Increased Frequency of Circulating Follicular Helper T Cells in Children with Hand, Foot, and Mouth Disease Caused by Enterovirus 71 Infection

Wu, Jianping; Cui, David; Yang, Xianzhi; Lou, Jianzhou; Lin, Jie; Ye, Xianfei; Qin, Zhimei; Huang, Li Min; Zhao, Dejian; Huo, Zhaoxia; Xie, Guoliang; Zheng, Shufa; Yu, Fei; Lu, Liwei; Chen, Yu

doi:10.1155/2014/651872

Cited by 20 publications

(24 citation statements)

References 37 publications

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“…In this study, correlation analysis showed an increase in the plasma levels of IL-17A and the frequencies of cTh17 cells, which also implied that the increased IL-17A expressions might be predominantly produced by cTh17 cells and associated with the pathogenesis of EV71-associated HFMD. Moreover, plasma levels of TNF-α, IL-6 and IL-23 cytokines were significantly higher in the EV71-associated HFMD patients than in HC, particularly in the severe patients, which was consistent with previous reports [4, 29, 30]. These findings indicated that increased plasma levels of cytokines (TNF-α, IL-6 and IL-23) possibly could explain the increased percentages of cTh22 and cTh17 cells and plasma levels of IL-22 and IL-17A in patients with EV71-associated HFMD, particularly in the severe patients.…”

Section: Discussionsupporting

confidence: 93%

“…Mild cases were defined by typical clinical features and spontaneously recovered within one week. Severe cases were usually defined in accordance with previous reports [4, 26]. Clinical data and specimens were collected from the patients with EV71-associated HFMD., and Ppatients were excluded if they were also infected by bacteria before treatment, but specimens were.…”

Section: Methodsmentioning

confidence: 99%

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Changes of circulating Th22 cells in children with hand, foot, and mouth disease caused by enterovirus 71 infection

Cui

Zhong

Lin³

et al. 2016

Oncotarget

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Interleukin (IL)-22+CD4+T (Th22) cells play crucial roles in the pathogenesis of autoimmune diseases and infectious diseases, although the role of Th22 cells remains largely unclear in children with hand, foot, and mouth disease (HFMD) caused by enterovirus 71 (EV71). This study aims to explore the role of circulating IL-22+IL-17A−CD4+T (cTh22) cells in children with EV71-associated HFMD. We found that during the acute stage of illness, the frequencies of cTh22 and circulating IL-22+IL-17A+CD4+T (IL-22+cTh17) cells in CD4+T cells infrom affected patients, and especially in severely affected patients, were significantly higher than in healthy controls (HC). The major source of IL-22 production was cTh22 cells, partially from cTh17 cells. Moreover, the protein and mRNA levels of IL-22, IL-17A, IL-23, IL-6, and TNF-α were significantly different among the mild patients, severe patients and HC, as well as AHR and RORγt mRNA levels. A positive correlation was found between plasma IL-22 levels and cTh22 cell frequencies, and cTh17 cell and IL-22+ cTh17 cell frequencies. Furthermore, the frequencies of cTh22 were significantly decreased in the convalescent patients. Our findings indicated that cTh22 cells could play critical roles in the pathogenesis of EV71 infection, and are potential therapeutic targets for patients with EV71-associated HFMD.

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Section: Discussionsupporting

confidence: 93%

Section: Methodsmentioning

confidence: 99%

Changes of circulating Th22 cells in children with hand, foot, and mouth disease caused by enterovirus 71 infection

Cui

Zhong

Lin³

et al. 2016

Oncotarget

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“…It has been suggested that cellular immunity, rather than humoral immunity, is associated with the clinical outcomes of EV-A71 infection (43). In addition, previous reports have shown that the number of circulating immune cells, including T follicular helper cells, type 1 helper and cytotoxic T cells, and T helper 17 and 22 cells, increases with the severity of HFMD after EV-A71 infection, accompanied by an increase in the secretion of various cytokines, such as IL-6, IL-17, IL-21, IL-22, and TNF-␣ (44)(45)(46). In another report, a decrease in the number of CD4 ϩ and CD8 ϩ T cells and NK cells was observed when the patients advanced from autonomic nervous system dysregulation to pulmonary edema (27), suggesting that cellular immunity is one of the factors that governs disease severity.…”

Section: Discussionmentioning

confidence: 97%

Enterovirus A71 Infection Activates Human Immune Responses and Induces Pathological Changes in Humanized Mice

Liu

Her

et al. 2019

J Virol

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Since the discovery of enterovirus A71 (EV-A71) half a century ago, it has been recognized as the cause of large-scale outbreaks of hand-foot-and-mouth disease worldwide, particularly in the Asia-Pacific region, causing great concern for public health and economic burdens. Detailed mechanisms on the modulation of immune responses after EV-A71 infection have not been fully known, and the lack of appropriate models hinders the development of promising vaccines and drugs. In the present study, NOD-scid IL2Rγ−/− (NSG) mice with a human immune system (humanized mice) at the age of 4 weeks were found to be susceptible to a human isolate of EV-A71 infection. After infection, humanized mice displayed limb weakness, which is similar to the clinical features found in some of the EV-A71-infected patients. Histopathological examination indicated the presence of vacuolation, gliosis, or meningomyelitis in brain stem and spinal cord, which were accompanied by high viral loads detected in these organs. The numbers of activated human CD4+ and CD8+ T cells were upregulated after EV-A71 infection, and EV-A71-specific human T cell responses were found. Furthermore, the secretion of several proinflammatory cytokines, such as human gamma interferon (IFN-γ), interleukin-8 (IL-8), and IL-17A, was elevated in the EV-A71-infected humanized mice. Taken together, our results suggested that the humanized mouse model permits insights into the human immune responses and the pathogenesis of EV-A71 infection, which may provide a platform for the evaluation of anti-EV-A71 drug candidates in the future. IMPORTANCE Despite causing self-limited hand-food-and-mouth disease in younger children, EV-A71 is consistently associated with severe forms of neurological complications and pulmonary edema. Nevertheless, only limited vaccines and drugs have been developed over the years, which is possibly due to a lack of models that can more accurately recapitulate human specificity, since human is the only natural host for wild-type EV-A71 infection. Our humanized mouse model not only mimics histological symptoms in patients but also allows us to investigate the function of the human immune system during infection. It was found that human T cell responses were activated, accompanied by an increase in the production of proinflammatory cytokines in EV-A71-infected humanized mice, which might contribute to the exacerbation of disease pathogenesis. Collectively, this model allows us to delineate the modulation of human immune responses during EV-A71 infection and may provide a platform to evaluate anti-EV-A71 drug candidates in the future.

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“…Furthermore, increasing evidence has shown that cytotoxic CD8+T cells contribute to platelet destruction 36 . It is well known that TFH cells play pivotal roles in autoimmune diseases and virus infection 13 , 37 - 39 . However, the role of TFH cells remains unclear in the development and progression of ITP.…”

Section: Discussionmentioning

confidence: 99%

Changes in Follicular Helper T Cells in Idiopathic Thrombocytopenic Purpura Patients

et al. 2015

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Background: Idiopathic thrombocytopenic purpura (ITP) is a primary autoimmune disease with a decreased platelet count caused by platelet destruction mediated mainly by platelet antibodies. T follicular helper (TFH) cells have demonstrated important roles in autoimmune diseases. The aim of this study is to explore the might role of TFH cells in the patients of ITP.Methods: Twenty-three ITP patients and 12 healthy controls (HC) were enrolled in this study. The frequency of circulating TFH cells in both the patients and HC was analyzed by flow cytometry. Serum interleukin (IL)-21 and IL-6 levels were measured using ELISA, and platelet antibodies were tested using a solid phase technique. Additionally, IL-21, IL-6, Bcl-6 and c-Maf mRNA expressions in peripheral blood mononuclear cells (PBMCs) were detected using real-time PCR.Results: The percentages of circulating CXCR5+ CD4+TFH cells with ICOShigh or PD-1high expression were significantly higher in the ITP patients than in the HC. Moreover, the frequencies of circulating CXCR5+ CD4+TFH cells with inducible costimulator (ICOS)high or programmed death-1 (PD-1)high expression were notably higher in ITP with platelet-antibody-positive ( ITP (+) ) patients than in ITP with platelet-antibody-negative ( ITP (-) ) patients and HC, as were the serum IL-21 and IL-6 levels (significant). Moreover, a positive correlation was found between the CXCR5+CD4+TFH cells with ICOShigh or PD-1high expression and the serum IL-21 levels of ITP (+) patients. Additionally, the mRNA expression levels of IL-21, IL-6, Bcl-6 and c-Maf were significantly increased in ITP patients, especially in ITP (+) patients.Conclusions: This study demonstrated TFH cells and effector molecules might play an important role in the pathogenesis of ITP, which are possible therapeutic targets in ITP patients.

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Increased Frequency of Circulating Follicular Helper T Cells in Children with Hand, Foot, and Mouth Disease Caused by Enterovirus 71 Infection

Cited by 20 publications

References 37 publications

Changes of circulating Th22 cells in children with hand, foot, and mouth disease caused by enterovirus 71 infection

Changes of circulating Th22 cells in children with hand, foot, and mouth disease caused by enterovirus 71 infection

Enterovirus A71 Infection Activates Human Immune Responses and Induces Pathological Changes in Humanized Mice

Changes in Follicular Helper T Cells in Idiopathic Thrombocytopenic Purpura Patients

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