**Background:** Primary B cell defects manifesting as predominantly antibody deficiencies result from inborn errors in B cell lineage development, including impairments in early bone marrow development, class switch recombination (CSR), or terminal B cell differentiation. While autoimmunity is a known component of immune deficiency, comprehensive studies on the prevalence of autoimmunity based on B cell developmental stages are insufficient. This study aimed to investigate autoimmune manifestations in monogenic patients with B cell development and differentiation defects.
**Methods:** Patients with known genetic defects in B cell development and differentiation were recruited from the Iranian inborn errors of immunity registry at Children's Medical Center Hospital. Diagnosis was based on ESID criteria and Middle East and North Africa Diagnosis and Management Guidelines. Genes were categorized according to Amirifar et al. into intrinsic and mixed extrinsic/intrinsic groups, and by developmental stage (early, CSR, terminal). Data were collected retrospectively from medical records and direct interviews, including demographic data, medical history, physical examination, immunological assays, and molecular findings. Autoimmune diagnosis was confirmed with clinical manifestations and complementary paraclinical findings. Statistical analysis used chi-square, Fisher's exact, Mann-Whitney U, and t-tests as appropriate.
**Key Results:** A total of 393 patients (257 males; 65.4%) with a median age of 12 (IQR 6–20) years were enrolled. The median age at onset was 1 (IQR 0.4–2) year, and median diagnostic delay was 2 (IQR 0.3–5) years. Consanguinity was present in 265 patients (69%). Genetic analysis identified 37 mutated genes: 21 genes in the terminal stage (115 patients), 9 in the early stage (138 patients), and 7 in the CSR stage (140 patients). The most frequent mutated genes were ATM (85 patients), BTK (76 patients), LRBA (34 patients), and DOCK8 (33 patients). Autoimmunity was reported in 81 patients (20.6%) at a median age of 4 (IQR 2–7) years, with 26 (32.1%) developing poly-autoimmunity. The first episode of autoimmunity occurred before IEI diagnosis in 55.1% of patients. Autoimmune diseases involved hematologic (46.9%), rheumatologic (28.4%), gastrointestinal (21%), dermatologic (16%), neurologic (7.4%), and endocrine (6.2%) systems. The most common autoimmune disorders were ITP (7.9%), JIA (5.3%), and AIHA (4.8%). Based on B cell defect stage, 13% of patients with early B cell defects, 17% with CSR defects, and 40% with terminal B cell defects presented at least one type of autoimmunity. Among patients with the four main gene defects, LRBA-deficient patients had the highest frequency of autoimmunity (70.6%), with over half having more than one autoimmune disease. Patients with autoimmunity had significantly higher age at onset (2 vs. 1 year, P=0.023) and later IEI diagnosis (6 vs. 4 years, P=0.003). Lymphoproliferation was significantly higher in patients with autoimmunity (P<0.001). IEI patients with autoimmunity had lower CD16+56+ NK cells (P=0.016) and higher CD19+ B cells (P=0.040). No significant differences in survival were observed based on B cell defect stage (P=0.377) or autoimmunity presence (P=0.10).
**Clinical Implications:** This study demonstrates that autoimmune complications are common in patients with monogenic B cell defects, occurring in 20.6% of cases, with the highest prevalence in terminal-stage defects (40%) and particularly LRBA gene mutations (70.6%). Autoimmune manifestations often precede IEI diagnosis (55.1% of cases), suggesting that autoimmunity—especially autoimmune cytopenias—should prompt evaluation for underlying immunodeficiency. The findings support the need for regular autoimmune surveillance in patients with B cell defects, particularly those with terminal-stage mutations. The study is limited by its retrospective design and single-country population, which may affect generalizability. Further prospective studies are needed to validate these findings and explore the underlying mechanisms linking specific genetic defects to autoimmune phenotypes.