BackgroundPrimary immune thrombocytopenia (ITP) is an autoimmune heterogeneous disorder that is characterized by decreased platelet count. Regulatory T (Treg) cells and T helper type 17 (Th17) cells are two subtypes of CD4+ T helper (Th) cells. They play opposite roles in immune tolerance and autoimmune diseases, while they share a common differentiation pathway. The imbalance of Treg/Th17 has been demonstrated in several autoimmune diseases. In this study, we aimed to investigate the ratio of the number of Treg cells to the number of Th17 cells in ITP patients and evaluate the clinical implications of the alterations in this ratio.MethodsThirty adult patients with newly diagnosed ITP enrolled in this study. Twelve patients had been clinically followed up for 12 months. The percentages of CD4+CD25hiFoxp3+ Treg cells and CD3+CD4+IL-17-producing Th17 cells in these patients and healthy controls (n = 17) were longitudinally analyzed by flow cytometry.ResultsThe percentage of Treg cells in ITP patients was significantly lower than that of healthy controls, and the percentage of Th17 cells increased significantly at disease onset. The ratio of Treg/Th17 correlated with the disease activity.ConclusionThe ratio of Treg/Th17 might be relevant to the clinical diversity of ITP patients, and this Treg/Th17 ratio might have prognostic role in ITP patients.

Primary immune thrombocytopenia (ITP) is an autoimmune heterogeneous disorder. Excessive activated CD4(+) T effector cells (Teffs) and compromised regulatory T cells (Tregs) were reported in ITP patients, yet little is known about the mechanisms. Interleukin-10 (IL-10) is an important regulatory cytokine of Tregs in inflammatory condition. It has been recently highlighted that IL-10-producing Tregs contribute to the effective controls of several autoimmune diseases. Hence this study was aimed to examine the role of IL-10 produced by Tregs in newly diagnosed ITP patients. Newly diagnosed ITP patients and healthy volunteers were enrolled to assess the numbers of peripheral Th1, Th17 cells and Tregs. CD4(+)CD25(-)Teffs and CD4(+)CD25(+)Tregs were purified. CD4(+)CD25(-)Teffs, labeled with CFSE, were cultured alone or with Tregs for 5 days, and the supernatants were then collected for IL-10 concentration test. The role of IL-10 in Tregs' inhibitory function was also determined. In ITP patients, Teffs were excessively activated, while the Tregs were numerically and functionally impaired. The percentages of IL-10(+) Tregs in Tregs' population were found elevated dramatically in ITP patients but decreased in the remitted patients. The IL-10 concentrations in the cultured supernatant were decreased in ITP patients but elevated in the remitted patients. Furthermore, the IL-10 secretion by Tregs was dramatically decreased in ITP patients. IL-10 treatment enhanced the suppression effect of Tregs toward Teffs, whereas anti-IL-10 treatment boosted the proliferation of Teffs and Th17 cells. Excessive activated Teffs and impaired Tregs play major roles in the exuberant CD4(+) T cells immune responses of ITP. The inhibitory effect of Tregs toward Teffs is largely exerted by IL-10. Insufficient secretion of IL-10 compromises the inhibitory capability of Tregs against Teffs in newly diagnosed ITP patients.

Background. Regulatory B cells (Breg) are a distinct B cell subset with immunoregulatory properties. Pivotal to Breg function is interleukin-10. This study was to investigate the role of IL-10-producing B cell (B10) and its association with Treg and Th17 subsets in immune thrombocytopenia (ITP) patients. Methods. Peripheral blood mononuclear cells from ITP patients and controls were stimulated with PMA, ionomycin, and Brefeldin A. The frequencies of CD19+IL-10+ B cells, CD3+CD4+IL-17+ Th17 cells, and CD4+CD25hiFoxp3+ Treg cells were analyzed by flow cytometry. The mRNA expression of Foxp3 and RORγt was detected by real-time quantitative PCR. Results. The number of B10 cells was elevated in ITP patients. After first-line therapies, it remained at high level in patients who achieved complete or partial response but decreased in those who acquired no response. There was a positive correlation between B10 cells and Tregs in ITP both before and after therapies. The ratio of Treg/Th17 decreased in ITP, and it strongly correlated with B10 cells. Conclusions. The frequency of B10 cells is elevated in ITP and it correlates with both the Tregs counts and the Treg/Th17 ratio. B10 cells to regulate functional T cell subsets might be impaired in patients with ITP.

BackgroundAlthough impaired myeloid-derived suppressor cells (MDSCs) recently have been studied in immune thrombocytopenia (ITP), another myeloid-derived cell population signified as M2 macrophages has not been investigated properly in ITP patients. In the present study, we intended to determine the features of circulating M2-like macrophages, to examine its relationship with MDSCs, and to explore their prognostic values in ITP.MethodsPeripheral blood mononuclear cells from healthy controls and primary ITP patients were isolated to test the circulating M2-like macrophages and MDSCs. The circulating M2-like macrophage population defined as CD68+CD163+ and circulating MDSC population as CD11b+CD33+HLA-DR− were determined by flow cytometry. Plasma inflammatory cytokines were measured by multiplex ELISA.ResultsThe percentages of MDSCs were found to be expanded in newly diagnosed patients of ITP, especially among those of the complete response (CR) group (p < 0.0001). Positive linear correlation was verified between percentages of M2-like macrophages and MDSCs. The same correlation was also determined in the CR group. After treatment, the percentages of M2-like macrophages and MDSCs were both increased significantly in CR group, while those patients among the PR + NR group manifested a significant numeric decrease of MDSCs but only a moderate decrease in M2-like macrophages. MIP-1α/CCL3 was negatively correlated with M2-like macrophages while MCP-1 possessed a positive correlation with M2-like macrophages, eotaxin-1/CCL11 was negatively correlated with MDSCs and interleukin-1β (IL-1β) was found to be negatively correlated with both M2-like macrophages and MDSCs.ConclusionsThe present findings indicated critical roles of both circulating M2-like macrophages and MDSCs in ITP. The positive correlation between them might be related to inflammatory factors-mediated bidirectional interactions or partially due to their similar background patterns during differentiation. MIP-1α/CCL3, MCP-1, eotaxin-1/CCL11 and IL-1β might play a critical role in the expansion of both M2 macrophages and MDSCs population in ITP patients, which deserves further investigation.Electronic supplementary materialThe online version of this article (10.1186/s12967-018-1424-8) contains supplementary material, which is available to authorized users.

Hypoxia is a common phenomenon in solid tumors. The roles of exosomes from hypoxic breast cancer stroma are less studied. So, the study was aimed to investigate the role of exosomes from hypoxic cancer-associated fibroblasts (CAFs) cells in breast cancer. The circRNA array analysis was performed to screen differential expressed circRNAs between hypoxic and normoxic CAFs exosomes. Candidate circHIF1A (circ_0032138) was screened out and it was confirmed that circHIF1A was up-regulated in the exosomes from hypoxic CAFs and their exosomes. Through investigating cellular functions including cell proliferation and stem cell features, it was demonstrated that hypoxic CAFs exosomes transferred circHIF1A into breast cancer cells, which played an important role in cancer stem cell properties sponging miR-580-5p by regulating CD44 expression. In a summary, circHIF1A from hypoxic CAFs exosomes played an important role in stem cell properties of breast cancer. CircHIF1A may act as a target molecule of breast cancer therapy.

B-cell lymphomas are heterogeneous blood disorders with limited therapeutic options, largely because of their propensity to relapse and become refractory to treatments. Carabin, a key suppressor of B-cell receptor signaling and proliferation, is inactivated in B-cell lymphoma by unknown mechanisms. Here, we identify prolyl 4-hydroxylase 2 (P4HA2) as a specific proline hydroxylase of Carabin. Carabin hydroxylation leads to its proteasomal degradation, thereby activating the Ras/extracellular signal-regulated kinase pathway and increasing B-cell lymphoma proliferation. P4HA2 is undetectable in normal B cells but upregulated in the diffuse large B-cell lymphoma (DLBCL), driving Carabin inactivation and lymphoma proliferation. Our results indicate that P4HA2 is a potential prognosis marker for DLBCL and a promising pharmacological target for developing treatment of molecularly stratified B-cell lymphomas.

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