Dysfunctional BLK in common variable immunodeficiency perturbs B-cell proliferation and ability to elicit antigen-specific CD4+ T-cell help.

Abstract

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.

• Authors: Ewoud B Compeer, Willemijn Janssen, Annet van Royen-Kerkhof, Marielle van Gijn, Joris M van Montfrans, Marianne Boes
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 13 Pg. 10759-71 (May 10 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 25926555 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Intracellular Signaling Peptides and Proteins
• Receptors, Antigen, B-Cell
• CD40 Ligand
• Protein-Tyrosine Kinases
• BLK protein, human
• SYK protein, human
• Syk Kinase
• src-Family Kinases

Topics

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