The inborn errors of immunity (IEIs) are a group of heterogeneous disorders. Although autoimmunity frequently coexists with IEIs, the manifestations vary greatly across different disorders. Most cases are recognized only after clinical symptoms emerge, impacting outcomes. However, limited research has been reported on how to achieve early identification. In this study, we aim to identify early or subclinical autoimmune reactivity and associated immunological patterns in patients with IEIs, and to explore differences among various IEI genotypes. The clinical records and laboratory data of 26 patients were reviewed. Immunophenotypes were evaluated by multiparametric flow cytometry. Genetic findings were confirmed by whole-exome sequencing (WES). Autoantibodies were detected via antigen microarray analysis. We focused on several types of inborn errors of immunity that are prone to autoimmune diseases including 5 CD40LG mutations, 4 RAG1/2 mutations, 1 IL2RG mutation, 1 DOCK8 mutation, 1 SH2D1A mutation, 1 FAS mutation, 1 FOXP3 mutation, 1 TNFAIP3 mutation, 6 STAT3 gain-of-function (GOF) mutations, 3 STAT3 loss-of-function (LOF) mutations, and 2 CTLA4 mutations. Approximately 31% had clinical autoimmune manifestations, while several asymptomatic patients showed elevated autoantibodies. Some patients exhibited broad IgG and/or IgM autoantibody profiles targeting nuclear, cell membrane, and organ-specific antigens, which were associated with certain clinical features or immune subsets, such as increased double-negative T (DNT) cells and marginal zone B (MZB) cells. Antigen microarrays may enable early identification of autoimmune risk in IEI patients even before symptoms arise. Patients with genotypes such as STAT3 GOF were more likely to develop autoimmunity. The breadth of IgM autoantibodies correlated positively with MZB cell frequency, and higher DNT cell levels were significantly associated with clinical autoimmunity, suggesting potential utility for early risk stratification.
Zhang et al. (Tue,) studied this question.