CD19 – Common variable immunodeficiency

Common variable immunodeficiency (CVID) is the most prevalent symptomatic primary antibody deficiency, characterized by hypogammaglobulinemia, recurrent bacterial infections, and impaired specific antibody responses. Since 2003, mutations in multiple B-cell coreceptor genes including CD19 have been implicated in a subset of CVID patients ([PMID:17467261]). CD19 encodes a critical co-receptor that amplifies B-cell receptor (BCR) and Toll-like receptor 9 (TLR9) signaling to support B-cell activation and antibody production.

CD19 deficiency follows an autosomal recessive inheritance pattern with biallelic loss-of-function variants reported in unrelated individuals. Two probands have been described: an 8-year-old Japanese boy with a maternal splice-acceptor mutation c.947-1G>T and a paternal gross deletion encompassing CD19 ([PMID:17882224]), and a patient with a homozygous missense variant c.156G>T (p.Trp52Cys) disrupting immunoglobulin superfamily domain folding ([PMID:21330302]). No additional affected relatives have been documented, and population frequency data support pathogenicity of these variants.

The principal variant spectrum in CD19-related CVID comprises splice-site and missense mutations leading to absent or immaturely glycosylated protein. A representative pathogenic allele is c.947-1G>T, which abolishes the intron 5 acceptor site and results in exon skipping and premature truncation of CD19. These variants result in complete loss of surface CD19 expression on B cells and are absent from control populations.

Functional studies support haploinsufficiency as the mechanism of pathogenicity. Cd19-deficient mice exhibit impaired B-cell development, lack of B-1 cells, low serum immunoglobulins and defective humoral responses, phenocopying human CVID ([PMID:9317126]). In human B cells, CD19 is required for TLR9-induced upregulation of activation markers CD86 and TACI via a MYD88/PYK2/LYN/PI3K/BTK/AKT axis; CD19-deficient cells fail to phosphorylate downstream effectors and cannot mount proper activation ([PMID:26478008]).

No conflicting reports have challenged the role of CD19 loss-of-function in CVID. Animal models, patient biochemical assays, and the absence of CD19 expression in affected B cells converge to confirm causality. Additional rare CD19 variants and larger cohorts may further refine genotype-phenotype correlations but are unlikely to alter the core association strength.

Together, genetic and experimental data fulfill ClinGen criteria for a strong gene–disease relationship. CD19 testing has clear diagnostic utility for AR CVID and informs prognosis and therapeutic decisions, particularly in patients with early onset hypogammaglobulinemia. Key take-home: Biallelic CD19 loss-of-function variants cause an autosomal recessive form of CVID characterized by absent CD19 expression, defective B-cell signaling, and hypogammaglobulinemia.

References

• Current opinion in genetics & development • 2007 • Deconstructing common variable immunodeficiency by genetic analysis. [PMID:17467261]
• Pediatric research • 2009 • Common variable immunodeficiency. [PMID:19190529]
• Genes and immunity • 2007 • Novel mutations in a Japanese patient with CD19 deficiency. [PMID:17882224]
• Human molecular genetics • 2011 • Antibody deficiency due to a missense mutation in CD19 demonstrates the importance of the conserved tryptophan 41 in immunoglobulin superfamily domain formation. [PMID:21330302]
• Journal of immunology • 1997 • Regulation of B lymphocyte development and activation by the CD19/CD21/CD81/Leu 13 complex requires the cytoplasmic domain of CD19. [PMID:9317126]
• The Journal of allergy and clinical immunology • 2016 • CD19 controls Toll-like receptor 9 responses in human B cells. [PMID:26478008]

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