Dysfunctional BLK in common variable immunodeficiency perturbs B-cell proliferation and ability to elicit antigen-specific CD4+ T-cell help.
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.
Department of Pediatric Immunology, Laboratory of Translational Immunology, Wilhelmina Children's Hospital, University Medical Center Utrecht, The Netherlands.
Ewoud B
EB
Compeer
Department of Pediatric Immunology, Laboratory of Translational Immunology, Wilhelmina Children's Hospital, University Medical Center Utrecht, The Netherlands.
Willemijn
W
Janssen
Department of Pediatric Immunology, Laboratory of Translational Immunology, Wilhelmina Children's Hospital, University Medical Center Utrecht, The Netherlands.
Annet
A
van Royen-Kerkhof
Department of Medical Genetics, Laboratory of Translational Immunology, Wilhelmina Children's Hospital, University Medical Center Utrecht, The Netherlands.
Marielle
M
van Gijn
Department of Pediatric Immunology, Laboratory of Translational Immunology, Wilhelmina Children's Hospital, University Medical Center Utrecht, The Netherlands.
Joris M
JM
van Montfrans
Department of Pediatric Immunology, Laboratory of Translational Immunology, Wilhelmina Children's Hospital, University Medical Center Utrecht, The Netherlands.
Marianne
M
Boes
D017951:Antigen Presentation; D001402:B-Lymphocytes / Q000201:enzymology* / Q000276:immunology; D023201:CD40 Ligand / Q000378:metabolism; D002450:Cell Communication; D049109:Cell Proliferation; D002478:Cells, Cultured; D002648:Child; D017074:Common Variable Immunodeficiency / Q000175:diagnosis / Q000201:enzymology* / Q000235:genetics / Q000276:immunology; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008213:Lymphocyte Activation; D008297:Male; D010375:Pedigree; D010641:Phenotype; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D000072377:Syk Kinase; D006377:T-Lymphocytes, Helper-Inducer / Q000201:enzymology* / Q000276:immunology; D014162:Transfection; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
D047908:Intracellular Signaling Peptides and Proteins; D011947:Receptors, Antigen, B-Cell; D023201:CD40 Ligand; D011505:Protein-Tyrosine Kinases; C584409:BLK protein, human; C000606896:SYK protein, human; D000072377:Syk Kinase; D019061:src-Family Kinases
B-lymphoid tyrosine kinase; BLK; antigen presentation; common variable immunodeficiency; pathology; spleen tyrosine kinase