Autoimmune cytopenias in inborn errors of immunity: associations with monogenic mutations and immunologic parameters

Autoimmune cytopenias (AICs) are among the most frequent non-infectious complications in inborn errors of immunity (IEIs) and may represent early or even initial manifestations. The genetic underpinnings of AICs in IEIs remain heterogeneous and incompletely defined.

This study aimed to determine the prevalence and distribution of AICs and to investigate their associations with underlying monogenic mutations and selected immunophenotypic parameters in adult patients with IEI.

A total of 121 adult IEI patients from a single tertiary immunology center were evaluated retrospectively. Clinical, immunophenotypic, and genetic data were obtained from electronic medical records. Comparisons were made between patients with and without autoimmune manifestations and AICs. Monogenic mutations were identified using targeted next-generation sequencing (NGS).

Autoimmune manifestations were present in 48 of 121 patients (39.6%), and autoimmune cytopenias (AICs) were identified in 33 patients (27.5%). Autoimmune hemolytic anemia (AIHA) was the most frequently observed subtype, followed by combined cytopenias and immune thrombocytopenia (ITP). The most common genetic alteration detected was a mutation in TNFRSF13B (TACI), with additional variants identified in DOCK8, RAG1, LRBA, PRF1, PSTPIP1, CECR1, PRKDC, and MRTFA. Logistic regression revealed a strong independent association between TACI mutations and ITP (OR: 46.5, p = 0.002), while no significant relationship was found with autoimmune cytopenias overall. No statistically significant differences were found in class-switched memory B cells (CD27⁺IgD⁻) percentages, CD4⁺/CD8⁺ T-cell ratios, or baseline IgG concentrations between patients with and without autoimmune manifestations or AICs.

AICs represent a significant clinical burden in adult IEIs and may occur in association with a wide range of genetic variants. Class-switched memory B cells (CD27⁺IgD⁻) percentages, CD4⁺/CD8⁺ T-cell ratio, and baseline IgG were not significantly associated with autoimmunity in this cohort. These findings underscore the need for broader immunophenotypic and genetic screening to improve the early recognition and management of autoimmune complications in IEIs.