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Common Variable Immunodeficiency (CVID) is the most prevalent primary antibody deficiency, and characterized by defective generation of high-affinity antibodies. Patients have therefore increased risk to recurrent infections of the respiratory and intestinal tract. Development of high-affinity antigen-specific antibodies involves two key actions of B-cell receptors (BCR): transmembrane signaling through BCR-complexes to induce B-cell differentiation and proliferation, and BCR-mediated antigen internalization for class-II MHC-mediated presentation to acquire antigen-specific CD4(+) T-cell help.We identified a variant (L3P) in the B-lymphoid tyrosine kinase (BLK) gene of 2 related CVID-patients, which was absent in healthy relatives. BLK belongs to the Src-kinases family and involved in BCR-signaling. Here, we sought to clarify BLK function in healthy human B-cells and its association to CVID.BLK expression was comparable in patient and healthy B-cells. Functional analysis of L3P-BLK showed reduced BCR crosslinking-induced Syk phosphorylation and proliferation, in both primary B-cells and B-LCLs. B-cells expressing L3P-BLK showed accelerated destruction of BCR-internalized antigen and reduced ability to elicit CD40L-expression on antigen-specific CD4(+) T-cells.In conclusion, we found a novel BLK gene variant in CVID-patients that causes suppressed B-cell proliferation and reduced ability of B-cells to elicit antigen-specific CD4(+) T-cell responses. Both these mechanisms may contribute to hypogammaglobulinemia in CVID-patients.


Journal article



Publication Date





10759 - 10771


Department of Pediatric Immunology, Laboratory of Translational Immunology, Wilhelmina Children's Hospital, University Medical Center Utrecht, The Netherlands.


B-Lymphocytes, T-Lymphocytes, Helper-Inducer, Cells, Cultured, Humans, Common Variable Immunodeficiency, Genetic Predisposition to Disease, src-Family Kinases, Intracellular Signaling Peptides and Proteins, CD40 Ligand, Receptors, Antigen, B-Cell, Transfection, Pedigree, Lymphocyte Activation, Cell Communication, Signal Transduction, Cell Proliferation, Antigen Presentation, Phosphorylation, Phenotype, Child, Female, Male, Protein-Tyrosine Kinases, Genetic Variation, Syk Kinase