Inborn errors of immunity (IEIs) frequently present with rheumatologic and autoimmune manifestations that closely mimic common polygenic conditions, including systemic lupus erythematosus, juvenile idiopathic arthritis, and vasculitis, posing significant challenges to early recognition and diagnosis. Current data indicate that autoimmunity represents the first clinical manifestation in approximately 18% of IEI cases and the sole presentation in nearly 9%. The majority of affected patients belong to the categories of predominantly antibody deficiencies, combined immunodeficiencies with syndromic features, or disorders of immune dysregulation. In contrast to autoimmunity in the general population, IEI-associated autoimmunity characteristically presents at an earlier age, lacks a marked female predominance, and more frequently involves multiple organ systems, particularly hematopoietic, endocrine, and barrier tissues. Concurrently, the conceptual framework of autoimmunity is undergoing a fundamental shift: the classical model centered on central and peripheral tolerance is increasingly giving way to a pathway-oriented paradigm that foregrounds dominant immunologic mechanisms, including disturbances in T cell development, interferon signaling, and complement regulation. In line with this, a novel multilayer model of autoimmunity has recently been proposed, which integrates causative genes, the functional consequence of allelic variants (loss-of-function, gain-of-function, hypomorphic, haploinsufficient, or dominant-negative), disrupted molecular mechanisms, and their humoral and cellular immune effectors. A deeper understanding of these pathways is essential for enhancing diagnostic precision and for developing targeted, mechanism-based therapeutic strategies.
