Background/Purpose: B cell development in the bone marrow is followed by specification into several functional subsets in the spleen, including marginal zone B (MZB) cells or follicular cells (FO). Both subsets have been shown to contribute to autoimmune phenotypes by secretion of autoantibodies, such as dsDNA in systemic lupus erythematosus (SLE). Recently, microRNAs, short non-coding RNAs, have been shown to influence a myriad of aspects in immune cell development, including B cell development. Recent work has demonstrated that deficiency of the NFkB feedback regulator, miR-146a, led to a range of hematopoietic phenotypes, but B cell phenotypes have not been extensively characterized. Here, we have found that autoimmune lupus-prone miR-146a deficient mice demonstrate a reduction in MZB cells that likely represents a developmental block, while displaying a corresponding increase in FO cells.

Methods:  We use high-throughput sequencing and comparative analysis of developmental stage-specific transcriptomes to characterize this defect.

Results:  We determined that the differentiation of MZB cells was impaired due to a miR-146a-dependent decrease in Notch signaling. Further, we discovered that the cell-fate regulator protein, Numb, is a direct target of miR-146a, and that its derepression in miR-146a-deficent B-cells likely underlies the decrease in Notch signaling.

Conclusion: Collectively, we describe a new role for the function of miR-146a in regulating marginal zone B cell development, which may ultimately contribute to autoimmune and/or inflammatory phenotypes.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/regulation-of-marginal-zone-b-cell-differentiation-by-microrna-146a/