Treg细胞和Th17细胞在多发性骨髓瘤中的研究进展

多发性骨髓瘤(MM)系血液系统的恶性肿瘤,以老年人多见.目前治疗以化疗和自身干细胞移植为主,仍难以治愈.多发性骨髓瘤的进展涉及到一系列基因和骨髓微环境的改变,这些改变恰好促进了肿瘤细胞的生长并瓦解了局部的免疫反应.CD4+和CD8+T细胞在多发性骨髓瘤患者体内数量和功能的改变都已经阐明.Treg细胞和Th17细胞的平衡在维持多发性骨髓瘤患者的抗肿瘤免疫中起着至关重要的作用.Treg细胞负责维持机体对外来抗原和自身抗原的免疫耐受.Th17细胞主要参与机体抵抗真菌和寄生虫感染、炎症反应和自身免疫.多发性骨髓瘤患者体内TGF-β和IL-6高水平表达,并可直接或通过其他促炎因子影响Th17细胞的分化,进而调节机体的抗肿瘤免疫应答.因此我们针对Treg细胞和Th17细胞在多发性骨髓瘤中的研究进展进行阐述.     

辅助性T细胞17的研究进展

CD4 T细胞根据释放细胞因子不同可分为不同的亚型:辅助性T细胞(T helper cells, Th)1、Th2和调节性T细胞(regulatory T cells, Treg).最近发现了一种新的CD4 T细胞亚型:以分泌白细胞介素-17为主要特征的Th17细胞.Th17细胞的发现对CD4 T细胞分化、Th细胞漂移等传统理论提出了挑战,同样也为感染、免疫性疾病提供了新的研究思路,尤其是Treg、Th1、Th2和Th17细胞在体内的平衡对于维持正常免疫应答反应有重要意义.     

SGK1 Governs the Reciprocal Development of Th17 and Regulatory T Cells

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抑制性寡脱氧核苷酸的生物学效应及研究进展

DNA对于机体免疫系统具有很多复杂的作用。存在于细菌DNA中的刺激性CpG基序能够促进机体免疫细胞分泌多种细胞因子,使机体产生偏向Th1方向的免疫应答,而抑制性寡脱氧核苷酸（oligodeoxynucleotide,ODN）可以选择性阻断刺激性CpG诱导的免疫激活作用。抑制性ODN按其结构不同大致分为三类,它可能通过影响细胞对CpG-S的结合及摄取、降低CpG-S特异性受体TLR9的表达发挥抑制作用。本综述主要介绍抑制性ODN的结构特征、作用机制和它在一些疾病中发挥的作用。     

抑制性寡脱氧核苷酸的生物学效应及研究进展

DNA对于机体免疫系统具有很多复杂的作用。存在于细菌DNA中的刺激性CpG基序能够促进机体免疫细胞分泌多种细胞因子,使机体产生偏向Th1方向的免疫应答,而抑制性寡脱氧核苷酸(oligodeoxynucleotide,ODN)可以选择性阻断刺激性CpG诱导的免疫激活作用。抑制性ODN按其结构不同大致分为三类,它可能通过影响细胞对CpG-S的结合及摄取、降低CpG-S特异性受体TLR9的表达发挥抑制作用。本综述主要介绍抑制性ODN的结构特征、作用机制和它在一些疾病中发挥的作用。     

Smad2 Positively Regulates the Generation of Th17 Cells

Development of Foxp3⁺ regulatory T cells and pro-inflammatory Th17 cells from naive CD4⁺ T cells requires transforming growth factor-β (TGF-β) signaling. Although Smad4 and Smad3 have been previously shown to regulate Treg cell induction by TGF-β, they are not required in the development of Th17 cells. Thus, how TGF-β regulates Th17 cell differentiation remains unclear. In this study, we found that TGF-β-induced Foxp3 expression was significantly reduced in the absence of Smad2. More importantly, Smad2 deficiency led to reduced Th17 differentiation in vitro and in vivo. In the experimental autoimmune encephalomyelitis model, Smad2 deficiency in T cells significantly ameliorated disease severity and reduced generation of Th17 cells. Furthermore, we found that Smad2 associated with retinoid acid receptor-related orphan receptor-γt (RORγt) and enhanced RORγt-induced Th17 cell generation. These results demonstrate that Smad2 positively regulates the generation of inflammatory Th17 cells.     

Arming Th17 Cells for Antifungal Host Defense

Interleukin 17 (IL-17)-mediated immunity has emerged as a crucial host defense mechanism against fungal infections. The family of IL-17 cytokines is phylogenetically ancient, but remains the least understood of all cytokine subclasses. The effects mediated by IL-17 are pleiotropic and include the induction of antimicrobial peptides as well as cytokines and chemokines that lead to the recruitment and activation of neutrophils. Neutrophils in turn are key effector cells of the antifungal defense. CD4⁺ T cells act as a major source of IL-17 and a lot has been learned about these cells since their discovery a decade ago. This review highlights key aspects of the underlying mechanisms regulating the development of Th17 responses during fungal infections. We discuss the impact of different subsets of antigen-presenting cells, innate cytokine signals and tissue-specific factors on Th17 differentiation, and we highlight the prerequisites for the mediation by Th17 cells of vaccine immunity against fungi.     

Th1-Th17 Cells Contribute to the Development of Uropathogenic Escherichia coli-Induced Chronic Pelvic Pain

The etiology of chronic prostatitis/chronic pelvic pain syndrome in men is unknown but may involve microbes and autoimmune mechanisms. We developed an infection model of chronic pelvic pain in NOD/ShiLtJ (NOD) mice with a clinical Escherichia coli isolate (CP-1) from a patient with chronic pelvic pain. We investigated pain mechanisms in NOD mice and compared it to C57BL/6 (B6) mice, a strain resistant to CP-1-induced pain. Adoptive transfer of CD4+ T cells, but not serum, from CP-1-infected NOD mice was sufficient to induce chronic pelvic pain. CD4+ T cells in CP-1-infected NOD mice expressed IFN-γ and IL-17A but not IL-4, consistent with a Th1/Th17 immune signature. Adoptive transfer of ex-vivo expanded IFN-γ or IL-17A-expressing cells was sufficient to induce pelvic pain in naïve NOD recipients. Pelvic pain was not abolished in NOD-IFN-γ-KO mice but was associated with an enhanced IL-17A immune response to CP1 infection. These findings demonstrate a novel role for Th1 and Th17-mediated adaptive immune mechanisms in chronic pelvic pain.     

Endurance Exercise Diverts the Balance between Th17 Cells and Regulatory T Cells

Endurance, marathon-type exertion is known to induce adverse changes in the immune system. Increased airway hyper-responsiveness and airway inflammation are well documented in endurance athletes and endurance exercise is considered a major risk factor for asthma in elite athletes. Yet, the mechanisms underlying this phenomenon are still to be deduced. We studied the effect of strenuous endurance exercise (marathon and half-ironman triathlon) on CD4+ lymphocyte sub-populations and on the balance between effector and regulatory CD4+ lymphocytes in the peripheral blood of trained athletes, Endurance exercise induced a significant increase in Th17 cells and a sustained decrease in peripheral blood regulatory T cells (Tregs). While interleukin (IL)-2 levels remained undetectable, post-race serum IL-6 and transforming growth factor (TGF) β levels were significantly elevated. Treg levels in sedentary controls'' decreased in vitro after incubation with athletes'' post-exercise serum, an effect that was attenuated by supplements of IL-2 or anti IL-6 neutralizing antibodies. Our data suggest that exercise-induced changes in serum cytokine levels promote alterations in Tregs and Th17 cell populations, which may divert the subtle balance in the immune system towards inflammation. This may explain allergic and autoimmune phenomena previously reported in endurance athletes and contribute to our understanding of exercise-related asthma.     

Bordetella pertussis Commits Human Dendritic Cells to Promote a Th1/Th17 Response through the Activity of Adenylate Cyclase Toxin and MAPK-Pathways

The complex pathology of B. pertussis infection is due to multiple virulence factors having disparate effects on different cell types. We focused our investigation on the ability of B. pertussis to modulate host immunity, in particular on the role played by adenylate cyclase toxin (CyaA), an important virulence factor of B. pertussis. As a tool, we used human monocyte derived dendritic cells (MDDC), an ex vivo model useful for the evaluation of the regulatory potential of DC on T cell immune responses. The work compared MDDC functions after encounter with wild-type B. pertussis (BpWT) or a mutant lacking CyaA (BpCyaA−), or the BpCyaA− strain supplemented with either the fully functional CyaA or a derivative, CyaA*, lacking adenylate cyclase activity. As a first step, MDDC maturation, cytokine production, and modulation of T helper cell polarization were evaluated. As a second step, engagement of Toll-like receptors (TLR) 2 and TLR4 by B. pertussis and the signaling events connected to this were analyzed. These approaches allowed us to demonstrate that CyaA expressed by B. pertussis strongly interferes with DC functions, by reducing the expression of phenotypic markers and immunomodulatory cytokines, and blocking IL-12p70 production. B. pertussis-treated MDDC promoted a mixed Th1/Th17 polarization, and the activity of CyaA altered the Th1/Th17 balance, enhancing Th17 and limiting Th1 expansion. We also demonstrated that Th1 effectors are induced by B. pertussis-MDDC in the absence of IL-12p70 through an ERK1/2 dependent mechanism, and that p38 MAPK is essential for MDDC-driven Th17 expansion. The data suggest that CyaA mediates an escape strategy for the bacterium, since it reduces Th1 immunity and increases Th17 responses thought to be responsible, when the response is exacerbated, for enhanced lung inflammation and injury.     

Th17细胞在肺部感染免疫中的作用

Th17细胞是近年来发现的一种新的效应T细胞亚群,在自身免疫性疾病和感染中发挥重要的作用,其分泌产生几种致炎细胞因子,包括新发现的细胞因子白细胞介素17。Th17产生的细胞因子与Th1、Th2不同并且与其相互对抗。Th17细胞很可能对防御胞外病原菌的感染及自身免疫性疾病产生影响。综述了Th17细胞产生的细胞因子及其在肺部感染免疫中的作用相关方面的进展。     

Th17细胞分化和功能的研究进展

近年研究发现了效应性辅助性T细胞的新亚群-Th17细胞,它主要分泌IL-17、IL-17F、IL-21和IL-22等细胞因子。Th17细胞及其效应分子被认为与自身免疫病和其他多种疾病相关。该文从Th17细胞的发现、人和小鼠Th17细胞的分化、Th17细胞的效应性因子及与健康和疾病的相关性几个方面对目前的研究进展进行了综述。     

Cell Surface Galectin-9 Expressing Th Cells Regulate Th17 and Foxp3+ Treg Development by Galectin-9 Secretion

Galectin-9 (Gal-9), a β-galactoside binding mammalian lectin, regulates immune responses by reducing pro-inflammatory IL-17-producing Th cells (Th17) and increasing anti-inflammatory Foxp3⁺ regulatory T cells (Treg) in vitro and in vivo. These functions of Gal-9 are thought to be exerted by binding to receptor molecules on the cell surface. However, Gal-9 lacks a signal peptide for secretion and is predominantly located in the cytoplasm, which raises questions regarding how and which cells secrete Gal-9 in vivo. Since Gal-9 expression does not necessarily correlate with its secretion, Gal-9-secreting cells in vivo have been elusive. We report here that CD4 T cells expressing Gal-9 on the cell surface (Gal-9⁺ Th cells) secrete Gal-9 upon T cell receptor (TCR) stimulation, but other CD4 T cells do not, although they express an equivalent amount of intracellular Gal-9. Gal-9⁺ Th cells expressed interleukin (IL)-10 and transforming growth factor (TGF)-β but did not express Foxp3. In a co-culture experiment, Gal-9⁺ Th cells regulated Th17/Treg development in a manner similar to that by exogenous Gal-9, during which the regulation by Gal-9⁺ Th cells was shown to be sensitive to a Gal-9 antagonist but insensitive to IL-10 and TGF-β blockades. Further elucidation of Gal-9⁺ Th cells in humans indicates a conserved role of these cells through evolution and implies the possible utility of these cells for diagnosis or treatment of immunological diseases.     

Suppressive effect of IL-27 on encephalitogenic Th17 cells and the effector phase of experimental autoimmune encephalomyelitis

IL-27 has been shown to play a suppressive role in experimental autoimmune encephalomyelitis (EAE) as demonstrated by more severe disease in IL-27R-deficient (WSX-1(-/-)) mice. However, whether IL-27 influences the induction or effector phase of EAE is unknown. This is an important question as therapies for autoimmune diseases are generally started after autoreactive T cells have been primed. In this study, we demonstrate maximal gene expression of IL-27 subunits and its receptor in the CNS at the effector phases of relapsing-remitting EAE including disease peak and onset of relapse. We also show that activated astrocyte cultures secrete IL-27p28 protein which is augmented by the endogenous factor, IFN-gamma. To investigate functional significance of a correlation between gene expression and disease activity, we examined the effect of IL-27 at the effector phase of disease using adoptive transfer EAE. Exogenous IL-27 potently suppressed the ability of encephalitogenic lymph node and spleen cells to transfer EAE. IL-27 significantly inhibited both nonpolarized and IL-23-driven IL-17 production by myelin-reactive T cells thereby suppressing their encephalitogenicity in adoptive transfer EAE. Furthermore, we demonstrate a strong suppressive effect of IL-27 on active EAE in vivo when delivered by s.c. osmotic pump. IL-27-treated mice had reduced CNS inflammatory infiltration and, notably, a lower proportion of Th17 cells. Together, these data demonstrate the suppressive effect of IL-27 on primed, autoreactive T cells, particularly, cells of the Th17 lineage. IL-27 can potently suppress the effector phase of EAE in vivo and, thus, may have therapeutic potential in autoimmune diseases such as multiple sclerosis.     

Th17/Treg 细胞在银屑病的发病机制研究进展

Th17细胞和Treg细胞是CD4+T细胞在不同细胞因子环境中分化出的新亚群,发挥不同的生物学效应,使机体的免疫系统处于平衡状态.Th17/Treg细胞失衡可引起一系列自身免疫性疾病.银屑病是与遗传、免疫异常有关的皮肤炎症性疾病,其发病机制尚不清楚.越来越多的研究发现,Th17细胞增多和Treg细胞减少及其分泌的细胞因子在银屑病的发病中有着重要作用.本文围绕这一机制综述了近年来有关Th17细胞、Treg细胞在银屑病发病机制中作用的研究,帮助我们更深入地了解银屑病的发病机制并为今后临床诊断和治疗提供依据.     

多发性肌炎肌组织中Th17 细胞的浸润

目的:探讨多发性肌炎(PM)患者肌肉炎性组织中是否存在Th17细胞及数量多少。方法:临床和病理诊断确诊的多发性肌炎患者16例;对照组来自非炎性肌病患者6例。应用免疫荧光组织化学方法检测Th17淋巴细胞的定位及数量。结果:与非肌炎患者比较,免疫荧光组织化学检测到肌炎患者肌肉组织中IL-17表达阳性,主要分布在细胞内,且细胞数量的多少与炎症的严重程度成正相关。结论:Th17细胞有可能参与了多发性肌炎的发病过程。     

Th22 Cells as Well as Th17 Cells Expand Differentially in Patients with Early-Stage and Late-Stage Myelodysplastic Syndrome

Background

Immunological mechanisms are increasingly recognized in the progression of myelodysplastic syndrome (MDS). Early-stage MDS (E-MDS) is characterized by autoimmune-mediated myelosuppression whereas late-stage MDS (L-MDS) involves immune evasion, giving dysplastic cells growth potential to progress into acute myeloid leukemia. T-helper (Th) 22 is involved in the pathogenesis of inflammatory autoimmunity and tumorigenesis. The roles of Th22 cells in the pathophysiology of E-MDS and L-MDS remain unsettled.

Design and Methods

We studied 37 MDS patients (E-MDS, n = 17; L-MDS, n = 20) and 20 healthy controls to characterize their peripheral blood (PB), as well as 25 MDS patients and 10 healthy controls to characterize their bone marrow(BM). The expression of Interleukin-22 (IL-22), IL-17 or interferon gamma (IFN-γ) was examined in E-MDS, L-MDS patients and controls by flow cytometry. The mRNA expression levels of RAR-related orphan receptor C (RORC), IL-6, tumor necrosis factor alpha (TNF-α) and IL-23 in peripheral blood mononuclear cells (PBMCs) were determined by real-time quantitative polymerase chain reaction. The levels of IL-22 and IL-17 both in PB and BM plasma were examined by enzyme-linked immunosorbent assay.

Results

In E-MDS, peripheral Th17 cells were significantly elevated and correlated with peripheral Th22 cells compared with healthy controls and L-MDS. Significantly higher levels of peripheral Th22 expansion, mRNA expression of IL-6, TNF-α and lower level of RORC mRNA expression were observed in L-MDS compared with E-MDS. No statistical difference was found in IL-23 mRNA expression or plasma IL-22, IL-17 levels among E-MDS, L-MDS and controls.

Conclusions

Our data demonstrated that L-MDS cohort had increased frequencies of peripheral Th22 cells and higher mRNA expression levels of IL-6 and TNF-α, indicating that Th22 cells along with Th17 cells or not are involved in the dynamic immune responses of MDS.