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.
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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)
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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
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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)
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