CTLA-4 Deficiency: Pathophysiology, Clinical Manifestations, and Immunological Findings

Abstract

Cytotoxic T-lymphocyte associated protein 4 (CTLA-4) deficiency is a primary immune regulatory disordercaused by heterozygous germline loss-of-function variants in the CTLA4 gene. CTLA-4 is expressed mainlyon activated T cells and regulatory T cells that plays a key role in maintaining immune tolerance by limitingT-cell activation. Also, CTLA-4 has recently become a key target in immune checkpoint-based therapeutics,particularly in cancer treatment via the use of monoclonal antibodies against this molecule. Loss of CTLA-4function leads to uncontrolled T-cell activation and impaired Treg-mediated immune regulation. Conse-quently, this immune dysregulation underlies the coexistence of autoimmunity and immune deficiency.Hypogammaglobulinemia is one of the most common immunologic findings in CTLA-4 deficiency andmay resemble common variable immunodeficiency. However, CTLA-4 deficiency is a multisystem disorder.Clinical manifestations are highly variable and may include recurrent respiratory infections, bronchiectasis,chronic diarrhea, malabsorption, autoimmune cytopenia, lymphadenopathy, splenomegaly, and organ infil-tration. Laboratory findings commonly include lymphopenia, reduced naïve CD4+ T cells, increased activat-ed T cells, impaired regulatory T-cell function, reduced CD19+ B cells, decreased class-switched memory Bcells, expanded CD21-low B cells, reduced natural killer cells, and low serum immunoglobulin levels. Rec-ognition of these clinical and laboratory features is essential for early diagnosis, appropriate management,and improved long-term outcomes in patients with CTLA-4 deficiency. This study reviews the pathophysi-ology, clinical manifestations and laboratory findings in patients with CTLA-4 deficiency