Background/Purpose: Rheumatoid arthritis (RA) is a debilitating autoimmune disorder characterized by chronic inflammation and joint damage. This study investigates the role of Dual Specificity Phosphatase 22 (DUSP22), also known as JKAP, in the pathogenesis of RA, with a specific focus on its interaction with UBR2 and the downstream effects on T cell activation. We also explore the hypothesis that single nucleotide polymorphisms (SNPs) within the UBR2 gene may lead to functional changes in the protein, affecting its role in the immune response and contributing to the variability in RA disease progression observed among patients.

Methods:  Peripheral blood samples were collected from 14 RA patients and 6 healthy controls. DUSP22 expression was analyzed using Western blotting. T cells were purified and activated, followed by proximity ligation assays (PLA) to assess Lck ubiquitination and UBR2-Lck interactions. JKAP knockout (KO) mice were generated to evaluate arthritis severity and cytokine profiles. Histological analyses and ELISAs were performed to assess joint damage and cytokine levels, respectively. Genotyping of the UBR2 gene in RA patients and healthy controls was conducted using next-generation sequencing to identify prevalent SNPs.

Results:  DUSP22 expression was significantly reduced in the peripheral blood leukocytes and T cells of RA patients compared to healthy controls. UBR2 is implicated in protein degradation pathways and interacts with key signaling molecules involved in immune cell activation, such as Lck. UBR2 modulates Lck activity through K63-linked ubiquitination, suggesting a critical role in T cell signaling and autoimmune disease pathogenesis. JKAP KO mice exhibited more severe arthritis with increased synovial proliferation and cartilage damage. Elevated levels of pro-inflammatory cytokines IL-6 and IL-17A were observed in the serum and joint tissues of JKAP KO mice. Genotyping revealed significant SNPs within the UBR2 gene, which may lead to functional changes in the protein and affect immune response variability, potentially contributing to RA disease progression.

Conclusion: Our findings suggest that DUSP22 plays a critical role in modulating inflammatory processes in RA. The downregulation of DUSP22 in RA patients may influence UBR2-mediated pathways, contributing to the heightened T cell activation and inflammation observed in RA. Additionally, SNPs within the UBR2 gene may lead to functional changes affecting immune response variability and RA disease progression. These results highlight DUSP22 and UBR2 as potential therapeutic targets for RA and provide insights into the molecular mechanisms underlying RA pathogenesis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-role-of-dual-specificity-phosphatase-22-dusp22-in-rheumatoid-arthritis-mechanism-and-genetic-investigations/