The Autoimmune Manifestations in Patients With Genetic Defects in the B Cell Development and Differentiation Stages

The aim of the study was to investigate the prevalence of autoimmunity in patients with monogenic B cell development and differentiation defects and evaluate if clinical or immunologic features affect autoimmunity phenotype.

This study included 393 patients with known pathogenic gene mutations in B cell development and differentiation, based on the American College of Medical Genetics and Genomic criteria. Patients were recruited from the Iranian inborn errors of immunity (IEI) registry.

This was a retrospective analysis of 393 patients with known genetic defects in B cell development and differentiation. Demographics, initial clinical presentation, autoimmune manifestations, and laboratory data were collected and compared using χ square test or Fisher’s exact test (SPSS software).

In this cohort, 257 patients were male (65.4%) with a median age of 12 (range 6–20). Consanguinity was noted in 69% of patients. The most commonly identified genetic defects included ATM, BTK, LRBA, and DOCK8. Autoimmunity was reported in 20.6% of patients at a median age of diagnosis of 4 years. Autoimmunity was the first presentation in 15 patients (3.8%), whereas the most common initial presentations were infection in the majority (56%). The most commonly reported autoimmune disorders were idiopathic thrombocytopenic purpura (7.90%), juvenile idiopathic arthritis (5.3%), and autoimmune hemolytic anemia (4.8%). In patients with autoimmunity, 32.1% developed poly-autoimmunity. The diagnosis of a B cell defect was made at a later age in patients with autoimmunity versus patients without autoimmunity (median age of 6 years vs 4 years, P = .003). In patients with autoimmunity, the first episode of autoimmunity preceded an IEI diagnosis in 55% of patients. Lymphoproliferation (eg, lymphadenopathy, splenomegaly, hepatomegaly) was seen at a higher rate in patients with autoimmunity (P < .001). Patients with terminal B cell defects had higher rates of autoimmunity (40%), especially those with LRBA mutations (70.6% patients with autoimmunity). Kaplan- Meier curve demonstrated no significant difference in the survival states of patients with B cell defects and the presence or absence of autoimmunity.

Autoimmunity is commonly seen in patients with known genetic defects in B cell development and differentiation and may be the first presenting symptom.

Autoimmunity can affect all patients with IEI, but those with B cell defects have higher rates of autoimmunity. This study investigated the prevalence of autoimmunity specifically in patients with monogenic B cell development and differentiation defects and compared clinical features of patients with and without autoimmunity. This study found higher rates of autoimmunity in patients with terminal B cell defects, particularly in patients with LRBA mutations. Autoimmunity can be the first presenting manifestation of an IEI (especially idiopathic thrombocytopenic purpura and autoimmune hemolytic anemia), and the presence of autoimmunity was associated with a statistically significant delay in the diagnosis of IEI. A major limitation of this study was its high rate of consanguinity; thus, it may not be generalizable to other populations. General pediatricians and subspecialists need to be aware that autoimmunity, especially early onset and/or poly- autoimmunity, may be a warning sign of IEI, and a referral to an immunologist may be warranted.