T-cell epitope of alpha3 chain of type IV collagen induces severe glomerulonephritis.
BACKGROUND
Anti-glomerular basement membrane (GBM) glomerulonephritis is among the earliest recognized human autoimmune diseases. However, the etiology of anti-GBM glomerulonephritis remains unclear. We have previously shown that CD4+ T cells, specific to alpha3 NC1 of type IV collagen (Col4alpha3NC1), were able to induce anti-GBM glomerulonephritis in Wistar-Kyoto (WKY) rats. In the present study, we continued to map the nephritogenic T cell epitope in Col4alpha3NC1.


METHODS
Synthetic peptides, which covered Col4alpha3NC1, were used as immunogens to induce glomerulonephritis in WKY rats. T-cell and B-cell responses to the peptides in the animals were analyzed.


RESULTS
One potent nephritogenic T-cell epitope, pCol(28-40) (SQTTANPSCPEGT), was identified. A single immunization with pCol(28-40) induced extremely severe glomerulonephritis in all 23 rats. Renal pathology revealed nearly 100% of glomeruli with crescentic lesions or tuft necrosis in 21 animals. pCol(28-40) elicited a T-cell response to the peptide; T cells isolated from rats immunized with recombinant Col4alpha3NC1 reacted with pCol(28-40). pCol(28-40) elicited a peptide specific antibody response, which did not react with polypeptide Col4alpha3NC1 or native GBM. An 11-mer peptide, pCol(a30-40) (Ac-TTANPSCPEGT), was further mapped to be the core of the T-cell epitope in pCol(28-40). As expected, immunization with pCol(a30-40) induced severe glomerulonephritis in 10 out of 19 rats.


CONCLUSIONS
Our study not only demonstrated that a single T-cell epitope of Col4alpha3NC1 is sufficient to induce severe glomerulonephritis, but also provides a unique model for studying T-cell-mediated mechanisms in anti-GBM glomerulonephritis pathogenesis.
Wu
Jean
J
Department of Basic Science, Dental Branch, University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
Borillo
Jason
J
Glass
William F
WF
Hicks
John
J
Ou
Ching-Nan
CN
Lou
Ya-Huan
YH
D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D001324:Autoantigens / Q000276:immunology*; D024141:Collagen Type IV / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D007114:Immunization; D010446:Peptide Fragments / Q000276:immunology; D051381:Rats; D011921:Rats, Inbred WKY; D012720:Severity of Illness Index
D001324:Autoantigens; D024141:Collagen Type IV; D018984:Epitopes, T-Lymphocyte; D010446:Peptide Fragments; C000608266:collagen 4alpha3 chain (28-40), rat; C057112:type IV collagen alpha3 chain