Abstract
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.
Highlights
Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder, characterized by persistent thrombocytopenia in which the destruction of autoantibody-opsonized platelets by phagocytic cells plays an important role
To investigate whether the immunoproteasome plays a role in human ITP, we compared the levels of large multifunctional protease 2 (LMP2) and LMP7 in the Peripheral blood mononuclear cells (PBMCs) of ITP patients (Table 1) and healthy individuals
enzyme-linked immunosorbent assay (ELISA) and RT-PCR analysis showed that LMP2 protein expression and gene transcription were both significantly upregulated in ITP patients compared to healthy controls (Figures 1A, B)
Summary
Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder, characterized by persistent thrombocytopenia in which the destruction of autoantibody-opsonized platelets by phagocytic cells plays an important role. As an acquired autoimmune disease, the immune response underlying ITP pathogenesis involves a complex interaction between antigen-presenting cells (APCs), T cells, and B cells, in which the recognition of platelet antigens by autoreactive T helper (Th) cells, as well as Th cell activation, are critical events. The proteasome is a multi-subunit proteolytic complex that degrades the majority of non-lysosomal proteins in eukaryotic cells. The catalytic activity of proteasomes is exerted by three subunits, b1, b2, and b5, which are constitutively expressed in all cells [3]. The immunoproteasomes have higher chymotrypsin-like activity and a higher ability to process and present antigens, as compared to standard proteasomes [5]
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