Autoimmune pathogenesis can be characterised by “rogue” clonal expansions within a patient’s B cell repertoire that evolve to evade immune checkpoints. Rogue B cell clones that make pathogenic rheumatoid factor autoantibodies share a common mechanism of malignancy with lymphoid neoplasms, including a compounding somatic mutation profile (Singh et al. 2020, Cell). However, there are still knowledge gaps concerning the intracellular chain of events determining pathogenic B cell fate.
We employ single-cell methylation and transcriptome sequencing (scM&T-Seq) to characterise flow-sorted rogue clones and normal polyclonal memory B cells from four Sjögren’s syndrome patients. A more pronounced separation is seen between these groups from their methylation profiles than from their transcriptome profiles. Furthermore, the rogue methylation profile resembles that of chronic lymphocytic leukaemia (CLL), both at a macro and CpG level, in the form of age- and cancer-associated epigenetic drift, indicated by general loss of methylation punctuated by methylation gain at certain CpG islands. We find 869 differentially methylated regions (DMRs) at the population level between rogue B cells and normal memory B cells, with 77% of these hypermethylated in rogue. Many of these DMRs overlap gene loci critical to B cell function, including EGR3 and FCMR. We report a hypomethylated DMR at a known enhancer region and differential expression of TCF4, a transcription factor overexpressed in CLL and implicated in chromatin occupancy and remodelling. Our findings suggest a putative mechanism of genome disruption in B cell malignancy and autoimmunity via hypomethylation of enhancer regions and silencing of genes essential for B cell function.