CTLA4-related primary immune dysregulatory disorders

PURPOSE OF REVIEW: CTLA4-related immune disorders are primary immune dysregulation characterized by susceptibility to infections, autoimmunity, hyperinflammation, and malignancies. As new insights into their molecular mechanisms and therapeutic approaches emerge, we aim to provide a review that guides clinicians in diagnosing and adapting management strategies for LRBA deficiency and CTLA-4 insufficiency. RECENT FINDINGS: Recent studies highlight the importance of LRBA/DEF6-mediated CTLA-4 recycling to maintain immune tolerance. Novel interactions (e.g., NBEAL2, Arf1-Rab4) and BEACH-domain protein function further elucidate disease pathogenesis. Clinically, phenotypic heterogeneity spans susceptibility to infections with CVID, IPEX, and ALPS-like presentations, with emerging recognition of pulmonary and neurological involvement and malignancies. Abatacept and sirolimus therapies have shown superior efficacy in controlling disease manifestations, while hematopoietic stem cell transplantation (HSCT) remains the only curative option. Integration of multiomics data may personalize future therapies. SUMMARY: Tailored immunomodulation using abatacept and sirolimus improves disease control and quality of life in LRBA deficiency and CTLA-4 insufficiency. Early diagnosis, multidisciplinary care, and timely HSCT in high-risk patients are critical for optimal outcomes. Ongoing research into gene therapy and artificial intelligence-driven care pathways offers hope for durable, personalized treatment strategies.