Immune dysregulation in immune thrombocytopenia: impaired establishment of exhaustion-associated regulatory...

Immune thrombocytopenia (ITP) is a chronic autoimmune disorder characterized by increased platelet destruction and impaired platelet production. Conventional models attribute its pathogenesis to persistent activation of autoreactive T cells and dysregulated T-B cell interactions. However, this framework does not adequately explain a key immunological paradox: despite prolonged exposure to self-antigens, T cells in patients with ITP rarely exhibit classical features of exhaustion. Recent studies indicate that ITP is associated not only with abnormalities in immune checkpoint pathways and related epigenetic modifications but also with multilayered regulatory dysfunction, including impaired transcriptional stability of regulatory T cells (Tregs), imbalance in the T follicular helper/T follicular regulatory (Tfh/Tfr) axis, and immunometabolic reprogramming. These findings suggest that negative-feedback mechanisms that normally constrain chronic immune responses may be insufficiently established in ITP. This review synthesizes current evidence on T-cell function, checkpoint signaling, epigenetic regulation, and immunometabolism and explores a plausible explanatory framework in which impaired establishment of exhaustion-related regulatory programs enables autoreactive T cells to sustain metabolic activity and a proinflammatory state, thereby promoting aberrant B-cell responses. This model provides a basis for immunopharmacological strategies aimed at restoring defective inhibitory regulatory networks through epigenetic modulation, selective targeting of pathogenic helper T cells and costimulatory pathways, and immunometabolic reprogramming. Future studies integrating single-cell multi-omics, longitudinal follow-up, and functional validation are required to further elucidate the cellular and molecular basis of exhaustion-related regulatory defects in ITP and to support the development of precision therapeutic strategies.