Anti -double -stranded DNA B cells in health and disease

Anti-double-stranded DNA (dsDNA) antibodies, while absent from the sera of most individuals, are a serologic hallmark of the disease systemic lupus erythematosus. To better understand how anti-dsDNA B cells are regulated in healthy individuals, and how regulation breaks down in disease, we have tracked a population of anti-dsDNA B cells in both non-autoimmune and autoimmune mice. We have previously shown that in BALB/c mice, these cells are developmentally arrested, halted at the T/B interface in the splenic white pulp, and they fail to secrete antibody. In Fas-deficient (lpr/ lpr) mice, a murine lupus model, the anti-dsDNA B cells exhibit several differences. In mice as young as four weeks of age, the anti-dsDNA B cells are able to mature and enter the B cell follicle. By 10–12 weeks of age, anti-dsDNA antibody-forming cells (AFCs) become visible in the spleen, and anti-dsDNA antibodies are detectable in the serum. In this study, we investigated the role of CD4 T cells in determining these different phenotypes. While T cells were not required for maintaining the regulated phenotype of anti-dsDNA B cells in BALB/c mice, they appeared to drive the maturation and follicular entry of anti-dsDNA B cells in lpr/lpr mice. Consistent with this, provision of T cell help to BALB/c anti-dsDNA B cells resulted in maturation and follicular entry within 10 days; strikingly, however, BALB/c anti-dsDNA B cells were also able to form AFCs in this time period. To understand why anti-dsDNA B cells in young lpr/lpr mice do not rapidly form AFCs, we investigated how changes in the quality, quantity, and timing of T cell help affect the response of anti-dsDNA B cells. Intriguingly, the presence of anergic/suppressor T cells caused an abortive response like that seen in young lpr/lpr mice. Finally, to determine if a breakdown in B cell anergy was a general feature of murine lupus, we examined the fate of anti-dsDNA B cells in lyn−/− mice, a second model of lupus. Here, we found that functional inactivation of anti dsDNA B cells remained intact, reinforcing the idea that defects in distinct mechanisms of tolerance can result in very similar manifestations of autoimmune disease