ORIGINAL RESEARCH article
Front. Immunol.
Sec. Primary Immunodeficiencies
Familial patterns of immune dysregulation in CVID: insights from B- and T-cell phenotyping and antibody profiling
Suzanne ET Comans 1
Evelien GG Sprenkeler 1
Mischa H Koenen 2
Elles Simonetti 1
Bram Van Cranenbroek 1
Esther van Rijssen 1
Riet Strik-Albers 3
Hans JPM Koenen 1
Jacques JM Van Dongen 4,5,6
Lilly M Verhagen 3,1
Marien Isaäk De Jonge 1
Stefanie SV Henriet 3
1. Department of Laboratory Medicine, Laboratory of Medical Immunology, Radboud Community for Infectious Diseases, Radboud university medical center, Nijmegen, Netherlands
2. Department of Pediatrics, Erasmus Medical Center, Rotterdam, Netherlands
3. Department of Pediatric Infectious Diseases and Immunology, Amalia Children’s Hospital, Radboud university medical center, Nijmegen, Netherlands
4. Cytometry Service, NUCLEUS; Department of Medicine, University of Salamanca (Universidad de Salamanca), Salamanca, Spain
5. Translational and Clinical Research Program, Cancer Research Center (IBMCC, CSIC - University of Salamanca), Salamanca, Spain
6. Department of Immunology, Leiden University Medical Center, Leiden, Netherlands
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Abstract
Introduction: Common Variable Immunodeficiency (CVID) is a heterogeneous immune disorder characterized by a broad range of clinical manifestations. Its etiology is not yet fully understood. To gain insights into the immunological background of CVID in patients without a clearly defined genetic cause, we employed a genealogical research approach that included family members. This strategy aims to provide a more comprehensive understanding of immune dysregulation in CVID, of potential hereditary patterns, and subclinical immunological traits within families. Methods: Fifty-eight participants from nine families were included: Five families with a negative family history for CVID (FH-) and four families with a positive family history for CVID (FH+). Screening for known CVID-associated genes was negative in all cases. The non-affected family members completed a questionnaire covering medical history relevant to primary immunodeficiency. Flow cytometry was used to analyze T- and B-cell subsets in peripheral blood, while mucosal and systemic IgA and IgG levels were measured using a multiplex immunoassay. Results: Immune aberrancies in CVID patients were observed in the B- and T-cell compartments. In both FH− and FH+ family members, symptoms suggestive of Primary Immunodeficiency (PID) were present in 32.1 to 61.5% (p = 0.29). B-cell subsets were 5- to 10-fold reduced compared with the 5th percentile of age specific reference values. A combination of T-cell and B-cell reductions was observed in eight of the nine families in a non-affected member. Serum and mucosal IgG and IgA levels in FH− families did not differ significantly from FH+ families. There were no significant correlations between systemic and mucosal IgA levels in non-affected family members from either FH- or FH+ families. Conclusion: Overall, our findings show that B- and T-cell aberrancies are present not only in CVID patients but also in non-affected family members, irrespective of family history. Systemic IgA does not reflect mucosal IgA, and systemic IgG replacement therapy does not restore mucosal antibody levels, highlighting compartmentalized immune regulation.
Summary
Keywords
Antibodies, Common variable immunodeficiency (CVID), Familial pattern, Immunophenotyping, mucosal immunology, Primary Immunodeficency
Received
07 November 2025
Accepted
17 February 2026
Copyright
© 2026 Comans, Sprenkeler, Koenen, Simonetti, Van Cranenbroek, van Rijssen, Strik-Albers, Koenen, Van Dongen, Verhagen, De Jonge and Henriet. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Stefanie SV Henriet
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