473:pathology; D018716:Molecular Mimicry; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D051381:Rats; D011921:Rats, Inbred WKY; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D000942:Antigens, Bacterial; D000956:Antigens, Viral; D001323:Autoantibodies; D001324:Autoantigens; D024141:Collagen Type IV; D000939:Epitopes; D010455:Peptides; C057112:type IV collagen alpha3 chain