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Purpose <p>Hyper-IgM syndromes (HIGM) are primary immunodeficiencies characterized by defective class-switch recombination (CSR) and impaired humoral immunity. While genetic causes such as <i>CD40L</i> and <i>AICDA</i> mutations are well established, a detailed comparison of B cell maturation dynamics across HIGM subtypes remains limited.&#xa0;To comprehensively characterize B cell immunophenotypes and functional responses in patients with HIGM and to delineate mutation-specific differences in B cell maturation and proliferation.</p> Method <p>Four patients with genetically confirmed HIGM (one <i>CD40L</i> and three homozygous <i>AICDA</i> mutations, c.70C&gt;T; p.R24W) and age- and sex-matched healthy controls were studied. Peripheral blood mononuclear cells were analyzed by multiparameter flow cytometry to define B cell subsets based on CD19, CD20, CD24, CD27, CD38, IgD, and IgM expression. B cell proliferation was assessed following CpG stimulation.</p> Results <p>All patients exhibited a marked reduction of class-switched memory B cells (CD27⁺IgD⁻) and accumulation of naive B cells (CD27⁻IgD⁺), consistent with defective CSR. The <i>CD40L</i>-deficient patient demonstrated profound depletion of plasmablasts and precursor skewing, reflecting failure of germinal center formation. In contrast, <i>AID</i> patients showed preserved CD27 expression with variable expansion of transitional and plasmablast populations, suggesting intact T cell–dependent activation but intrinsic failure of CSR. Functional assays revealed heterogeneous proliferative responses in <i>CD40L</i> deficiency and <i>AICDA</i>-deficient patient, but impaired proliferation in another <i>AICDA</i>-deficient individual, highlighting inter-individual variability.</p> Conclusion <p>Detailed immunophenotyping reveals distinct B cell maturation arrest points in <i>CD40L</i>- versus <i>AICDA</i>-associated HIGM. Flow cytometric analysis of B cell subsets provides valuable insights into disease mechanisms, supports differential diagnosis, and may inform clinical monitoring and therapeutic decision-making in HIGM.</p>

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Deciphering B cell Maturation Dynamics in Hyper-IgM Syndromes

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月9日

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  • Hande Üçler Çınar,
  • Murat Cansever,
  • Şerife Erdem,
  • Abdullah Arık,
  • Ahmet Eken

摘要

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 HIGM subtypes remains limited. To comprehensively characterize B cell immunophenotypes and functional responses in patients with HIGM and to delineate mutation-specific differences in B cell maturation and proliferation.

Method

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 by multiparameter flow cytometry to define B cell subsets based on CD19, CD20, CD24, CD27, CD38, IgD, and IgM expression. B cell proliferation was assessed following CpG stimulation.

Results

All patients exhibited a marked reduction of class-switched memory B cells (CD27⁺IgD⁻) and accumulation of naive B cells (CD27⁻IgD⁺), consistent with defective CSR. The CD40L-deficient patient demonstrated profound depletion of plasmablasts and precursor skewing, reflecting failure of germinal center formation. In contrast, AID patients showed preserved CD27 expression with variable expansion of transitional and plasmablast populations, suggesting intact T cell–dependent activation but intrinsic failure of CSR. Functional assays revealed heterogeneous proliferative responses in CD40L deficiency and AICDA-deficient patient, but impaired proliferation in another AICDA-deficient individual, highlighting inter-individual variability.

Conclusion

Detailed immunophenotyping reveals distinct B cell maturation arrest points in CD40L- versus AICDA-associated HIGM. Flow cytometric analysis of B cell subsets provides valuable insights into disease mechanisms, supports differential diagnosis, and may inform clinical monitoring and therapeutic decision-making in HIGM.