title: Maintenance of tolerance by regulation of anti-myeloperoxidase B cells.
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 anti-myeloperoxidase Vkappa1C-Jkappa5 light-chain transgene, which confers anti-myeloperoxidase specificity when combined with a variety of heavy chains. Vkappa1C-Jkappa5 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.
authors.affiliation: UNC Kidney Center, Department of Medicine, Division of Nephrology and Hypertension, University of North Carolina, 5005 Burnett-Womack, Campus Box #7155, Chapel Hill, NC 27599, USA. donna_bunch@med.unc.edu
authors.forename: Donna O
authors.initials: DO
authors.lastname: Bunch
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Silver
authors.forename: Melanie C
authors.initials: MC
authors.lastname: Majure
authors.forename: Pamela
authors.initials: P
authors.lastname: Sullivan
authors.forename: David A
authors.initials: DA
authors.lastname: Alcorta
authors.forename: Hyunsook
authors.initials: H
authors.lastname: Chin
authors.forename: Susan L
authors.initials: SL
authors.lastname: Hogan
authors.forename: Yoshi I
authors.initials: YI
authors.lastname: Lindstrom
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Clarke
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Falk
authors.forename: Patrick H
authors.initials: PH
authors.lastname: Nachman
mesh_terms: D000818:Animals; D000906:Antibodies / Q000378:metabolism; D017209:Apoptosis; D001327:Autoimmune Diseases / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology; D002452:Cell Count; D007108:Immune Tolerance; D007145:Immunoglobulin kappa-Chains / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009195:Peroxidase / Q000276:immunology*; D013154:Spleen / Q000166:cytology
chemical_list: D000906:Antibodies; D007145:Immunoglobulin kappa-Chains; D009195:Peroxidase