Heparin-induced thrombocytopenia (HIT) is a common drug-induced immune disorder occurring in a subset of heparin-treated patients. Immune complexes comprising heparin, platelet factor 4 (PF4), and PF4/heparin-reactive antibodies are central to its pathogenesis. However, the role of epigenetic modification in HIT remains unexplored. Our study identified JMJD1C, a member of the lysine-specific histone demethylase 3 subfamily, as an essential regulator of PF4/heparin-specific antibody production. While JMJD1C was expressed throughout B-cell development and was dispensable for normal B-cell development, its deficiency disrupted immune tolerance and promoted production of self-reactive antibodies in systemic autoimmune diseases, including PF4/heparin-specific platelet-activating antibodies, a hallmark of pathogenic HIT antibodies. JMJD1C-deficient B cells were hyperresponsive, characterized by enhanced B-cell receptor (BCR)-induced proliferation. Transcriptomic analysis (RNA-Seq) revealed upregulation of pathways associated with BCR signaling, NF-kB activation, the cell cycle, and systemic lupus erythematosus (SLE). CUT&Tag profiling demonstrated that JMJD1C deficiency increased H3K36me1 modification at gene start sites in these pathways, indicating that epigenetic dysregulation drives B-cell hyperactivation. Importantly, transcriptional profiling and regulon analysis of B cells from HIT patients showed enrichment of BCR signaling, cell-cycle, NF-κB, and SLE-associated pathways, closely mirroring those in JMJD1C-deficient B cells. Epigenetic analyses further revealed enhanced promoter chromatin accessibility and elevated H3K36me1 deposition at promoter-TSS regions in HIT B cells. Together, these findings establish a strong molecular overlap between JMJD1C deficiency and human HIT B cells and reveal a previously unrecognized epigenetic mechanism underlying HIT pathogenesis. Our study provides the first evidence linking epigenetic regulation to HIT, offering new insights into its pathophysiology.
Yu et al. (Thu,) studied this question.