ICOS – Common Variable Immunodeficiency (CVID)

The inducible T cell co‐stimulator (ICOS) is expressed on activated CD4⁺ T cells and is critical for germinal center formation, Ig class switching, and T follicular helper cell support. Autosomal recessive ICOS deficiency causes a monogenic form of common variable immunodeficiency (Common Variable Immunodeficiency; CVID) characterised by profound hypogammaglobulinemia, recurrent bacterial infections, enteropathy, and lymphoproliferation.

Genetic evidence supports a definitive gene–disease relationship. Homozygous ICOS deletions and frameshift, splice‐site, and missense loss‐of‐function variants have been identified in over 30 probands from at least 12 unrelated families ([PMID:16384931], [PMID:26399252], [PMID:31858365]), including a recurrent founder deletion NM_012092.4(ICOS):c.59-594_501+93del ([PMID:15507387]). Segregation analysis in autosomal recessive families demonstrated complete cosegregation of biallelic ICOS variants with CVID phenotype in 5 affected relatives across multiple pedigrees ([PMID:15507387]).

Variant spectrum encompasses large genomic deletions, frameshifts, canonical splice‐site mutations, and missense changes. A representative missense allele is c.356T>C (p.Phe119Ser) ([PMID:31858365]), which abolishes ICOS surface expression and impairs T follicular helper cell differentiation. Most variants lead to truncated proteins or absent transcripts, consistent with a loss‐of‐function mechanism.

Functional studies are concordant with clinical findings. ICOS‐deficient patients exhibit absent germinal centers, severely reduced class‐switched memory B cells, and diminished circulating CXCR5⁺ T follicular helper cells, with impaired IL-10, IL-17 and enhanced IL-12 responses. Murine models and in vitro rescue experiments confirm that ICOS loss disrupts T–B cell collaboration and immunoglobulin production ([PMID:16384931], [PMID:31858365]).

No credible studies dispute the association; no pathogenic ICOS variants have been found in large CVID cohorts without corresponding functional deficits. The mechanistic and genetic concordance across diverse populations meets ClinGen criteria for a definitive classification.

Key Take-home: ICOS deficiency is a monogenic autosomal recessive cause of CVID, with clear diagnostic markers (biallelic LOF variants and absent ICOS expression) and therapeutic implications for immunoglobulin replacement and tailored immunomodulation.

References

• Blood • 2006 • Human ICOS deficiency abrogates the germinal center reaction and provides a monogenic model for common variable immunodeficiency. PMID:16384931
• Clinical immunology (Orlando, Fla.) • 2004 • ICOS deficiency in patients with common variable immunodeficiency. PMID:15507387
• Journal of clinical immunology • 2015 • Astute Clinician Report: A Novel 10 bp Frameshift Deletion in Exon 2 of ICOS Causes a Combined Immunodeficiency Associated with an Enteritis and Hepatitis. PMID:26399252
• Journal of clinical immunology • 2020 • Expanding Clinical Phenotype and Novel Insights into the Pathogenesis of ICOS Deficiency. PMID:31858365

Evidence Based Scoring (AI generated)