title: Does oxidative inactivation of CD45 phosphatase in rheumatoid arthritis underlie immune hyporesponsiveness?
abstract: The protein tyrosine phosphatase (PTP) CD45 is critical in regulating the earliest steps in T-cell-receptor signaling but, similar to all PTPs, it is susceptible to oxidative inactivation. Given the widely reported effects of oxidant damage associated with rheumatoid arthritis (RA), we examined whether CD45 phosphatase activity was altered in CD4(+) T cells from RA patients and related this to CD4(+) T-cell function and redox status. CD45 phosphatase specific activity in T cells from RA peripheral blood (PB) and synovial fluid was 56% and 59% lower than in healthy control (HC) PB, respectively. In contrast, CD45 activity in T cells from disease controls (DSC) was not significantly different from HC. Both reduced glutathione (GSH) (p<0.001) and oxidized glutathione (GSSG) (p<0.05) were significantly lower in RA PB T cells compared with HC PB T cells. Treatment of RA PB T cells with the GSH precursor N-acetyl cysteine increased CD45 phosphatase activity and proliferation, while it decreased Lck kinase phosphorylation, which is regulated by CD45. Our observations lead to the hypothesis that the largely reversible oxidative inactivation of the CD45 phosphatase may underlie the decreased signaling efficiency and functional responsiveness which are characteristic of RA PB CD4(+) T cells.
authors.affiliation: Rheumatology Research Group, Centre for Translational Inflammation Research, College of Medical and Dental Sciences, School of Immunity and Infection, University of Birmingham , Birmingham, United Kingdom .
authors.forename: David A
authors.initials: DA
authors.lastname: Rider
authors.forename: Rachel
authors.initials: R
authors.lastname: Bayley
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Clay
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Young
mesh_terms: D001172:Arthritis, Rheumatoid / Q000201:enzymology* / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D017493:Leukocyte Common Antigens / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000276:immunology
chemical_list: D017493:Leukocyte Common Antigens