Deciphering B cell Maturation Dynamics in Hyper IgM Syndromes

Purpose: Hyper-IgM syndromes (HIGM) are primary immunodeficiencies characterized by defective class-switch recombination (CSR) and impaired humoral immunity. While genetic causes such as CD40L and AICDA mutations are well-established, a detailed comparison of B cell maturation dynamics across different HIGM subtypes remains limited. This study aims to comprehensively characterize B cell immunophenotypes and functional responses in HIGM patients and to delineate mutation-specific differences in B cell maturation and proliferation. Methods: Four patients with genetically confirmed HIGM (one CD40L and three homozygous AICDA mutations, c.70C>T; p.R24W) and age- and sex-matched healthy controls were studied. Peripheral blood mononuclear cells were analyzed via multiparameter flow cytometry to define B cell subsets based on CD19, CD20, CD24, CD27, CD38, IgD, and IgM expression. Additionally, B cell proliferation was assessed following CpG stimulation. Results: All patients exhibited a marked reduction in class-switched memory B cells (CD27 ⁺ IgD ^- ),and an accumulation of naive B cells (CD27 ⁻ IgD ⁺ ), consistent with defective CSR. The CD40L-deficient patient demonstrated profound depletion of plasmablasts and precursor skewing, reflecting a failure in germinal center formation. In contrast, AICDA patients showed preserved CD27 expression with variable expansion of transitional and plasmablast populations, suggesting intact T cell–dependent activation but an intrinsic failure of CSR. Functional assays revealed heterogeneous proliferative responses, with inter-individual variability observed particularly among AICDA-deficient patients. Conclusion: Detailed immunophenotyping reveals distinct B cell maturation arrest points in CD40L- versus AICDA-associated HIGM. Flow cytometric analysis provides valuable insights into disease mechanisms, supports differential diagnosis, and informs clinical monitoring and therapeutic decision-making in HIGM