title: Enhanced Tyrosine Phosphatase Activity Underlies Dysregulated B Cell Receptor Signaling and Promotes Survival of Human Lupus B Cells.
abstract: Systemic lupus erythematosus (SLE) is associated with hyperactivity of B cells and abnormalities of B cell receptor (BCR) signaling. To address the linkage between dysregulated BCR signaling and increased B cell function, we assessed immediate phosphorylation events in lupus B cells.
  
  
  
  B cells from SLE patients and healthy donors were analyzed by flow cytometry to assess phosphorylated CD22, Syk, and Akt as well as the basal expression of the BCR coreceptors CD22 and CD19. Confocal microscopy studies determined the recruitment of CD22 and the tyrosine phosphatase SH2 domain-containing phosphatase 1 to the activated BCR complex. Additionally, phosphatase activity in SLE versus healthy donor B cells was measured.
  
  
  
  B cells from SLE patients showed diminished Syk phosphorylation and reduced intracellular calcium release after BCR activation as compared to B cells from healthy donors. This was related to an enhanced activity of tyrosine, but not serine/threonine, phosphatases and was corrected by inhibition of tyrosine phosphatase activity. In contrast to reduced Syk phosphorylation after BCR activation, phosphorylation of Akt was significantly increased in SLE B cells. The disturbed balance between Syk and Akt phosphorylation was significantly correlated with B cell survival following BCR engagement. Furthermore, CD27-, but not CD27+, B cells from SLE patients displayed increased expression and phosphorylation of the inhibitory BCR coreceptor CD22.
  
  
  
  These results indicate that an imbalance between serine and tyrosine phosphatases in SLE contributes to an intrinsically disturbed balance of BCR-initiated signaling pathways, resulting in enhanced survival of lupus B cells and differentiation into plasma cells.
authors.affiliation: Charité University Medicine Berlin and German Rheumatism Research Center Berlin, Berlin, Germany.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Fleischer
authors.affiliation: Charité University Medicine Berlin and German Rheumatism Research Center Berlin, Berlin, Germany.
authors.forename: Capucine
authors.initials: C
authors.lastname: Daridon
authors.affiliation: Charité University Medicine Berlin and German Rheumatism Research Center Berlin, Berlin, Germany.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Fleischer
authors.affiliation: National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Lipsky
authors.affiliation: Charité University Medicine Berlin and German Rheumatism Research Center Berlin, Berlin, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Dörner
mesh_terms: D000328:Adult; D000368:Aged; D018941:Antigens, CD19 / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D016022:Case-Control Studies; D002454:Cell Differentiation / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000378:metabolism; D008297:Male; D018613:Microscopy, Confocal; D008875:Middle Aged; D010766:Phosphorylation / Q000276:immunology; D010950:Plasma Cells / Q000276:immunology / Q000378:metabolism; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D000072377:Syk Kinase / Q000378:metabolism; D055815:Young Adult
chemical_list: D018941:Antigens, CD19; C000604811:CD19 molecule, human; D011947:Receptors, Antigen, B-Cell; D051918:Sialic Acid Binding Ig-like Lectin 2; C000606896:SYK protein, human; D000072377:Syk Kinase; D051057:Proto-Oncogene Proteins c-akt; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6