Cell Biology – Immunology – Pathology

Kidney International (2005) 68, 1061–1070; doi:10.1111/j.1523-1755.2005.00498.x

Characterization of the T-cell epitope that causes anti-GBM glomerulonephritis

JULIE ROBERTSON, JEAN WU, JON ARENDS, WILLIAM GLASS II, SCOTT SOUTHWOOD, ALESSANDRO SETTE and YA-HUAN LOU

Department of Diagnostic Sciences, Dental Branch, University of Texas Health Science Center at Houston, Houston, Texas; Department of Pathology and Anatomy, Eastern Virginia Medical School, Norfolk, Virginia; and La Jolla Institute for Allergy and Immunology, San Diego, California

Correspondence: Dr Ya-Huan Lou, Department of Diagnostic Sciences, Dental Branch, University of Texas Houston Health Science Center, Houston, TX 77030. E-mail: Yahuan.Lou@uth.tmc.edu

Received 5 January 2005; Revised 3 March 2005; Accepted 14 April 2005.

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Abstract

Characterization of the T-cell epitope that causes anti-GBM glomerulonephritis.

Background

 

We have demonstrated that a single T-cell epitope pCol(28-40) (SQTTANPSCPEGT) alone, which is derived from NC1 domain of alpha3 chain of type IV collagen (Col4alpha3 NC1), can induce severe glomerulonephritis in Wistar Kyoto rats. This study further characterized this T-cell epitope.

Methods

 

A series of synthetic peptides derived from pCol (28-40) were tested in vivo and in vitro for their T-cell epitope activity and nephritogenicity. Major histocompatability complex (MHC) class II molecules in Wistar Kyoto rats were cloned, and MHC restriction of pCol(28-40) was determined.

Results

 

The T-cell epitope pCol(28-40) was restricted by rat MHC class II RT.1Bl. Ten amino acid residues (29 to 38) were mapped to be the minimum core of the T-cell epitope, which was capable of inducing the T-cell response and severe glomerulonephritis. Only three residues were identified as absolutely critical for the T-cell epitope: position 31 (T) was an anchor residue to the class II molecule, and positions 33 (N) and 34 (P) contributed to the specificity of the T-cell epitope. Thus, only substitution at those positions completely abrogated nephritogenicity of the T-cell epitope. Interestingly, pCol (28-40) also bound to human MHC class II human MHC class II molecule HLA-DRB*1501, which has been linked to human anti-glomerular basement membrane (GBM) disease, suggesting that human homologue of pCol(28-40) could be a potential human T-cell epitope.

Conclusion

 

Our study demonstrated that only few residues in the nephritogenic T-cell epitope pCol(28-40) were critical. Our finding also revealed that pCol(28-40) is a potential nephritogenic T-cell epitope in Goodpasture's syndrome.

Keywords:

autoimmunity, T epitope, MHC class II, rat, anti-GBM disease, collagen IValpha3

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