Background/Purpose: Systemic lupus erythematosus (SLE) is a complex multisystem autoimmune disorder characterized by the production of anti-nuclear antibodies (ANA) which form immune complexes and promote end-organ damage. Studies in our lab have focused on identifying genetic defects that contribute to a loss of immune regulation in autoimmune prone New Zealand Black (NZB) mice. Previous work has shown that the introgression of a NZB chromosome 1 (c1) interval extending from 135 to179 Mb onto the non-autoimmune C57BL/6 (B6) background results in increased B and T cell activation, elevated ANA levels, and fatal kidney disease. Despite the presence of mapped susceptibility loci on NZB c4, introgression of an interval extending from 30 to 150Mb onto the B6 background resulted in the expansion of splenic NKT and CD5⁺ B cells in the absence of autoimmunity. To further investigate the role of NZB c4 in autoimmunity, bicongenic (c1c4) mice were produced with both NZB c4 and c1 intervals. Although bicongenic mice had c1 autoimmune augmenting genes, c1c4 mice had reduced renal disease, increased survival, and a shift towards less pathogenic IgG1 autoantibodies. Interestingly, bicongenic mice retained the expansion of splenic CD5⁺ B cells. Recent studies on experimental autoimmune encephalitis and arthritis models have identified a non-redundant role for a population of IL-10 producing CD5⁺CD1d^hi regulatory B cells in preventing disease progression. Given the consistent expansion of splenic CD5⁺ B cells in bicongenic mice, we sought to investigate their role in the suppression of fatal autoimmunity.

Methods: Cellular phenotypes were examined by flow cytometry of de novo splenocytes. Intracellular production of IL-10 or IFNγ and IL-17 was measured following 4 to 5 hour stimulation with LPS, PMA and Ionomycin or PMA and Ionomycin, respectively. Serum levels of anti-nuclear antibodies were measured by ELISA. Adoptive transfer experiments were performed by injecting 5-10 million B cells intravenously into c1.Thy1^aIgH^a recipients.

Results: There was a significant increase in IL-10 producing B cells in bicongenic and c4 mice when compared to B6 and c1 controls. Interestingly, the expansion of IL-10 producing cells in c1c4 and c4 mice is distinct from previously documented B regulatory populations and localizes to the CD5⁺CD1d^int B cell compartment. There was an inverse correlation between the levels of anti-ssDNA IgG and the frequency of IL-10 producing B cells in c1c4 but not B6 mice suggesting that they may play a role in disease suppression. There was no correlation between the proportion of conventional Treg or iNKT cells and anti-ssDNA IgG antibodies. In support of a direct suppressive capacity for the expanded CD5⁺ B cells, adoptive transfer of total B cells from c4, but not B6, mice into autoimmune prone c1.Thy1^aIgH^a recipients reduced the proportion of activated B cells, germinal centre B cells, memory/effector T cells, and IFN-g or IL-17-secreting T cells.

Conclusion: Taken together, these data indicate the presence of a phenotypically novel IL-10 producing B cell population in c4 mice which can suppress the progression of fatal autoimmunity.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/regulatory-b-cells-supress-the-progression-of-fatal-autoimmunity-in-lupus-prone-mice/