title: Unimpaired activation of c-Jun NH2-terminal kinase (JNK) 1 upon CD40 stimulation in B cells of patients with X-linked agammaglobulinemia.
abstract: X-linked agammaglobulinemia (XLA) is caused by mutations in the gene encoding the cytoplasmic Bruton's tyrosine kinase (Btk). Btk has been shown to play an essential role in the development of B1 (CD5+) and conventional circulating mature B cells (B2) in mouse and man. It has been shown in earlier studies that Btk is involved in both the BCR- and CD40-mediated signaling pathways. In this study, we analyzed the responsiveness of Epstein-Barr virus (EBV) transformed B cells from nine XLA patients to CD40 stimulation, particularly the CD40 induced activation of c-Jun N-terminal kinase (JNK). In eight XLA patients the JNK activation was unimpaired and in one case INK could not be activated by anti-CD40 stimulation. Btk protein expression was detectable by Western blotting in six cases, in one case Btk expression was drastically reduced, and in three cases no Btk expression could be observed. Btk kinase activity was found in three cases and it was reduced in one and not detectable in five cases. Furthermore, in one female patient with an agammaglobulinemia, Btk expression and function as well as JNK activation by CD40 stimulation was unimpaired. Our findings demonstrate that INK activation via the CD40 signaling pathway is intact in EBV-transformed B cells of most if not all XLA patients, independent of the mutation and its effect on Btk expression and kinase activity. We suggest that Btk is not necessary for the activation of INK upon CD40 stimulation, at least in the B cell subpopulation we had studied. We cannot exclude that these B cells belong to a "leaky" B-cell subpopulation in which the CD40 signaling pathway has become independent of Btk function.
authors.affiliation: Children's Hospital, University of Würzburg, Germany. Cornelia.Brunner@medizin.uni-ulm.de
authors.forename: Cornelia
authors.initials: C
authors.lastname: Brunner
authors.forename: Hans Wolfgang
authors.initials: HW
authors.lastname: Kreth
authors.forename: Hans D
authors.initials: HD
authors.lastname: Ochs
authors.forename: Volker
authors.initials: V
authors.lastname: Schuster
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000361:Agammaglobulinemia / Q000201:enzymology / Q000235:genetics / Q000276:immunology*; D000818:Animals; D001402:B-Lymphocytes / Q000201:enzymology* / Q000276:immunology*; D019013:CD40 Antigens / Q000378:metabolism*; D002460:Cell Line; D002472:Cell Transformation, Viral; D041321:Chromosomes, Human, X / Q000235:genetics; D004789:Enzyme Activation; D008040:Genetic Linkage; D004854:Herpesvirus 4, Human; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009154:Mutation; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014763:Viral Matrix Proteins / Q000235:genetics
chemical_list: D019013:CD40 Antigens; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D014763:Viral Matrix Proteins; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases