title: Role of protein tyrosine kinases and phosphatases in isotype switching: crosslinking CD45 to CD40 inhibits IgE isotype switching in human B cells.
abstract: Protein tyrosine kinases and protein tyrosine phosphatases play an important role in the transduction of signals via antigen receptors in T and B cells, and in CD40-dependent B-cell activation. To examine the role of tyrosine kinases and phosphatases in B-cell isotype switching, we examined the effects of the engagement of the transmembrane phosphatase CD45 on the synthesis of IgE induced by IL-4 and anti-CD40 monoclonal antibody (mAb). Crosslinking CD45 to CD40 using biotinylated mAbs and avidin strongly inhibited CD40-mediated IgE synthesis in IL-4-treated human B cells. CD40/CD45 crosslinking did not affect epsilon germline transcription in B cells stimulated with IL-4, but strongly inhibited induction of S mu/S epsilon switch recombination as detected by a nested primer polymerase chain reaction assay. The B-cell src-type tyrosine kinase lyn, which is activated following CD40 engagement, is a potential target for the effects of CD45 observed in our experiments, because CD45/CD40 crosslinking resulted in the inhibition of CD40-mediated lyn phosphorylation and activation. These results suggest an important role for protein tyrosine kinases and phosphatases in CD40-mediated induction of isotype switching to IgE.
authors.affiliation: Children's Hospital/Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: R K
authors.initials: RK
authors.lastname: Loh
authors.forename: H H
authors.initials: HH
authors.lastname: Jabara
authors.forename: C L
authors.initials: CL
authors.lastname: Ren
authors.forename: S M
authors.initials: SM
authors.lastname: Fu
authors.forename: D
authors.initials: D
authors.lastname: Vercelli
authors.forename: R S
authors.initials: RS
authors.lastname: Geha
mesh_terms: D015703:Antigens, CD / Q000378:metabolism*; D000944:Antigens, Differentiation, B-Lymphocyte / Q000378:metabolism*; D001402:B-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*; D001483:Base Sequence; D019013:CD40 Antigens; D015322:Gene Rearrangement, B-Lymphocyte; D006801:Humans; D017578:Immunoglobulin Class Switching; D007073:Immunoglobulin E / Q000096:biosynthesis / Q000235:genetics*; D015847:Interleukin-4 / Q000494:pharmacology; D017493:Leukocyte Common Antigens / Q000378:metabolism*; D008969:Molecular Sequence Data; D010749:Phosphoprotein Phosphatases / Q000502:physiology*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011505:Protein-Tyrosine Kinases / Q000378:metabolism / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction; D014158:Transcription, Genetic; D019061:src-Family Kinases
chemical_list: D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; D019013:CD40 Antigens; D011994:Recombinant Proteins; D015847:Interleukin-4; D007073:Immunoglobulin E; D011505:Protein-Tyrosine Kinases; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D010749:Phosphoprotein Phosphatases; D017493:Leukocyte Common Antigens