Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune disease characterized by a profound loss of immune tolerance, leading to the production of pathogenic autoantibodies and immune complex–mediated tissue damage. Its clinical heterogeneity, ranging from mild cutaneous manifestations to severe, life- threatening organ involvement, reflects the complex interplay of genetic, environmental, and immunological factors underlying disease pathogenesis. Among the genetic contributors, Cytotoxic T-Lymphocyte–Associated Protein 4 (CTLA-4), an inhibitory immune checkpoint receptor expressed on activated T cells and regulatory T cells (Tregs), has emerged as a key regulator of peripheral tolerance.

CTLA-4 plays a central role in controlling T-cell activation by competing with CD28 for binding to CD80/CD86 on antigen-presenting cells, thereby limiting co-stimulatory signaling. At the molecular level, CTLA-4 interferes with T-cell receptor signaling pathways, reduces pro-inflammatory cytokine production, and restrains cell proliferation. In Tregs, constitutive CTLA-4 expression is essential for their suppressive function, including the induction of immunoregulatory mechanisms such as indoleamine-2,3-dioxygenase expression in antigen-presenting cells. Disruption of CTLA-4 expression or intracellular trafficking—regulated by proteins such as Rab5, Rab7, Rab11, and LRBA—can impair immune homeostasis and promote autoimmunity.

Genetic polymorphisms within the CTLA-4 gene have been associated with increased susceptibility to SLE, although their impact varies across ethnic populations. Reduced CTLA-4 expression in SLE patients correlates with disease activity and severity, highlighting its role in disease progression. Therapeutically, CTLA- 4–based strategies, including CTLA-4Ig fusion proteins such as abatacept, show potential in modulating immune responses, although clinical outcomes in SLE remain heterogeneous. A deeper understanding of CTLA-4–mediated regulation may pave the way for personalized therapeutic approaches in SLE.

Hajar Fadili is a 29-year-old medical doctor and currently a resident in the Biology Department at Mohammed VI University of Sciences and Health (UM6SS). She is also pursuing a PhD at the Clinical Immunology, Inflammation and Allergy Laboratory (LICIA), Faculty of Medicine and Pharmacy, Hassan II University of Casablanca. Her research interests focus on the immunogenetics of systemic lupus erythematosus.