IL21 – Common Variable Immunodeficiency

Common variable immunodeficiency (CVID) is a primary antibody deficiency characterized by hypogammaglobulinemia and recurrent infections. Despite known monogenic causes in genes such as ICOS, TACI and CD19, the role of IL21 in CVID has been unclear.

Initial genetic screening of 24 familial and recessive CVID cases revealed no pathogenic coding variants in IL21, with eleven IL21 SNPs observed at population frequencies comparable to controls, indicating absence of obvious disease‐causing mutations in this cohort (PMID:18254984).

A separate consanguineous family study identified a homozygous IL21 c.146T>C (p.Leu49Pro) mutation segregating with disease in 3 children (PMID:24746753). These individuals exhibited hypogammaglobulinemia, reduced IgM⁺ and class-switched IgG memory B cells, and elevated transitional B cells, mirroring CVID immunophenotypes.

Functional assays demonstrated that p.Leu49Pro IL-21 fails to induce STAT3 phosphorylation and immunoglobulin class-switch recombination in vitro, confirming a loss‐of‐function mechanism consistent with impaired humoral immunity (PMID:24746753).

Further evidence from analyses of primary immunodeficiency patients showed that IL21 loss‐of‐function mutations reduce circulating T follicular helper cell frequencies and compromise B‐cell maturation, reinforcing IL-21’s critical role in germinal center responses (PMID:26162572).

No cohorts have yet identified additional unrelated IL21 variants in CVID, and genetic evidence remains limited. However, concordant functional data support haploinsufficiency of IL-21 as a mechanistic driver of antibody deficiency.

Key Take‐home: IL21 deficiency disrupts TFH‐dependent B‐cell maturation, phenocopying CVID; targeted IL21 genetic testing may aid diagnosis and guide immunomodulatory therapies.

References

• BMC immunology • 2008 • Screening of functional and positional candidate genes in families with common variable immunodeficiency. PMID:18254984
• The Journal of allergy and clinical immunology • 2014 • Early-onset inflammatory bowel disease and common variable immunodeficiency-like disease caused by IL-21 deficiency. PMID:24746753
• The Journal of allergy and clinical immunology • 2015 • Monogenic mutations differentially affect the quantity and quality of T follicular helper cells in patients with human primary immunodeficiencies. PMID:26162572

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