Th17细胞分化调节机制及与自身免疫性疾病关系研究进展

Th17细胞是CD4+辅助T细胞中的一个亚群,以表达特征性的IL-17而得名,在促炎症反应中发挥重要作用。Th17细胞的生物学功能和分化过程均有其特殊性,在慢性炎症、自身免疫性疾病、肿瘤等疾病的发展中因为扮演着重要的角色,对Th17的进一步研究可以加深对相关疾病的认识并指导临床的治疗。对Th17细胞的表面标志物、分化成熟过程的信号通路以及其与自身免疫性疾病的关系研究取得了新的进展。本文对Th17细胞的生物学特性、分化、负性调节以及Th17细胞与自身免疫性疾病之间的关系进行综述。     

IL-17与感染性疾病的研究进展

白介素17(IL-17)是一个具有强大促炎作用的细胞因子,其生物学活性至今仍未被完全明确。先前对IL-17的研究主要集中于其在肿瘤、自身免疫性疾病中的致病作用,近几年来,许多研究报道IL-17能够通过招募和活化中性粒细胞、促进促炎细胞因子、趋化因子及抗体的生成以及激活T细胞等功能,对细菌、病毒、真菌等病原体发挥重要的抗感染作用。本文就近年来关于IL-17与感染性疾病的关系做一综述。     

IL-17与自身免疫性疾病相关研究进展

白细胞介素17（interleukin-17，IL-17）及IL-17家族是近年来发现的一组促炎症性细胞因子，具有强大的招募中性粒细胞的作用，调节并促进多种炎性介质的产生，参与了机体多种炎性疾病，与感染、肿瘤、过敏、移植及自身免疫性疾病均有密切关系。本文就IL-17的发现及近年IL-17与自身免疫性疾病的相关研究进展加以综述。     

调节性B细胞与自身免疫性疾病

以往认为,B细胞通过产生特异性抗体提呈抗原产生共刺激分子活化T细胞、并通过细胞因子发挥免疫作用.但是近年来研究发现,B细胞对免疫应答和炎性反应有调节作用,这种B细胞被命名为调节性B细胞(Br).Br通过分泌调节性的细胞因子IL-10和TGF-β影响B细胞和致病性T细胞之间的相互作用而抑制病理性免疫反应.因而了解Br的生物学功能、活化机制以及在自身免疫性疾病中的作用具有重要意义.     

固有免疫在自身免疫性中枢神经系统疾病中的作用及机制

自身免疫性中枢神经系统(CNS)疾病是一组靶向CNS组织的自身免疫病,导致严重临床症状包括药物抵抗性癫痫、认知障碍和精神病学障碍等。目前研究显示这些疾病是抗体介导的,但固有免疫应答在其中的作用有待进一步阐明。小胶质细胞和浸润的单核细胞在病灶部位的扩增以及血脑屏障损伤均对该疾病发生有关键作用。固有和适应性免疫细胞产生促炎因子,维持神经炎症并促进癫痫的发生,最终出现神经退行性改变和长期神经系统后遗症。本文对固有免疫在自身免疫性CNS疾病中的作用和机制最新研究进展做一综述,期待对相关领域临床医生和研究人员提供参考和借鉴。     

钠、钾干预对成人血清和尿中肾胺酶表达的影响

目的:动物实验表明高盐摄入可降低循环及肾脏中肾胺酶的表达水平。本研究拟探讨钠、钾摄入对成人血清和尿中肾胺酶表达的影响。方法:42名(28~65岁)来自中国北方农村的受试者参与了这项研究。所有受试者依次接受低盐饮食7 d(氯化钠3 g/d),高盐饮食7 d(氯化钠18 g/d),高盐补钾饮食7 d(氯化钠18 g+氯化钾4.5 g/d)。血清及尿中肾胺酶水平用ELISA试剂盒进行检测。结果:低盐饮食期,血清中肾胺酶水平较基线期显著升高。低盐转向高盐饮食期时,血清肾胺酶水平随之下降,但同时给予补钾后,可阻止高盐所致的肾胺酶水平下降。尿中肾胺酶水平在高盐饮食期显著高于低盐期。高盐补钾期,尿中肾胺酶水平与单纯高盐期相比无显著差异,但显著高于低盐饮食期。24 h尿钠排泄与血清中肾胺酶水平呈负相关,与尿中肾胺酶水平呈正相关。结论:饮食中钠、钾含量的变化可显著影响中国人血清及尿中肾胺酶的表达水平。     

自身抗体检测在风湿免疫性疾病诊治中的作用

风湿免疫性疾病是指由于多种原因使体内免疫功能紊乱而引起的疾病, 发病机制复杂且发病率高, 易反复发作。自身免疫耐受机制失调会产生多种针对自身细胞、组织及器官的自身抗体。目前已发现越来越多的风湿免疫性疾病相关自身抗体与临床表现、疾病过程、临床并发症及预后存在关联。总结自身抗体的临床意义对风湿免疫性疾病的早期诊断、病情活动度评估、预后判断尤为重要。     

Th17细胞及其相关细胞因子在中药干预炎症机制中的研究进展

辅助性T细胞17(Th17)参与宿主防御、自身免疫、维持黏膜屏障稳态等,具有强烈的致炎效应,与多种自身免疫性疾病及炎症诱导的癌变发生密切相关。Th17细胞相关细胞因子通过调控Th17细胞发育分化、可塑性与稳定性,维持增强其功能,并发挥细胞因子致炎效应等,影响炎症发生发展。中医药在炎症性疾病治疗中有一定潜力,部分中药被证实通过多途径机制发挥抗炎及免疫调节的作用。研究Th17细胞及其相关细胞因子的致炎效应、中药调节Th17细胞及其相关细胞因子的抗炎机制,将为炎症性疾病的治疗提供新的方向。     

CD4+T淋巴细胞亚群在自身免疫性疾病中的研究进展

自身免疫性疾病是指机体对自身抗原发生免疫应答导致自身组织损害所引起的疾病.其发病机制尚不十分明了,但大量研究表明自身免疫性疾病患者体内存在多种免疫异常,特别是效应T淋巴细胞紊乱及细胞因子网络失衡.自身反应性T细胞增殖和B细胞活化,可产生大量炎性因子和自身抗体引起免疫损伤.近年来,人们逐渐把研究的焦点放在不同效应T淋巴细胞的分化调节、相互作用及产生的细胞因子变化方面. 根据产生的细胞因子及功能不同,原始CD4+T淋巴细胞可分化为经典的Th1、Th2及新近发现的Th17、Tr(调节性T细胞)、Th22、Th9、Tfh(滤泡性辅助性T细胞)等不同效应T细胞.     

IL-17+γδT细胞在相关疾病中的免疫作用

IL-17是一类重要的促炎症因子,近年来大量研究发现,除了Th17细胞外,γδT细胞也是IL-17的重要来源。IL-17+γδT细胞可以参与多种疾病的诱发和发展,在感染性疾病、自身免疫性疾病和肿瘤等的发生发展中发挥重要作用。     

The deviated balance between regulatory T cell and Th17 in autoimmunity

Identifying the regulatory T cells (Tregs) and Th17 cells led to breaking the dichotomy of Th1/Th2 cells axis in immune responses involved in several autoimmune diseases. It is now well known that Tregs and Th17 cells are main orchestra leaders in pathogenesis symphony of autoimmunity. While Tregs are protective cells in autoimmune diseases, Th17 cells enhance the progression of autoimmune responses through induction of various pro-inflammatory reactions. It seems that the progression of autoimmunity may be associated with increase in Th17 and decrease in Treg levels, so that skewed balance between Tregs and Th17 toward Th17 is a phenomenon, which could be observed during progression of several autoimmune diseases. Although it is suggested that expansion and transfer of Tregs can be a new therapeutic target for autoimmune diseases, however, recent data about the phenotype conversion of Tregs into Th17 cells obligate us to more investigation on this approaching. Thus, identifying the new factors that induce stable phenotype in Tregs and prevent their phenotype conversion into Th17 cells as well as targeting the factor, which can modulate their balance, might be recommended as a new promising therapeutic method for autoimmune therapy. In this review, we try to clarify the factors, which can affect on this balance in various autoimmune diseases, as new targets in treatment of these diseases.     

The deviated balance between regulatory T cell and Th17 in autoimmunity

Identifying the regulatory T cells (Tregs) and Th17 cells led to breaking the dichotomy of Th1/Th2 cells axis in immune responses involved in several autoimmune diseases. It is now well known that Tregs and Th17 cells are main orchestra leaders in pathogenesis symphony of autoimmunity. While Tregs are protective cells in autoimmune diseases, Th17 cells enhance the progression of autoimmune responses through induction of various pro-inflammatory reactions. It seems that the progression of autoimmunity may be associated with increase in Th17 and decrease in Treg levels, so that skewed balance between Tregs and Th17 toward Th17 is a phenomenon, which could be observed during progression of several autoimmune diseases. Although it is suggested that expansion and transfer of Tregs can be a new therapeutic target for autoimmune diseases, however, recent data about the phenotype conversion of Tregs into Th17 cells obligate us to more investigation on this approaching. Thus, identifying the new factors that induce stable phenotype in Tregs and prevent their phenotype conversion into Th17 cells as well as targeting the factor, which can modulate their balance, might be recommended as a new promising therapeutic method for autoimmune therapy. In this review, we try to clarify the factors, which can affect on this balance in various autoimmune diseases, as new targets in treatment of these diseases.     

Functional roles for T cell CD40 in infection and autoimmune disease: The role of CD40 in lymphocyte homeostasis

CD40 stimulation on monocytes/macrophages, dendritic cells, and B-lymphocytes has been the subject of much study. It is well recognized that activation of CD40 on antigen presenting cells by its ligand, CD154, expressed on T-lymphocytes, contributes to the pro-inflammatory response necessary for eradication of infection, yet pathological in autoimmunity. However, there is evidence that CD40 is also expressed on T-lymphocytes and can act as a costimulatory molecule. While the exact role of CD40 on CD8 T cells remains controversial, it does appear to contribute to the adaptive immune response against infection. CD40 on CD4 T cells, on the other hand, plays a functional role in the autoimmune disease process. Further dissection of the exact nature and role of CD40 in T cell activation could lead the way to more effective vaccines and novel therapeutics for autoimmune diseases.     

IL-23 and Th17 cells in infections and psoriasis

IL-23 is produced by dendritic cells, and other antigen presenting cells. IL-23 is required for the induction, expansion, maintenance and downstream effector functions of Th17 cells. Th17 cells upregulate neutrophil chemokines, antimicrobial peptides, and other pro-inflammatory cytokines. The lack of Th17 cells results in susceptibility to Candida, Streptococcal and Staphylococcal infections. On the contrary, the excess of Th17 cells induce various autoimmune diseases such as psoriasis. Several studies revealed that infections were more common in psoriatics than in healthy individuals. Superantigens released by microorganisms have been suggested as exogenous triggers that stimulate T cells to initiate psoriasis. Understanding the Th17 responses and their interactions with the immune system will likely provide crucial insights in the host defense and autoimmune diseases like psoriasis, and this will provide new tools for the development of effective immunomodulatory treatment strategies for infectious diseases and autoimmune diseases.     

State of the union between metabolism and the immune system in type 2 diabetes

Lymphocytes and myeloid cells (monocyte/macrophages) have important roles in multiple types of diseases characterized by unresolved inflammation. The relatively recent appreciation of obesity, insulin resistance and type 2 diabetes (T2D) as chronic inflammatory diseases has stimulated interest in understanding the role of immune cells in metabolic imbalance. Myeloid cells regulate inflammation through cytokine production and the adipose tissue remodeling that accompanies hyper-nutrition, thus are critical players in metabolic homeostasis. More recently, multiple studies have indicated a role for T cells in obesity-associated inflammation and insulin resistance in model organisms, with parallel work indicating that pro-inflammatory changes in T cells also associate with human T2D. Furthermore, the expansion of T cells with similar antigen-binding sites in obesity and T2D indicates these diseases share characteristics previously attributed to inflammatory autoimmune disorders. Parallel pro-inflammatory changes in the B-cell compartment of T2D patients have also been identified. Taken together, these studies indicate that in addition to accepted pro-inflammatory roles of myeloid cells in T2D, pro-inflammatory skewing of both major lymphocyte subsets has an important role in T2D disease pathogenesis. Basic immunological principles suggest that alterations in lymphocyte function in obesity and T2D patients are an integral part of a feed-forward pro-inflammatory loop involving additional cell types. Importantly, the pro-inflammatory loop almost inevitably includes adipocytes, known to respond to pro-inflammatory, pro-diabetogenic cytokines originating from the myeloid and lymphoid compartments. We propose a model for inflammation in T2D that functionally links lymphocyte, myeloid and adipocyte contributions, and importantly proposes that tools for B-cell ablation or regulation of T-cell subset balance may have a place in the endocrinologist's limited arsenal.     

Therapeutic potential of chimeric antigen receptor based therapies in autoimmune diseases

Chimeric antigen receptor (CAR) based therapies have been adopted as an option for treating autoimmune diseases from the field of blood malignancies by targeting immune cells or rebalancing the pro-inflammatory milieu. Important questions still remained about the efficacy and safety regarding the dynamic and complex autoimmune pathological networks. We here reviewed the emerged developments in basic, translational, and clinical studies of the CAR based therapies in a wide spectrum of autoimmune diseases. The primary goal of the study is to provide some future perspectives on how to optimize the performance of CAR based therapies. The fundamental strategy is to engineer the recognition domains in CAR products for precisely targeting the components in the pro-inflammatory milieu. The second strategy is to incorporate multiple CARs in one carrier, or use fluorescein isothiocyanate (FITC)-CAR T cells for enhancing the therapeutic efficacy. In addition, we reviewed the preclinical evidence in disease-specific context. Overall, we aim to attract more attention in the field of developing future precision CAR based therapies to tailor medial decisions in autoimmune diseases.     

Selective pharmacological inhibition of phosphoinositide 3-kinase p110delta opposes the progression of autoimmune diabetes in non-obese diabetic (NOD) mice

During the progression of autoimmune (type 1) diabetes, T cells and macrophages infiltrate the pancreas, disrupt islet function, and destroy insulin-producing beta cells. B-lymphocytes, particularly innate like B-cell populations such as marginal zone B cells and B-1 cells, have been implicated in many autoimmune diseases, and non-obese diabetic (NOD) mice that lack B cells do not develop spontaneous autoimmune diabetes. Hence, inhibitors of B cell signaling pathways could be useful for limiting the autoimmune processes that contribute to type 1 diabetes. Signaling via phosphoinositide 3-kinase (PI3K) regulates many cellular processes. The p110δ isoform of PI3K is expressed primarily in cells of hematopoietic origin and the catalytic activity of p110δ is important for B cell migration, activation, proliferation, and antigen presentation. Because innate-like B cells are particularly sensitive to inhibition of p110δ activity, and p110δ inhibitors also suppress pro-inflammatory functions of other cell types that contribute to autoimmunity, we tested whether a p110δ inhibitor could delay the onset or reduce the incidence of autoimmune diabetes in NOD mice. We found that long-term preventative treatment of pre-diabetic NOD mice with IC87114, a highly selective small molecule inhibitor of p110δ, reduced the infiltration of inflammatory cells into the pancreatic islets and, accordingly, delayed and reduced the loss of glucose homeostasis. Moreover in a therapeutic treatment mode, IC87114 treatment conferred prolonged protection from progression to overt diabetes in a number of animals. These findings suggest that PI3Kδ inhibitors could be useful for managing type 1 diabetes.     

Prior elevation of IL-18 promotes rapid early IFN-gamma production during staphylococcal infection

Systemic Staphylococcus aureus infection is associated with significant morbidity and mortality arising from both bacterial and host immune factors. IL-18 is a pro-inflammatory cytokine of the IL-1 superfamily that exhibits broad functional effects in innate and acquired immune responses and which has been found in high levels in several chronic inflammatory and autoimmune diseases. Over-expression of IL-18 may promote early resolution of infection or could promote a detrimental exaggerated immune response. This was explored in a model of S. aureus infection. We report increased mortality in Swiss mice that were given recombinant IL-18 prior to inoculation with S. aureus LS-1. IL-18 administration prior to infection induced preferentially enhanced IFN-gamma mRNA expression in peripheral blood leukocytes and spleen, especially splenic NK cells. This correlated with increased IFN-gamma protein detection in serum, and leukocyte and spleen cultures at subsequent discrete time points. These data suggest that increased mortality following gram-positive infection in autoimmune diseases could in part reflect the impact of high levels of pleiotropic pro-inflammatory cytokines such as IL-18 present prior to the onset of infection.     

The Multi-faceted Influences of Estrogen on Lymphocytes: Toward Novel Immuno-interventions Strategies for Autoimmunity Management

Early studies of the immune system disclosed that, generally, females exhibit stronger responses to a variety of antigens than males. Perhaps as a result of this response, women are more prone to developing autoimmune diseases than men. Yet, the precise cellular and molecular mechanisms remain under investigation. Recently, interferon-gamma and the related pro-inflammatory interleukin-12 were found to be under effects of sex steroid hormones, with potential implications in regulating immune cells and autoimmune responses. In B lymphocytes, functional binding sites for estrogen receptors were identified in the promoter of the gene encoding activation-induced deaminase, an enzyme required for somatic hypermutation, and class-switch recombination. The observation that estrogen exerts direct impacts on antibody affinity-maturation provides a potential mechanism that could account for generating pathogenic high-affinity auto-antibodies. Further deciphering the multi-faceted influences of sex hormones on the responsiveness of immune cells could lead to novel therapeutic interventions for autoimmunity management.     

The role of B cell metabolism in autoimmune diseases

B cells are major players in immune responses being the source of protective antibodies and antigen presenting cells. When self-tolerance fails, auto reactive B cells produce autoantibodies and pro-inflammatory cytokines leading to the development of autoimmune diseases. Many recent studies have assessed importance of metabolic pathways in B cells, demonstrating their role in controlling autoimmunity and maintaining immune homeostasis. Alterations in B cell functions in autoimmune diseases are closely associated with abnormal metabolic shifts, allowing auto reactive B cells to escape tolerogenic checkpoints. Understanding the metabolic changes in B cells, opens up new possibilities for targeting metabolic pathways and manipulating metabolic avenues as a therapeutic strategy for the treatment of autoimmune diseases.