Familial patterns of immune dysregulation in CVID: insights from B- and T-cell phenotyping and antibody profiling.

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.