CD81 – Common Variable Immunodeficiency

Autosomal recessive CD81 deficiency has been reported in two unrelated patients with biallelic loss-of-function variants leading to common variable immunodeficiency (CVID). The first case harbored a homozygous splice-site mutation resulting in intracellularly retained truncated CD81 protein and complete absence of CD19 surface expression on B cells ([PMID:25739915]). The second patient carried novel biallelic CD81 mutations that abolished surface CD81, led to IgA nephropathy, profound hypogammaglobulinemia, reduced switched memory and transitional B cells, and impaired BCR signaling ([PMID:35849269]). Multi-gene panel studies in CVID cohorts detected CD81 variants in <15% of cases but without clear pathogenicity, underscoring genetic heterogeneity ([PMID:21905497]; [PMID:33859323]).

Functional analyses demonstrate that truncated CD81 fails to traffic CD19 to the cell surface, preventing normal BCR assembly and signaling. Patient B cells show reduced phosphorylation of key BCR signaling molecules (pY, pBTK) and downregulation of immunoglobulin gene expression, consistent with haploinsufficiency of CD81 in B-cell development. These concordant genetic and experimental data support a causal role for autosomal recessive CD81 deficiency in CVID, although current evidence is limited to two families. Key Take-home: CD81 testing should be considered in CVID patients with absent CD19 expression and unexplained hypogammaglobulinemia.

References

• Journal of Clinical Immunology • 2015 • A mutation in the human tetraspanin CD81 gene is expressed as a truncated protein but does not enable CD19 maturation and cell surface expression. [PMID:25739915]
• Journal of Clinical Immunology • 2022 • Novel CD81 Mutations in a Chinese Patient Led to IgA Nephropathy and Impaired BCR Signaling. [PMID:35849269]
• Journal of Investigational Allergology & Clinical Immunology • 2011 • Evaluation of CARMA1/CARD11 and Bob1 as candidate genes in common variable immunodeficiency. [PMID:21905497]
• Scientific Reports • 2021 • The impact of rare and low-frequency genetic variants in common variable immunodeficiency (CVID). [PMID:33859323]

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