Genetic dissection of B cell traits in New Zealand black mice. The expanded population of B cells expressing up-regulated costimulatory molecules shows linkage to Nba2.
B cell abnormalities are a prominent feature of the immunologic derangement in NZB and NZB / W mice. We recently demonstrated that these mice have an increased proportion of splenic B cells expressing B7.1 and elevated levels of B7.2 and ICAM-1 that possess the characteristics of marginal zone B cells (CD23(low / -) CD5(-) CD44(hi) CD24(hi) IgD(- / low) IgM(hi)) and are found as early as 4 - 6 weeks of age. These findings suggest that activated B cells in NZB and NZB / W mice could serve a costimulatory function leading to activation of autoreactive T cells. However, it remains unclear whether there is any association between B abnormalities and nephritis in these mice. Here we have used genetic mapping techniques to address this issue. We show that increases in the proportion of B cells expressing costimulatory molecules, serum IgM levels, the number of IgM ELISpots, and IgG anti-single-stranded (ss) DNA antibody production, are significantly associated with a chromosomal region that overlaps with Nba2, a genetic locus previously linked to nephritis. Based on these findings we propose that immune mechanisms leading to polyclonal B cell activation and up-regulation of costimulatory molecules in these mice play a central role in the loss of tolerance that leads to production of pathogenic autoantibodies.
Wither
J E
JE
Arthritis Centre of Excellence, The Toronto Hospital Research Institute, The Toronto Western Hospital, Toronto, Canada. jwither@playfair.utoronto.ca
Paterson
A D
AD
Vukusic
B
B
D000818:Animals; D015703:Antigens, CD / Q000276:immunology*; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D004198:Disease Susceptibility / Q000276:immunology; D008040:Genetic Linkage; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D015854:Up-Regulation
D015703:Antigens, CD; D018799:Intercellular Adhesion Molecule-1