Targeting IL-10 producing B cells in SLE
Interleukin-10 (IL-10), an immunoregulatory cytokine, has various important functions in most immune cell types. Its role in the pathogenesis of SLE is supported by (1) elevated serum IL-10 levels in SLE patients correlating with increased disease activity, and (2) promising findings of anti-IL-10 monoclonal antibody treatment in patients with SLE. Variants of IL10 gene, which encodes (IL-10) with known function in promoting B-cell hyperactivity and autoantibody production, are associated with SLE and several other autoimmune diseases. We recently assessed the IL10 gene cluster variants and identified the SLE-risk allele that (1) exceeds the threshold for association of genome-wide significance, (2) exhibits dose-dependent association with elevated levels of IL10 mRNA and protein in peripheral blood samples from SLE patients and controls, and (3) preferentially binds to Elk-1, a transcription factor activated by phosphorylation and nuclear localization via ERK/MAPK signaling in SLE PBMCs. Unexpectedly, we found Elk-1 activation is a general feature of SLE that augments IL-10 production in risk-allele carriers. In addition, increased proportions of IL-10+p-Elk-1+ cells in B cells, but not in T cells and monocytes, were associated with SLE disease activity. IL-10 producing B cells (B10 cells) are normally regulatory; however, they produce less IL-10 and have impaired suppressive capacity in SLE, which seems to be an unlikely candidate to explain our observations. We hypothesize that the inflammatory milieu of SLE affects IL10 locus epigenetically upregulating IL-10 synthesis, especially in genetically predisposed individuals, which contributes to the development of IL-10 overproducing B effector cells that are pathogenic. If we could characterize the major defective mechanism(s) responsible for overproduction of IL-10 and defective regulatory function in SLE B10 cells, we might target specific mechanism to reduce disease activity while preserving important functions of IL-10 in other immune cell types. This proposal aims to explore whether there are defective molecular mechanisms regulating IL-10 production and function in SLE B cells, including Elk-1 activation and subsequent binding to the SLE-risk allele in vivo, feedback inhibition of the ERK/MAPK signaling, and/or microRNA regulation of the IL10 gene locus in specific B-cell subsets. Results of these mechanistic studies will provide molecular targets as novel therapeutics focusing on IL-10 production and function of B10 cells in preventing the development of lupus-like manifestations of a murine lupus model.