title: The protein tyrosine phosphatase PTP1B is a negative regulator of CD40 and BAFF-R signaling and controls B cell autoimmunity.
abstract: Tyrosine phosphorylation of signaling molecules that mediate B cell activation in response to various stimuli is tightly regulated by protein tyrosine phosphatases (PTPs). PTP1B is a ubiquitously expressed tyrosine phosphatase with well-characterized functions in metabolic signaling pathways. We show here that PTP1B negatively regulates CD40, B cell activating factor receptor (BAFF-R), and TLR4 signaling in B cells. Specifically, PTP1B counteracts p38 mitogen-activated protein kinase (MAPK) activation by directly dephosphorylating Tyr(182) of this kinase. Mice with a B cell-specific PTP1B deficiency show increased T cell-dependent immune responses and elevated total serum IgG. Furthermore, aged animals develop systemic autoimmunity with elevated serum anti-dsDNA, spontaneous germinal centers in the spleen, and deposition of IgG immune complexes and C3 in the kidney. In a clinical setting, we observed that B cells of rheumatoid arthritis patients have significantly reduced PTP1B expression. Our data suggest that PTP1B plays an important role in the control of B cell activation and the maintenance of immunological tolerance.
authors.affiliation: BIOSS Centre for Biological Signalling Studies; and 2 Department of Molecular Immunology, Institute of Biology III, Faculty of Biology; University of Freiburg, D-79104 Freiburg, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Medgyesi
authors.forename: Elias
authors.initials: E
authors.lastname: Hobeika
authors.forename: Robert
authors.initials: R
authors.lastname: Biesen
authors.forename: Florian
authors.initials: F
authors.lastname: Kollert
authors.forename: Adriano
authors.initials: A
authors.lastname: Taddeo
authors.forename: Reinhard E
authors.initials: RE
authors.lastname: Voll
authors.forename: Falk
authors.initials: F
authors.lastname: Hiepe
authors.forename: Michael
authors.initials: M
authors.lastname: Reth
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D018501:Antirheumatic Agents / Q000494:pharmacology; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D015551:Autoimmunity / Q000276:immunology*; D053265:B-Cell Activation Factor Receptor / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology*; D015153:Blotting, Western; D019013:CD40 Antigens / Q000378:metabolism*; D049109:Cell Proliferation; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008875:Middle Aged; D010957:Plasmids / Q000235:genetics; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000276:immunology* / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D014162:Transfection
chemical_list: D018501:Antirheumatic Agents; D053265:B-Cell Activation Factor Receptor; D019013:CD40 Antigens; C486662:Tnfrsf13c protein, mouse; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1