The immunoproteasome, a special isoform of the 20S proteasome, is expressed when the cells receive an inflammatory signal. Immunoproteasome inhibition proved efficacy in the treatment of autoimmune diseases. However, the role of the immunoproteasome in the pathogenesis of immune thrombocytopenia (ITP) remains unknown. We found that the expression of the immunoproteasome catalytic subunit, large multifunctional protease 2 (LMP2), was significantly upregulated in peripheral blood mononuclear cells of active ITP patients compared to those of healthy controls. No significant differences in LMP7 expression were observed between patients and controls. ML604440, an specific LMP2 inhibitor, had no significant impact on the platelet count of ITP mice, while ONX-0914 (an inhibitor of both LMP2 and LMP7) increased the number of platelets. In vitro assays revealed that ONX-0914 decreased the expression of FcγRI in ITP mice and decreased that of FcγRIII in ITP patients, inhibited the activation of CD4+ T cells, and affected the differentiation of Th1 cells in patients with ITP. These results suggest that the inhibition of immunoproteasome is a potential therapeutic approach for ITP patients.
Background: The E3 ubiquitin ligase casitas B-lineage lymphoma-b (CBLB) is a newly identified component of the ubiquitin-dependent protein degradation system and is thought to be an important negative regulator of immune cells. CBLB is essential for establishing a threshold for T cell activation and for regulating peripheral T cell tolerance through various mechanisms. However, the role of CBLB in the pathogenesis of immune thrombocytopenia (ITP) remains unknown. Methods: We performed quantitative proteomics to showed reduced CBLB expression and increased PI3K expression in CD4+ T cells from ITP patients. The regulating effect of CBLB on anergy induction was evaluated after transfecting with adenoviridae. We detected DNA methylation levels of the CBLB gene promoter and 5′UTR in CD4+ T cells using MassARRAY EpiTYPER. Results: We found that CD4+ T cells from patients with ITP showed resistance to anergy. Furthermore, highly activated PI3K-AKT signaling, and decreased CBLB expression were found in these pathogenic T cells, indicating that they may be involved in anergy resistance in ITP. Further research revealed that CBLB overexpression effectively decreased p-AKT and reversed anergy resistance. Notably, 5′ untranslated regions (UTR) hypermethylation of CBLB was found in CD4+ T cells from patients with ITP, and low-dose decitabine significantly increased the expression of CBLB in patients with ITP in remission. Conclusions: These results indicate that 5′UTR hypermethylation of the CBLB gene is involved in T cell anergy resistance in ITP through inhibition of CBLB expression. Upregulation of CBLB expression might be a potential therapeutic approach for ITP.
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