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J. Biol. Chem., Vol. 278, Issue 47, 46516-46522, November 21, 2003

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Point Mutations of Single Amino Acids Abolish Ability of ₃ NC1 Domain to Elicit Experimental Autoimmune Glomerulonephritis in Rats^*

Thomas Hellmark, Lanlin Chen, Sophie Ohlsson, Jörgen Wieslander, and Warren Kline Bolton¶

From the Department of Nephrology, Lund University Hospital, S-22185 Lund, Sweden and Department of Medicine, Division of Nephrology, University of Virginia Health Sciences Center, Post Office Box 800133, Charlottesville, Virginia 22908-0133

We previously showed concordance between Goodpasture syndrome antibody binding and production of experimental glomerulonephritis using human chimeric proteins. We now examine a more limited amino-terminal region of ₃(IV) non-collagenous domain (NC1) and the impact of single amino acid (AA) mutations of this region on glomerulonephritis induction. Rats were immunized with collagenase-solubilized glomerular basement membrane (csGBM), D3, an ₁(IV)NC1 chimeric protein with 69 AA of ₃(IV)NC1 (binds Goodpasture sera), D4, the D3 construct shortened by 4 AA (non-binding), P9, P10, single AA mutants (non-binding), and S2, ₁(IV)NC1 with 9 AA of ₃(IV)NC1 (binding). All rats immunized with csGBM and S2 and 50% of D3 rats developed glomerulonephritis. csGBM rats had intense GBM-bound IgG deposits, but S2 and D3 rats had minimal deposits. None of the D4, P9, or P10 rats developed glomerulonephritis. Lymphocytes from nephritic rats proliferated with csGBM, S2, and D3, but not with D4, P9, or P10. Discrete segments of ₃(IV)NC1 within the ₁(IV)NC1 backbone can induce glomerulonephritis. Single AA mutations within that epitope render the antigen unresponsive to Goodpasture sera and incapable of inducing glomerulonephritis. These studies support the concordance of glomerulonephritis inductivity and Goodpasture serum binding. Further, they define a critical limited AA sequence within ₃(IV)NC1 of nine or fewer AA, which confers nephritogenicity to the nonnephritogenic ₁(IV)NC1 without in vivo antibody binding. This region may be a T-cell epitope responsible for induction of glomerulonephritis in this model in rats and Goodpasture syndrome in man.

Received for publication, November 22, 2002 , and in revised form, September 5, 2003.

^* This work was supported by U.S. Public Health Service Grant DK 55801 from the NIDDK/National Institutes of Health and Grant K2001-71X-09487-11C from the Swedish Research Council, the Tegger Foundation, and the Swedish Society for Medical Research. This work was presented in part at the 33rd annual meeting of the American Society of Nephrology, Oct. 10–16, 2000. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: P.O. Box 800133, Univ. of Virginia Health Sciences Center, Charlottesville, VA 22908-0133. Tel.: 434-924-5125; Fax: 434-924-5848; E-mail: wkb5s{at}virginia.edu.

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