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Primary immune thrombocytopenia (ITP) is an autoimmune disease with many immune dysfunctions including T helper type 1 cell (Th1) polarization and regulatory T cells (Tregs) deficiency. This study aimed to determine the effects of TLR4 on Treg differentiation and the cytokine production of peripheral blood mononuclear cells (PBMCs) from patients with ITP. We found that expression of TLR4 on monocytes was significantly decreased in patients with active ITP than that in healthy controls and it had positive correlation with platelet count. However, there was no expression of TLR4 on CD4+ T cells. The result of further experimentsin vitroshowed that lipopolysaccharide (LPS) stimulation could enhance TLR4 expression on monocytes. Additionally, activation of TLR4 with LPS could promote differentiation of Treg cells and anti-TLR4 attenuated this effect. There was no significant difference about Th17 cells among three subgroups. However, the Th17/Treg cell ratio was decreased after stimulation with LPS and increased with anti-TLR4. Moreover, activation of TLR4 with LPS could significantly promote the secretion of interleukin-10 (IL-10) and transforming growth factor-β1 (TGFB1), while anti-TLR4 significantly suppressed the secretion of them. Nevertheless, the secretion of IL-17A did not reach the statistical difference among three subgroups. In summary, decreased TLR4 appears to cause Tregs abnormality in ITP by modulating Tregs differentiation and immunoregulatory cytokines. [ABSTRACT FROM AUTHOR]

TMEVPG1 is a long noncoding RNA, which can promote Interferon gamma (IFNG) transcript as an enhancer. It has been reported that plasma IFNG concentration was elevated and partly due to dysregulation of micro RNAs in patients with primary immune thrombocytopenia (ITP). However, the effect of long noncoding RNA on IFNG expression in ITP is currently not well understood. To explore whether TMEVPG1 is involved in ITP, this study examined the TMEVPG1 expression and analyzed the association between TMEVPG1 transcript and IFNG expression in patients with ITP and healthy controls. The result showed that TMEVPG1 expression in peripheral blood mononuclear cells (PBMCs) from active ITP patients were lower than in that of healthy controls. Further activation for 24 hin vitroresulted in decreased TMEVPG1 while elevated IFNG mRNA and protein expressions in activated PBMCs compared with un-activated PBMCs both in ITP patients and healthy controls. However, TMEVPG1 and IFNG mRNA had same up-regulated tendency after short-time activation (1, 2 and 4 h) in healthy controls. In addition, we detected T helper 1 (Th1) cell associated transcription factors T-bet, STAT1 and STAT4 mRNA levels, and found T-bet mRNA expression was lower in PBMCs from ITP patient in remission compared with healthy controls. In conclusion, we speculated that TMEVPG1 could promote IFNG transcription, and IFNG over-expression negative feedback regulated on TMEVPG1 expression, which resulted in decreased TMEVPG1 in ITP patients. [ABSTRACT FROM PUBLISHER]

Primary immune thrombocytopenia (ITP) is an autoimmune disorder that is characterized by low platelet count. Glucocorticoids (GCs) resistance is a great challenge in the treatment of ITP. P-glycoprotein (P-gp) is a widely studied protein, which is associated with drug resistance. However, in ITP, the functional activity and immune regulation mechanism of P-gp remain uncertain. In this study, we evaluated the expression and functional activity of P-gp in different lymphocyte subsets, explored the correlation between P-gp function and GCs resistance and investigated the role of P-gp in ITP pathogenesis. Results indicated that the functional activity and mRNA level of P-gp were significantly higher in GCs-nonresponsive patients than in GCs-responsive patients with ITP. However, these differences in P-gp were only significant in CD8+ T cells. P-gp function was related to disease activity rather than GCs therapy. P-gp was involved in secreting granzyme B and perforin, maintaining autoreactive lymphocytes survival and enhancing autologous platelets lysis in ITP. In conclusion, over-functional P-gp might play an important role in the pathogenesis of ITP and induce GCs resistance in nonresponsive ITP patients. The blockage of P-gp could be a promising therapeutic approach for GCs-resistant patients with ITP. [ABSTRACT FROM AUTHOR]

Primary immune thrombocytopenia (ITP) is an acquired autoimmune disease. 1α, 25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ] and vitamin D receptor (VDR) play important immune-suppressive roles in immune system. It has been reported that serum 1,25(OH) 2 D 3 were lower in ITP patients. In this study, we evaluated local 1,25(OH) 2 D 3 level and VDR mRNA expression further, and determined whether 1,25(OH) 2 D 3 /VDR were correlated with T cell dysfunction in ITP patients. We found that 1,25(OH) 2 D 3 /VDR levels were decreased in active ITP patients, and 1,25(OH) 2 D 3 had significant anti-inflammatory effects on ITP patients, including both anti-proliferation of peripheral blood mononuclear cells (PBMCs) and reversing the abnormal T cells polarization. 1,25(OH) 2 D 3 inhibited the differentiation of T helper (Th)1 and Tc1 cells but induced the differentiation of Th2, Tc2 and T regulatory (Treg) cells in ITP patients. However, the percentage of Th17 cells were not affected obviously with 1,25(OH) 2 D 3 . In addition, 1,25(OH) 2 D 3 also suppressed pro-inflammatory cytokines (INF-γ and IL-17A) but promoted anti-inflammatory cytokine (IL-10) secretion in ITP patients. In conclusion, decreased 1,25(OH) 2 D 3 /VDR might participate in the pathogenesis of ITP, and appropriate supplement of 1,25(OH) 2 D 3 may be a promising treatment. [ABSTRACT FROM AUTHOR]