JMJD1C-mediated epigenetic control of autoimmunity and HIT antibody production

Abstract

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.