Maintenance of tolerance by regulation of anti-myeloperoxidase B cells.
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.
Bunch
Donna O
DO
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
Silver
Jonathan S
JS
Majure
Melanie C
MC
Sullivan
Pamela
P
Alcorta
David A
DA
Chin
Hyunsook
H
Hogan
Susan L
SL
Lindstrom
Yoshi I
YI
Clarke
Stephen H
SH
Falk
Ronald J
RJ
Nachman
Patrick H
PH
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
D000906:Antibodies; D007145:Immunoglobulin kappa-Chains; D009195:Peroxidase