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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.

Original publication

DOI

10.18632/oncotarget.3577

Type

Journal article

Journal

Oncotarget

Publication Date

10/05/2015

Volume

6

Pages

10759 - 10771

Keywords

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