Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by synovial joint inflammation and systemic immune dysregulation. A hallmark feature of RA is the impaired responsiveness of peripheral blood (PB) and synovial fluid (SF) T cells, particularly in their ability to mount effective responses upon T-cell receptor (TCR) engagement. This hyporesponsiveness has been linked to defects in early TCR signaling events, including diminished calcium flux and altered phosphorylation dynamics of key signaling molecules. Central to this process is the protein tyrosine phosphatase CD45, which plays a pivotal role in regulating Src-family kinases such as Lck by dephosphorylating inhibitory tyrosine residues—most notably Tyr505. The activity of CD45 is highly sensitive to redox modulation due to the presence of a reactive cysteine residue at its catalytic site, rendering it vulnerable to inactivation by reactive oxygen intermediates (ROI).
In this study, we investigated whether oxidative inactivation of CD45 contributes to the functional impairment observed in RA CD4+ T cells.GATA4 Antibody Protocol We measured CD45 phosphatase activity in PB and SF-derived CD4+ T cells from RA patients (n = 11), disease control (DSC) patients (n = 8), and healthy controls (HC; n = 19). Results revealed a significant reduction in CD45 activity in RA PB (56% lower than HC, p < 0.02) and SF (59% lower, p < 0.05) T cells, while no such deficit was observed in DSC patients. This selective loss of activity suggests that the phenomenon is not simply a consequence of general inflammation but may be driven by specific redox alterations intrinsic to RA. Further analysis showed that reduced glutathione (GSH) levels were markedly decreased in RA PB CD4+ T cells compared to HC (p < 0.001), with oxidized glutathione (GSSG) also significantly elevated (p < 0.05), indicating a compromised antioxidant capacity. Despite these changes, the overall redox potential remained within normal physiological ranges, suggesting that cells maintain viability under redox stress but are functionally impaired. Importantly, treatment of RA PB T cells with N-acetyl cysteine (NAC), a GSH precursor, restored CD45 phosphatase activity by 35.Lithium acetate dihydrate References 8% (median), significantly greater than the 12.PMID:35064171 6% increase seen in HC cells (p < 0.05). This enhancement was accompanied by increased T-cell proliferation and reduced phosphorylation of Lck at Tyr505, confirming functional reactivation of the TCR signaling axis. These findings support the hypothesis that reversible oxidative inactivation of CD45 underlies the immune hyporesponsiveness seen in RA. The partial recovery of CD45 function with NAC indicates that the inactivation is primarily due to transient oxidation rather than irreversible damage, although some permanent modifications may persist. Structural studies have shown that PTP oxidation initially forms a sulfenyl-amide intermediate, which can protect against further irreversible oxidation to sulfinic or sulfonic forms—explaining the reversibility observed here. Given that CD45 governs the initial activation threshold of TCR signaling, even modest reductions in its activity can profoundly disrupt downstream events, leading to inadequate immune responses. This mechanism may explain why RA patients exhibit both defective T-cell activation and persistent autoimmunity—impaired regulation allows autoreactive clones to escape tolerance mechanisms. Furthermore, similar CD45 dysfunction has been reported in aging and systemic lupus erythematosus, suggesting a broader relevance of redox-sensitive phosphatase regulation in immune pathology. We conclude that oxidative inactivation of CD45 represents a critical link between chronic inflammation, redox imbalance, and immune cell dysfunction in RA. Targeting this pathway through antioxidant supplementation—particularly agents like NAC—may offer a novel therapeutic strategy to restore immune homeostasis and mitigate disease progression.MedChemExpress (MCE) offers a wide range of high-quality research chemicals and biochemicals (novel life-science reagents, reference compounds and natural compounds) for scientific use. We have professionally experienced and friendly staff to meet your needs. We are a competent and trustworthy partner for your research and scientific projects.Related websites: https://www.medchemexpress.com