Pathogenic epigenetic programming of expanded B cell subsets in systemic lupus erythematosus

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Abstract Systemic lupus erythematosus (SLE) is characterized by multiple B cell abnormalities that contribute to disease pathogenesis through the production of autoantibodies. The recent characterizations of immune cells from SLE patients suggest that distinct B cell subsets are expanded and that defects in epigenetic programming may be a contributing factor to disease etiology. Using high-dimensional flow cytometry, five B cell subsets were isolated from cohorts of SLE and HC subjects. To create a molecular map of each cell type, the transcriptome was defined by RNA-seq and the epigenome by dual DNA methylation (RRBS) and chromatin accessibility (ATAC-seq) profiling. These data reveal cell-type relationships that suggest pathogenic B cell subsets are programmed to differentiate down a different trajectory than normal B cells. Across all SLE B cell subsets a distinct disease signature was observed in each of the three data sets. Resting naïve B cells displayed a similar SLE signature to expanded B cell subsets indicating that a disease programming exists early in the differentiation pathway. Distinct epigenetic footprints were identified for transcriptional networks active in SLE B cells, revealing the unique environmental signals these cells receive. These results provide insights into the molecular programming of human B cell subsets, identify loci that may contribute to the expansion of distinct pathogenic B cell subsets, and suggest that early alterations in programming predispose B cells towards a disease fate.