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Restriction in V Gene Use and Antigen Selection in Anti-Myeloperoxidase Response in Mice

Hitendra S. Jethwa^*, Stephen H. Clarke, Yoshie Itoh-Lindstrom, Ronald J. Falk, J. Charles Jennette^* and Patrick H. Nachman

Departments of ^* Pathology and Laboratory Medicine, Microbiology and Immunology, and Medicine, University of North Carolina, Chapel Hill, NC 27599

Anti-neutrophil cytoplasmic Abs, directed primarily toward myeloperoxidase (MPO) and proteinase 3, are detected in the majority of patients with distinct forms of small vessel vasculitides and pauci-immune necrotizing glomerulonephritis. However, the origin of these autoantibodies remains unknown. We studied the V region gene use in murine anti-MPO Abs derived from Spontaneous Crescentic Glomerulonephritis/Kinjoh mice. A total of 13 anti-MPO-producing hybridomas were generated from four unimmunized mice. Ten of the 13 hybridomas (corresponding to 3 of 4 clones) expressed V1C but differed in their use of V_H genes. The remaining three hybridomas expressed a V5 gene. Anti-MPO hybridomas from individual mice were derived from single clones as deduced by sequence similarity and splice-site identity. We found a statistically significant bias of amino acid replacement mutations to the complementarity-determining regions (CDR) in the V1C-expressing hybridomas. Intriguingly, all 10 V1C hybridomas share a lysine to glutamate mutation in the CDR1. To determine the effects of somatic V gene mutations on binding to MPO, we generated an anti-MPO Ab with an unmutated V1C L chain and compared its ability to bind MPO with its mutated counterpart. The mutated hybridoma-derived Ab has a 4.75-fold higher avidity for MPO than the unmutated Ab. These results suggest that: 1) the L chain plays a dominant role in determining Ab specificity to MPO, 2) the anti-MPO Ab response is oligoclonal, consistent with Ag selection, and 3) MPO is a driving Ag in the murine anti-MPO Ab response.

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				D. O. Bunch, J. S. Silver, M. C. Majure, P. Sullivan, D. A. Alcorta, H. Chin, S. L. Hogan, Y. I. Lindstrom, S. H. Clarke, R. J. Falk, et al. Maintenance of Tolerance by Regulation of Anti-myeloperoxidase B Cells J. Am. Soc. Nephrol., September 1, 2008; 19(9): 1763 - 1773. [Abstract] [Full Text] [PDF]