A self T cell epitope induces autoantibody response: mechanism for production of antibodies to diverse glomerular basement membrane antigens.
The anti-glomerular basement membrane (GBM) Ab has been regarded as a prototypical example of pathogenic autoantibodies. However, the mechanism for elicitation of this Ab remains unknown. In the present paper, we report that the Ab to diverse GBM Ags was induced by a single nephritogenic T cell epitope in a rat model. The T cell epitope pCol(28-40) of noncollagen domain 1 of collagen type IV alpha3 chain not only uniformly induced severe glomerulonephritis but also elicited anti-GBM Ab in 76% of the immunized rats after prominent glomerular injury. Furthermore, we demonstrated that the anti-GBM Ab was not related to the peptidic B cell epitope nested in pCol(28-40); that is, 1) elimination of the B cell epitope, either by substitution of the critical residues of the B cell epitope or by truncation, failed to abrogate anti-GBM Ab production, and 2) the anti-GBM Ab, eluted from the diseased kidneys, reacted only with native GBM, but not with pCol(28-40). Confocal microscopy and immunoprecipitation further demonstrated that the eluted anti-GBM Ab recognized conformational B cell epitope(s) of multiple native GBM proteins. We conclude that autoantibody response to diverse native GBM Ags was induced by a single nephritogenic T cell epitope. Thus, anti-GBM Ab may actually be a consequence of T cell-mediated glomerulonephritis.
Wu
Jean
J
Department of Diagnostic Sciences, Dental Branch, Medical School, University of Texas Health Science Center at Houston, Baylor College of Medicine, Houston, TX 77030, USA.
Arends
Jon
J
Borillo
Jason
J
Zhou
Cindy
C
Merszei
Justin
J
McMahon
John
J
Lou
Ya-Huan
YH
D019264:Adoptive Transfer; D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000276:immunology; D000918:Antibody Specificity; D001323:Autoantibodies / Q000096:biosynthesis*; D001324:Autoantigens / Q000008:administration & dosage / Q000276:immunology*; D001485:Basement Membrane / Q000276:immunology / Q000378:metabolism; D001666:Binding Sites, Antibody; D024141:Collagen Type IV / Q000008:administration & dosage / Q000276:immunology*; D018985:Epitopes, B-Lymphocyte / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000008:administration & dosage / Q000276:immunology*; D005260:Female; D007074:Immunoglobulin G / Q000378:metabolism; D007678:Kidney Glomerulus / Q000276:immunology* / Q000378:metabolism; D010446:Peptide Fragments / Q000276:immunology; D017434:Protein Structure, Tertiary; D051381:Rats; D011921:Rats, Inbred WKY; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000637:transplantation
D001323:Autoantibodies; D001324:Autoantigens; D024141:Collagen Type IV; D018985:Epitopes, B-Lymphocyte; D018984:Epitopes, T-Lymphocyte; D007074:Immunoglobulin G; D010446:Peptide Fragments; C057112:type IV collagen alpha3 chain