Immunomodulatory effects of platelets on the severity of hand, foot, and mouth disease infected with enterovirus 71.

BACKGROUND: Enterovirus 71 (EV71) infection contributes to hand, foot, and mouth disease (HFMD) with severe neurogenic complications, leading to higher morbidity. In addition to their typical roles in coagulation, platelets could serve as essential immune regulatory cells to play a key role in the pathogenesis of this viral infection. METHODS: Platelet parameters were measured using an automatic hematology analyzer. T-helper type 1 (Th1) and Th2 cells were analyzed by flow cytometry. The levels of cytokines and key transcription factors were determined. RESULTS: The levels of platelet count and plateletcrit were positively associated with the severity of HFMD. Th1 and Th2 cells as well as their corresponding cytokines were increased in the severe group compared to the healthy volunteers. Moreover, the levels of platelets were negatively correlated with the level of interferon-γ (IFN-γ), but positively correlated with the frequency of Th1 cells. Coculture of platelets and naive CD4+ T cells showed that platelets from mild patients promote Th1 cell differentiation and IFN-γ secretion. CONCLUSIONS: Our study has shown for the first time that the distinct roles of platelets are responsible for the regulation of pathogenic CD4+ T cell differentiation and function in the pathogenesis of HFMD caused by EV71. IMPACT: Our study has shown for the first time that the distinct roles of platelets are responsible for the regulation of pathogenic CD4+ T cell differentiation and function in the pathogenesis of HFMD caused by EV71. For the first time, we have discovered the role of platelets in children's HFMD caused by EV71 infection, which may provide a better treatment for HFMD in the future. This article describes new discoveries in platelet immunity.

Gm15575 functions as a ceRNA to up-regulate CCL7 expression through sponging miR-686 in Th17 cells.

Compelling evidence has demonstrated that Th17 cells play an essential role in the pathogenesis of multiple sclerosis (MS). Long noncoding RNAs (lncRNAs) have been confirmed as vital regulators of immune cell differentiation and other functions. However, whether and how lncRNAs influence Th17 cell differentiation and functional behaviors remain largely unclear. Here, we identified that a lncRNA, namely Gm15575, is specifically enriched in Th17 cells and spleen tissues of EAE mice. Functionally, knockdown of Gm15575 in Th17 cells suppressed the secretion of IL17A. Mechanistically, Gm15575 served as a competing endogenous RNA (ceRNA) to block the function of miR-686, positively regulating the expression of CCL7, a pro-inflammatory chemokine with high expression in Th17 cells, and Th17 differentiation. Taken together, our study revealed that Gm15575-miR-686 axis promoted the progression of EAE by regulating Th17 differentiation and expression of CCL7 which elucidated the pathogenesis of autoimmune diseases at genetic level. Gm15575 can be involved in the course of Th17-related autoimmune diseases.

Immunomodulatory activity-guided isolation and characterization of a novel polysaccharide from Atractylodis macrocephalae Koidz.

The Rhizoma of Atractylodis macrocephala Koidz. is a traditional Chinese herbal medicine that has been widely and empirically used for unexplained recurrent spontaneous abortion. In this study, a polysaccharide from the Rhizoma of Atractylodis macrocephala Koidz., designated as RAMP2, with an absolute molecular weight of 4.354 × 103 Da was isolated and found to be composed of mannose, galacturonic acid, glucose, galactose and arabinose. The NMR results displayed that →3-ß-glcp-(1→, →3,6-ß-glcp-(1→, →6-ß-glcp-(1→, T-ß-glcp-(1→, →4-α-galpA-(1→, →4-α-galpA-6-OMe-(1→, →5-α-araf-(1→, →4,6-ß-manp-(1→ and →4-ß-galp-(1→ were the main linkages in RAMP2. TEM and SEM results indicated that RAMP2 was globular in structure. Furthermore, in vitro experiments on murine CD4+ T cells revealed that RAMP2 could increase the percentage of Treg cells, up-regulate Foxp3, IL-10 and IL-2 mRNA expressions and the secretion of IL-10 and IL-2. RAMP2 was further shown to increase STAT5 phosphorylation levels in Treg cells, suggesting that RAMP2 increased the number of Treg cells through IL-2/STAT5 pathway.

Anti-IL-12/23 p40 antibody attenuates chronic graft-versus-host disease with lupus nephritis via inhibiting Tfh cell in mice.

Systemic lupus erythematosus (SLE) is an autoimmune disease that is mainly caused by excessive accumulation of autoantibodies that target autoantibodies such as nucleic acids. T helper (Th) cell have been associated with the development of SLE. Typically, different subsets of Th cells secrete various cytokines to regulate the disease progression. IL-12 and IL-23 participate in the differentiation and activation of multiple Th cell subsets, including Th1, Th2, Th9, Th17, regulatory T (Treg) and follicular helper T (Tfh) cells. Because of the signature p40 subunit shared by IL-12 and IL-23, blocking IL-12/IL-23 signaling may interfere the differentiation of Th cell and directly inhibit the secretion of proinflammatory cytokines. In this study, we examined the effects of anti-IL-12/23 p40 antibody on chronic graft-versus-host disease with lupus nephritis, and found that the therapeutic effectiveness was mediated through the inhibition of Tfh cell in mice. Moreover, anti-IL-12/23 p40 antibody inhibited human Tfh cell differentiation in vitro. These results strongly suggest that Tfh cell contribute to the pathogenesis of SLE, and the neutralization of IL-12/IL-23 signaling during Tfh cell differentiation may be critical for the treatment of SLE.

Human IL-23R Cytokine-Binding Homology Region-Fc Fusion Protein Ameliorates Psoriasis via the Decrease of Systemic Th17 and ILC3 Cell Responses.

Interleukin (IL)-23 is considered an effective therapeutic target for the treatment of psoriasis because of the crucial role of the IL-23/IL-17 axis in the pathogenesis of psoriasis, and it has recently been reported to be involved in ILC3 cell differentiation. In this study, we report that eukaryotically expressed rhIL23R-CHR/Fc, as an endogenous extracellular receptor analogue, could be a natural antagonist in an imiquimod (IMQ)-induced psoriasis-like mouse model, including the antagonizing effect of suppressed inflammation in the skin lesion, decreased production of pro-inflammatory cells, and reduced the expression of pro-inflammatory factors. The rhIL23R-CHR/Fc fusion protein inhibits both innate immune and adaptive immune-mediated inflammatory responses. These findings shed light on rhIL23R-CHR/Fc as a promising candidate therapy for the treatment of psoriasis.

Involvement of lncRNA-1700040D17Rik in Th17 cell differentiation and the pathogenesis of EAE.

IL-23/STAT3 signaling pathway is a key process in Th17 cell differentiation, and Th17 cells are closely related to the development of autoimmune diseases. We previously designed and prepared rhIL23R-CHR protein to antagonize endogenous IL-23, showing effectiveness in the treatment of experimental autoimmune encephalomyelitis (EAE) in mice. To further elucidate the mechanism of action, mouse lncRNA microarray was used to screen expression profiles of lncRNAs, and a particular lncRNA, 1700040D17Rik was found to down-regulate in EAE model and its expression was significantly increased after the treatment by rhIL23R-CHR. The function of 1700040D17Rik was revealed to associate with the differentiation of Th17 cells through the regulation of the key transcription factor RORγt. Together, regulation of Th17 cells through lncRNA is responsible for the effects of rhIL23R-CHR to balance the immune responses, and 1700040D17Rik has the potential to serve as a therapeutic target or a biomarker for autoimmune diseases.

Anti-inflammatory effects of interleukin-23 receptor cytokine-binding homology region rebalance T cell distribution in rodent collagen-induced arthritis.

IL-23 is an important cytokine to regulate Th17 cell differentiation and promote the proliferation of inflammatory cells in Th17-mediated autoimmune diseases. The collagen-induced arthritis (CIA) in rat is a model of rheumatoid arthritis characterized by pronounced inflammatory auto-responses from B and T cells, especially Th17 cells in lesions. In the present study, we used rhIL23R-CHR to block the IL-23 signaling pathway to probe the importance of IL-23 in misbalancing the ratio of Th17/Th9/Treg cells in CIA rats. After treatments with rhIL23R-CHR, the CIA rats showed a significant decrease of secretions of IL-17 and IL-9, whereas FoxP3 was activated in the process, indicating that IL-23 can manipulate the balance of Th17/Th9/Treg cells. Similar to the animal model, IL-23 also possessed remarkable proinflammatory effects on human fibroblast-like synoviocyte cells (HFLS), showing synergetic outcomes with TNF-α. Together, IL-23 could act as a modulator to imbalance the ratio of Th17/Th9/Treg cells, and rhIL23R-CHR could serve as a potential therapeutic agent for RA patients.