CD70 – Severe Combined Immunodeficiency due to CD70 Deficiency

CD70 deficiency is an autosomal recessive primary immunodeficiency marked by recurrent bacterial airway infections, severe gingivitis, hypogammaglobulinemia and chronic Epstein–Barr virus (EBV) viremia. Two unrelated patients have been reported with biallelic CD70 variants: a 24-year-old woman homozygous for c.2T>C (missense) presenting childhood airway infections, herpes zoster, fulminant EBV infection followed by chronic EBV viremia and severe periodontal disease with high viral load, and confirmed absent CD70 expression on B cells and activated T cells (PMID:32849540); and a separate patient carrying homozygous c.250del (p.Ser84fs) with early-onset antibody deficiency, chronic viral infections and B-cell lymphoma (PMID:33996677).

Functional analyses demonstrate loss-of-function as the mechanism: patient lymphocytes lack CD70 surface expression, exhibit impaired B-cell immunoglobulin production and poor T-cell effector responses with reduced memory marker expression. CD70-dependent CD27 signaling is critical for T-cell expansion toward EBV-infected targets, supported by CD27-CD70 axis studies and RASGRP1-deficient T-cell assays showing defective proliferation that is restored by wild-type factors (PMID:29282224).

Key take-home: CD70 deficiency should be considered in patients with chronic EBV infection and hypogammaglobulinemia to guide immunoglobulin replacement and hematopoietic stem cell transplant decisions.

References

• Frontiers in immunology • 2020 • CD70 Deficiency Associated With Chronic Epstein-Barr Virus Infection, Recurrent Airway Infections and Severe Gingivitis in a 24-Year-Old Woman. PMID:32849540
• Frontiers in pediatrics • 2021 • Specific Immune Response and Cytokine Production in CD70 Deficiency. PMID:33996677
• EMBO molecular medicine • 2018 • Loss of RASGRP1 in humans impairs T-cell expansion leading to Epstein-Barr virus susceptibility. PMID:29282224

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