Maintenance of tolerance by regulation of anti-myeloperoxidase B cells

Donna O. Bunch, Jonathan S. Silver, Melanie C. Majure, Pamela Sullivan, David A. Alcorta, Hyunsook Chin, Susan L. Hogan, Yoshi I. Lindstrom, Stephen H. Clarke, Ronald J. Falk, Patrick H. Nachman

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Anti-neutrophil cytoplasmic autoantibodies directed toward myeloperoxidase or proteinase 3 are detected in sera of patients with small vessel vasculitis and participate in the pathogenesis of this disease. Autoantibodies develop when self-reactive B cells escape the regulation that ensures self-tolerance. In this study, regulation of anti-myeloperoxidase B cells was examined in mice that express an antimyeloperoxidase Vκ1C-Jκ5 light-chain transgene, which confers anti-myeloperoxidase specificity when combined with a variety of heavy chains. Vκ1C-Jκ5 transgenic mice have splenic anti-myeloperoxidase B cells but do not produce circulating anti-myeloperoxidase antibodies. Two groups of transgenic mice that differed by their relative dosage of the transgene were compared; high-copy mice had a mean relative transgene dosage of 1.92 compared with 1.02 in the low-copy mice. These mice exhibited a 90 and 60% decrease in mature follicular B cells, respectively. High-copy mice were characterized by a large population of anti-myeloperoxidase B cells, a preponderance of B-1 cells, and an increased percentage of apoptotic myeloperoxidase-binding B cells. Low-copy mice had similar changes in B cell phenotype with the exception of an expanded marginal zone population. B cells from low-copy mice but not high-copy mice produced anti-myeloperoxidase antibodies after stimulation with lipopolysaccharide. These results indicate that tolerance to myeloperoxidase is maintained by central and peripheral deletion and that some myeloperoxidase-binding B cells are positively selected into the marginal zone and B-1 B cell subsets. A defect in these regulatory pathways could result in autoimmune disease.

Original languageEnglish (US)
Pages (from-to)1763-1773
Number of pages11
JournalJournal of the American Society of Nephrology
Volume19
Issue number9
DOIs
StatePublished - Sep 2008
Externally publishedYes

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