Dysregulation of helper, regulatory, and follicular CD4+ T cells in primary antiphospholipid syndrome: Immunopathology and implications for targeted immunomodulatory therapy.

Antiphospholipid syndrome (APS) is a systemic autoimmune disorder defined by thrombotic and/or obstetric complications in the presence of antiphospholipid antibodies (aPL). While the clinical role of aPL is well established, the immune mechanisms sustaining their production remain poorly understood. Recent advances implicate CD4+ T cells in the immunopathogenesis of APS, with growing attention to the roles of helper (Th), regulatory (Treg), and follicular (helper, Tfh; and regulatory, Tfr) subsets in orchestrating autoreactive B cell responses within germinal centres. This review synthesizes the current evidence on CD4+ T cell dysregulation in APS, with particular emphasis on primary APS, which represents a valuable clinical model for studying immune dysregulation with limited therapeutic confounding, as treatment predominantly relies on anticoagulation rather than chronic immunosuppression. Experimental studies demonstrate that autoreactive aPL-specific CD4+ T cells are critical for initiating and maintaining aPL responses. In humans, APS is skewed toward Th1 and Th17 polarization, diminished Treg frequency or function, and a dysregulated Tfh/Tfr axis. Specifically, increased activated Tfh cells alongside reduced Tfr cells and skewing toward Tfh17-like subsets, have been linked to increased aPL titres and disease burden. Despite inconsistent findings across studies, likely reflecting phenotypical APS heterogeneity, distinct aPL profiles, and immunophenotyping methodological variations, the cumulative data support a model in which APS involves a coordinated disruption of CD4+ T cell homeostasis, encompassing both effector and regulatory arms. By delineating these immune alterations, this review provides a framework for understanding APS immunopathology and supports CD4+ T cell responses and T-B cell crosstalk as promising targets for mechanism-based immunomodulatory strategies to complement anticoagulation.