Investigating Biomarkers for Inborn Errors of Immunity in a Prospective Study of Patients With Autoimmune Cytopenia

In a prospective cohort from the Tampa Bay region (2016-2020), patients with autoimmune cytopenia (AIC) were evaluated to identify cellular and serum biomarkers that distinguish those with underlying inborn errors of immunity (IEI).

Clinical phenotype and genetic causes of IEI were assessed using targeted panel-based sequencing. Unique lymphocyte subsets, including activated naïve and transitional B cells, CD19^hiCD21^lo B cells, follicular helper T (T_FH) cells, regulatory T (T_reg) cells, and TCRαβ⁺CD4^-CD8^- double-negative T cells (DNTαβ), were assessed by flow cytometry. Serum levels of lipopolysaccharide (LPS), B-cell activating factor (BAFF), and soluble IL-2 receptor (sIL2R) were quantified by ELISA.

Among 104 AIC patients, 53 (51%) showed evidence of IEI, including 27 (26%) with monogenic disorders-most commonly partial DiGeorge syndrome (pDGS), followed by variants in NFKB1, CTLA4, and FAS. The prevalence of IEI was highest in autoimmune hemolytic anemia (AIHA) (62.5%) and Evans syndrome (61.5%). Low levels of IgG, IgA, and IgM, as well as reduced percentages of naïve CD4⁺ and CD8⁺ T cells, were significantly associated with increased odds of IEI. In AIC-IEI patients, transitional B cells, CD19^hiCD21^lo B cells, and T_FH cells were expanded, accompanied by elevated serum levels of BAFF and sIL2R.

Quantitative immunoglobulin levels and naïve T cells remain valuable indicators of IEI in AIC. Our findings highlight the diagnostic value of emerging cellular and serum biomarkers in identifying IEI, including dysregulation of early B-cell subsets (transitional B cells and CD19^hiCD21^lo B cells), expansion of T_FH cells, and elevated levels of BAFF and sIL2R.