The origin of anti-nuclear antibodies in bcl-2 transgenic mice

To determine the regulation of B cells specific for the ribonucleoprotein Sm, a target of the immune system in human and mouse lupus, we have generated mice carrying an anti-Sm H chain transgene (2-12H). Anti-Sm B cells in nonautoimmune 2-12H-transgenic (Tg) mice are functional, but, in the absence of immunization, circulating anti-Sm Ab levels are not different from those of non-Tg mice. In this report, we compare the regulation of anti-Sm B cells in nonautoimmune and autoimmune MRL/Mp-lpr/lpr (MRL/lpr) and bcl-2-22-Tg mice. Activation markers are elevated on splenic and peritoneal anti-Sm B cells of both nonautoimmune and autoimmune genetic backgrounds indicating Ag encounter. Although tolerance to Sm is maintained in 2-12H/bcl-2-22-Tg mice, it is lost in 2-12H-Tg MRL/lpr mice, as the transgene accelerates and increases the prevalence of the anti-Sm response. The 2-12H-Tg MRL/lpr mice have transitional anti-Sm B cells in the spleen similar to nonautoimmune mice. However, in contrast to nonautoimmune mice, there are few if any peritoneal anti-Sm B-1 cells. These data suggest that a defect in B-1 differentiation may be a factor in the loss of tolerance to Sm and provide insight into the low prevalence of the anti-Sm response in lupus.

Section: Discussionsupporting

confidence: 89%

Anti-Sm B Cell Differentiation in Ig Transgenic MRL/Mp-lpr/lprMice: Altered Differentiation and an Accelerated Response

Santulli-Marotto

Qian

Ferguson

et al. 2001

“…A second possibility is that although BM-induced tolerance remains intact, there is a failure to regulate anti-dsDNA B cells produced in GCs. We have previously suggested that this is the case for bcl-2 Tg mice (34). Strikingly, in both lyn Ϫ/Ϫ and bcl-2 Tg mice, autoantibody production is reduced by the presence of the VH3H9 Tg.…”

Section: Maintenance Of the Anergic Phenotype In Lyn ϫ/ϫ Anti-dsdna Bmentioning

confidence: 83%

Novel Roles for Lyn in B Cell Migration and Lipopolysaccharide Responsiveness Revealed Using Anti-Double-Stranded DNA Ig Transgenic Mice

Seo

Buckler

Erikson

2001

Self Cite

Lyn-deficient mice produce Abs against dsDNA, yet exhibit exaggerated tolerance to the model Ag hen-egg lysozyme. To investigate this apparent contradiction, and to further examine the function of Lyn in Ag-engaged cells, we have used an anti-dsDNA Ig transgenic model. Previously, looking at these anti-dsDNA B cells in Lyn-sufficient BALB/c mice, we showed that they are regulated by functional inactivation (anergy). In the absence of Lyn, these anti-dsDNA B cells remain unable to secrete Ab. This suggests that functional inactivation of anti-dsDNA B cells does not depend on Lyn, and that the anti-dsDNA Abs that are produced in lyn−/− mice arise from a defect in another mechanism of B cell tolerance. Although the anti-dsDNA B cells remain anergic, Lyn deficiency does restore their ability to proliferate to LPS. This reveals a novel role for Lyn in mediating the LPS unresponsiveness that normally follows surface Ig engagement. Furthermore, Lyn deficiency leads to an altered splenic localization and EBV-induced molecule 1 ligand chemokine responsiveness of anti-dsDNA B cells, as well as an absence of marginal zone B cells, suggesting additional roles for Lyn in controlling the migration and development of specific B cell populations.

“…In animal models, the failure of lymphocyte apoptosis in promulgating disease pathogenesis is clearly illustrated in Bcl-2-transgenic mice (30) and Bim-deficient mice (31), both of which show evidence of SLE-like clinical symptoms caused by inappropriate survival of autoreactive lymphocytes. It has been postulated that disease in some patients with lupus may have a similar etiology, as elevated Bcl-2 expression in lymphocytes has been reported (32).…”

Section: Discussionmentioning

confidence: 99%

The Bcl-2 Family Antagonist ABT-737 Significantly Inhibits Multiple Animal Models of Autoimmunity

Bardwell

McCarthy

et al. 2009

The Bcl-2 family of proteins plays a critical role in controlling immune responses by regulating the expansion and contraction of activated lymphocyte clones by apoptosis. ABT-737, which was originally developed for oncology, is a potent inhibitor of Bcl-2, Bcl-xL, and Bcl-w protein function. There is evidence that Bcl-2–associated dysregulation of lymphocyte apoptosis may contribute to the pathogenesis of autoimmunity and lead to the development of autoimmune diseases. In this study, we report that ABT-737 treatment resulted in potent inhibition of lymphocyte proliferation as measured by in vitro mitogenic or ex vivo Ag-specific stimulation. More importantly, ABT-737 significantly reduced disease severity in tissue-specific and systemic animal models of autoimmunity. Bcl-2 family antagonism by ABT-737 was efficacious in treating animal models of arthritis and lupus. Our results suggest that treatment with a Bcl-2 family antagonist represents a novel and potentially attractive therapeutic approach for the clinical treatment of autoimmunity.