Suppression of autoimmunity by CD5+ IL-10-producing B cells in lupus-prone mice

Abstract

Systemic lupus erythematosus is a complex autoimmune disorder characterized by the production of pathogenic anti-nuclear antibodies. Previous work from our laboratory has shown that the introgression of a New Zealand Black-derived chromosome 4 interval onto a lupus-prone background suppresses the disease. Interestingly, the same genetic interval promoted the expansion of both Natural Killer T- and CD5(+) B cells in suppressed mice. In this study, we show that ablation of NKT cells with a CD1d knockout had no impact on either the suppression of lupus or the expansion of CD5(+) B cells. On the other hand, suppressed mice had an expanded population of IL-10-producing B cells that predominantly localized to the CD5(+)CD1d(low) compartment. The expansion of CD5(+) B cells negatively correlated with the frequency of pro-inflammatory IL-17 A-producing T-cells and kidney damage. Adoptive transfer with a single injection of total B cells with an enriched CD5(+) compartment reduced the frequency of memory/activated, IFNγ-producing, and IL-17 A-producing CD4 T-cells but did not significantly reduce autoantibody levels. Taken together, these data suggest that the expansion of CD5(+) IL-10-producing B cells and not NKT cells protects against lupus in these mice, by limiting the expansion of pro-inflammatory IL-17 A- and IFNγ-producing CD4 T-cells.

IL-10 Production Is Critical for Sustaining the Expansion of CD5+ B and NKT Cells and Restraining Autoantibody Production in Congenic Lupus-Prone Mice

“…We have previously shown that crossing the full-length (32 to 151 Mb) NZB c4 interval onto the lupus-prone B6.NZBc1 background leads to suppression of autoantibody production and renal disease, and have provided evidence through adoptive transfer experiments that this was mediated by a suppressive effect of NZB c4 CD5 + B cells [ 6 , 7 ]. This led us to hypothesize that the suppression was the result of the expansion of CD5 + B cells in B6.NZBc4 mice.…”

“…In a recent follow-up publication, we investigated the immune mechanism leading to this suppression and ruled out a regulatory role for the expanded NKT cell population by creating CD1d knockout B6.NZBc1c4 bicongenic mice. Instead, a possible regulatory role for the expanded splenic CD5 + B cell compartment was identified [ 7 ]. Given the recent interest in regulatory B cells, we hypothesized that IL-10 production by CD5 + B cells was critical to suppression in our lupus-prone mice.…”

Regulation of IL-10 and IL-12 production and function in macrophages and dendritic cells

“…However, systemic IL-10 administration has proven to be of limited value 120 and this indicates that IL-10 production would need to be carefully targeted to be efficacious therapeutically. This is evidenced by adoptive transfers of specific types of IL-10-producing immune cells in some autoimmune disease models that result in protection against the development of inflammatory pathologies 121 – 127 . Thus, a far more comprehensive and precise understanding of which IL-10-producing cells are important in vivo , and what the critical target cells of this IL-10 are would be instrumental in the future development of the therapeutic potentials of IL-10.…”

Multiple Roles for B-Lymphocytes in Sjogren’s Syndrome

“…It should be noted that, in addition to MZB cells, increased numbers of B1 cells are noted in the salivary glands of IL-14α transgenic mice. B1 cells can generate B10 cells that produce IL-10 and these cells are known to inhibit inflammation in autoimmune disease [66,67,68,69]. …”