Research Papers: Pathology:
Dysfunctional BLK in common variable immunodeficiency perturbs B-cell proliferation and ability to elicit antigen-specific CD4+ T-cell help
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Ewoud B. Compeer1, Willemijn Janssen1, Annet van Royen-Kerkhof1, Marielle van Gijn2, Joris M. van Montfrans1 and Marianne Boes1
1 Department of Pediatric Immunology, Laboratory of Translational Immunology, Wilhelmina Children’s Hospital, University Medical Center Utrecht, The Netherlands
2 Department of Medical Genetics, Laboratory of Translational Immunology, Wilhelmina Children’s Hospital, University Medical Center Utrecht, The Netherlands
Marianne Boes, email:
Keywords: common variable immunodeficiency, B-lymphoid tyrosine kinase, BLK, spleen tyrosine kinase, antigen presentation
Received: February 12, 2015 Accepted: February 21, 2015 Published: March 14, 2015
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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