滤泡辅助性T细胞与风湿性疾病

滤泡辅助性T细胞(follicular helper Tcells,Tfh)是最近发现的一种能够辅助B细胞产生抗体反应的CD4+T细胞亚群。Tfh定位于生发中心,表面特异性标志为CD4+CXCR5+,其分化不仅由转录因子Bcl-6调控,而且需要人白细胞介素-21、诱导性协同刺激分子、抗体亲和力等多种因素参与。Tfh中的任何相关因子表达异常,将引发多种自身免疫性疾病。     

类风湿关节炎患者外周血滤泡辅助性T细胞及白细胞介素-21和白细胞介素-4水平

类风湿关节炎(RA)是一种病因未明的慢性全身性炎症性疾病,目前较为认可的机制是外源性感染作用于遗传易感个体,导致体内T细胞亚群和B细胞失衡等免疫系统紊乱[1-2].滤泡辅助性T细胞(Tfh)是新的CD4+T细胞亚群,主要功能是辅助B细胞参与体液免疫.而Tfh所产生的白细胞介素(IL)-21可以与转化生长因子-β(TGF-β)共同作用,诱导产生大量的分泌IgA的浆母细胞,参与黏膜免疫应答[3].因此Tfh细胞相关分子(如IL-21)的表达,很可能与某些自身免疫病的发病有关.本研究通过检测RA患者外周血Tfh表型、数量及相关细胞因子IL-21、IL-4,初步探讨Tfh在RA发病中的作用.     

滤泡辅助性T细胞与自身免疫性疾病

滤泡辅助性T细胞(follicular helper T cells,Tfh)是一类主要定位于B淋巴细胞滤泡形成生发中心的特殊CD4+T细胞亚群,它在诱导B细胞活化、分化、产生抗体的各个环节均发挥着重要的辅助功能。Tfh细胞在机体内的正常表达有利于维持机体正常的免疫应答和内环境的稳定,一旦其表达和(或)功能出现异常,则会引起体内抗体异常表达,从而导致自身免疫性疾病的发生。认识和研究Tfh细胞在自身免疫性疾病中可能的发病机制及其功能有利于临床上更好地认识疾病,为疾病的治疗提供新的思路。     

滤泡辅助性T细胞13在变态反应性疾病中的研究进展

高亲和力、过敏原特异性的免疫球蛋白E(IgE)与肥大细胞的交联可能会导致危及生命的过敏反应。过去一直认为2型辅助性T细胞(Th2)分泌的IL-4、IL-13是B细胞产生IgE的主要驱动者, 随着近年来免疫学的深入研究, 发现滤泡辅助性T细胞(Tfh)是指导B细胞生发中心反应、抗体亲和力成熟和同种型类别转换的重要CD4+T细胞亚型, 新近报道其也与IgE反应有关。Tfh细胞的发现, 尤其是包括滤泡辅助性T细胞13(Tfh13)在内的新型T细胞亚群的发现拓宽了免疫学界与临床对过敏性疾病复杂免疫网络的认识。这些"Tfh 13"细胞具有特殊的细胞因子谱, 即高表达IL-13、IL-4、IL-5, 低表达IL-21(IL-13hi, IL-4hi, IL-5hi, IL-21low), 并共同表达转录因子BCL6和GATA3。Tfh 13细胞是产生高亲和力IgE以及随后的过敏原诱导的过敏反应所必需的。在RA、SLE、硬皮病、1型糖尿病(DM1)等自身免疫病中亦存在滤泡辅助性T细胞/滤泡调节性T细胞(Tfh/Tfr)的免疫失衡、IL-13、IgE的异常。本文对Tfh13细胞在包括自身免疫性疾病在内...     

CD4+T细胞与支气管哮喘治疗研究新进展

在支气管哮喘(简称哮喘)中,Th2细胞及其细胞因子促使气道嗜酸粒细胞炎症浸润和气道高反应产生,是哮喘治疗的重要靶点.越来越多的研究结果显示,除Th2细胞外,其他CD4+T细胞[包括Th1、Th17及调节性T细胞(Treg)]也可以被招募至气道,共同参与哮喘发病.哮喘的免疫学治疗复杂,现将各亚群CD4+T细胞在哮喘治疗中的研究进展综述如下.     

气道平滑肌细胞与黏附分子及趋化因子的相互作用

气道平滑肌在支气管哮喘(简称哮喘)发生过程中,具有调节气道炎症程度和收缩功能的作用,其与细胞黏附分子和趋化因子的相互作用可能是重要的调节因素.气道平滑肌细胞能表达某些细胞黏附分子及趋化因子,其中平滑肌细胞表面表达的胞间黏附分子1和血管细胞黏附分子1是介导平滑肌细胞与免疫细胞黏附最重要黏附分子;同时,平滑肌细胞可分泌嗜酸粒细胞趋化因子等多种炎症趋化因子诱导炎症细胞向气道壁定向移动并定植.这些黏附分子和趋化因子使平滑肌细胞与各种免疫细胞的相互作用,加重哮喘炎症反应.而通过抑制上述黏附分子和趋化因子的作用,则能够改善局部炎症反应,减轻气道痉挛.这一现象提示,改变气道平滑肌细胞的功能,减少其对黏附分子和趋化因子的合成与表达,可能成为减轻哮喘气道炎症反应,改善哮喘症状的新途径.     

共刺激分子OX40/OX40L和哮喘

在过敏性哮喘的发病机制中,CD+4T细胞以其分泌的Th2类细胞因子参与了慢性气道炎症的启动和持续过程,成为介导嗜酸粒细胞炎症和气道高反应的主要炎性细胞。CD+4T细胞的增殖活化需要两个刺激信号:由T细胞受体(TCR)与抗原提呈细胞(APC)提呈的MHC抗原肽复合物相结合所产生的第一信号(识别信号),和由APC表面的共刺激分子与T细胞表面对应受体分子相结合产生的第二信号(共刺激信号)。许多研究表明,除了B7CTLA4/CD28和CD40/CD40L(CD154)两对共刺激分子外,OX40及其配体OX40L是又一对在T细胞初次和再次应答中发挥重要作用的共刺激分…     

滤泡调节性T细胞双向功能的研究进展

滤泡调节性T细胞(Tfr)主要定位于淋巴滤泡,目前多数研究认为其对生发中心(GC)形成和B细胞的功能发挥负向调控作用,且有助于严格选择高亲和力的B细胞。但也有研究发现Tfr细胞在GC B细胞增殖和自身抗体生成中起着积极的"辅助"作用。利用叉头样转录因子3(Foxp3)+T细胞特异性B细胞淋巴瘤家族基因敲除小鼠(Bcl6FC小鼠)模型,发现这种"辅助"作用的部分机制是源于Tfr细胞的,IL-10可促使B细胞生长及滤泡辅助性T细胞(Tfh)向GC暗区迁移,这为GC中Tfr细胞的功能提供了新的可能性。本文就Tfr细胞的发育、分化及其在抗体反应中的双向功能予以综述,分析了Tfr细胞在不同疾病中的研究进展,旨在探寻免疫治疗的新视角。     

调节性T细胞与支气管哮喘

最近,一种在过敏性炎症反应中发挥较强免疫抑制功能的CD4 T细胞群受到广泛关注,这一细胞群被称为调节性T细胞(Tr细胞)。CD25、CTLA-4、TGF-β、IL-10以及Foxp3等多种分子均与Tr细胞的活性及分化有关。其中CD4 CD25 Tr细胞可以抑制Th2反应,减轻哮喘气道炎症,提示Tr细胞参与哮喘气道炎症。深入研究Tr细胞的作用机制,将有助于理解CD4 T细胞各亚群在哮喘中的地位与作用方式,为哮喘的防治提供新的思路。     

滤泡辅助性T细胞与自身免疫性疾病

自身免疫性疾病系自身反应性T细胞和自身抗体形成存在受抑缺陷.高亲和力致病性自身抗体的产生是发病的核心.淋巴滤泡内生发中心(GC)是T细胞依赖应答的必需结构,是体细胞高频突变、抗体类别转换和高亲和力B细胞选择的场所.CD+4T细胞对于GC的形成是必需的,它可提供信号使经抗原选择的高亲和力GC B细胞分化为记忆B细胞或浆细胞,以维持长期体液免疫.所以CD+4 T细胞在滤泡内辅助B细胞分化或维持耐受是自身免疫性疾病能否发生的关键环节.     

Conventional type 2 lung dendritic cells are potent inducers of follicular helper T cells in the asthmatic lung

BackgroundFollicular helper T (Tfh) cells represent a unique subset of helper CD4⁺ T cells in lymphoid follicles. Recently, Tfh cells were shown to play an important role in asthma through B cell differentiation. Conventional lung DCs are classified into two major subsets: conventional type 1 (cDC1) and type 2 (cDC2). Although the two subsets are different in driving particular T cell responses, the subset that induces Tfh cells in the asthmatic lung primarily has yet to be fully elucidated.MethodsWe evaluated Tfh cells, defined by the expression of CD4 and CXCR5, in HDM-challenged mice. Next, we characterized cDC1 and cDC2 purified from antigen-primed lung and examined their Tfh cell-inducing capacity. Additionally, the ability of lung DC-induced Tfh cells to cause germinal center B (GCB) cells to produce antigen-specific IgE was assessed.ResultsIn HDM-challenged mice, Bcl-6-expressing Tfh cells were significantly increased in the mediastinal lymph nodes. Lung cDC2, but not lung cDC1, increased after HDM priming, and cDC2 secreted larger amounts of IL-6 with higher ICOS-L expression than cDC1. In the co-cultures with OVA-specific naïve CD4⁺ T cells, cDC2 from OVA-primed lung induced Bcl-6-expressing Tfh cells more efficiently, together with larger amounts of IL-6 and IL-21, than cDC1. Blockage of IL-6 or ICOS-L significantly reduced Tfh cell induction. Finally, cDC2-induced Tfh cells enabled GCB cells to produce OVA-specific IgE.ConclusionsIn asthmatic lung, cDC2 is the primary DC subset responsible for Tfh cell differentiation and plays an important role in humoral immunity in asthma by inducing Tfh cells.     

B Cell-mediated Humoral Immunity in Chronic Hepatitis B Infection

B cell-mediated humoral immunity plays a vital role in viral infections, including chronic hepatitis B virus (HBV) infection, which remains a critical global public health issue. Despite hepatitis B surface antigen-specific antibodies are essential to eliminate viral infections, the reduced immune functional capacity of B cells was identified, which was also correlated with chronic hepatitis B (CHB) progression. In addition to B cells, T follicular helper (Tfh) cells, which assist B cells to produce antibodies, might also be involved in the process of anti-HBV-specific antibody production. Here, we provide a comprehensive review of the role of various subsets of B cells and Tfh cells during CHB progression and discuss current novel treatment strategies aimed at restoring humoral immunity. Understanding the mechanism of dysregulated B cells and Tfh cells will facilitate the ultimate functional cure of CHB patients.     

白介素-13和哮喘发病的研究进展

支气管哮喘（简称哮喘）是一种严重威胁人类健康的慢性呼吸道疾病。在世界范围内,过敏性哮喘的发病率和病死率逐年上升。研究表明,哮喘的发病是由于Th2型细胞过度释放细胞因子后诱导IgE产生,导致肥大细胞和嗜酸粒细胞脱颗粒,引起气道速发性过敏反应和以嗜酸粒细胞、肥大细胞、T细胞等多种炎症细胞参与的慢性气道炎症。白介素-13（IL-13）是一种由CD4^＋、Th2型细胞分泌的多效性细胞因子,介导变态反应的发生,与哮喘的发生有密切的关联。     

PI3K信号通路对T细胞发育、活化、增殖、分化及支气管哮喘的作用

T细胞是参与支气管哮喘发病的重要效应细胞,而磷脂酰肌醇-3-激酶(PI3K)是T细胞的重要信号转导分子.PI3K信号通过影响双阴性细胞的β-选择而影响T细胞的成熟,还通过激活PKB、Rac等信号途径而参与T细胞的活化、分化.同时,PI3K通过参与Th1/Th2失衡的调节,嗜酸粒细胞、肥大细胞的黏附、脱颗粒等而参与支气管...     

Characterization of germinal center dendritic cells in follicular lymphoma

A subset of dendritic cells called germinal center dendritic cells (GCDC) has recently been described inside germinal center from reactive lymphoid organs. We investigated this newly recognized population in follicular lymphoma (FL), which is considered to be the pathologic counterpart of germinal center B cells. Immunohistochemistry analysis with a panel of antibodies demonstrated the presence of a cell population with the peculiar GCDC phenotype in FL biopsies and a similar localization of these cells inside tumoral and reactive follicles. Therefore, we analyzed the relationships between GCDC and the other cell subsets of the tumor follicles. Some of CD4+ and CD8+ T lymphocytes present inside the follicle were found to be in close association with GCDC, suggesting a potential implication of GCDC in their activation. In addition, the distribution of GCDC inside FL and reactive follicles did not appear disrupted, in contrast to follicular dendritic cells, the other follicle dendritic cell type. Finally, we demonstrated that GCDC could be detected from FL lymph node cell suspension by flow cytometry. Taken together, these results indicate that FL development is not associated with a disappearance of GCDC or with a lack of physical interactions between GCDC and T cells inside the follicles. In addition, the fact that GCDC can be observed in FL samples by flow cytometry should allow their purification to further study their putative role in FL development and maintenance.     

Cooperation of multiple signaling pathways in CD40-regulated gene expression in B lymphocytes

CD40/CD40L interaction is essential for multiple biological events in T dependent humoral immune responses, including B cell survival and proliferation, germinal center and memory B cell formation, and antibody isotype switching and affinity maturation. By using high-density microarrays, we examined gene expression in primary mouse B lymphocytes after multiple time points of CD40L stimulation. In addition to genes involved in cell survival and growth, which are also induced by other mitogens such as lipopolysaccharide, CD40L specifically activated genes involved in germinal center formation and T cell costimulatory molecules that facilitate T dependent humoral immunity. Next, by examining the roles of individual CD40-activated signal transduction pathways, we dissected the overall CD40-mediated response into genes independently regulated by the individual pathways or collectively by all pathways. We also found that gene down-regulation is a significant part of the overall response and that the p38 pathway plays an important role in this process, whereas the NF-kappa B pathway is important for the up-regulation of primary response genes. Our finding of overlapping independent control of gene expression modules by different pathways suggests, in principle, that distinct biological behaviors that depend on distinct gene expression subsets can be manipulated by targeting specific signaling pathways.     

Chronic rhinosinusitis and asthma: novel understanding of the role of IgE 'above atopy'

Chronic rhinosinusitis (CRS) affects more than 10% of the European population and is often associated with asthma. Phenotypes of CRS can be differentiated based on mucosal remodelling and inflammatory patterns. Understanding the role of central mediators, such as interleukin-5, in these different phenotypes may lead to the development of specific therapeutic approaches. The impact of staphylococcal superantigens has been shown to further modify the immune response, contributing to persistent severe disease via the activation of T and B cells and the formation of local IgE. It is clear that these mechanisms are involved in the systemic spread of upper airway disease with resulting asthma comorbidity, when IgE antibodies to staphylococcal enterotoxins are present at measurable levels in serum. Recent findings point to superantigens as possible causal agents in the intrinsic form of severe asthma, and an anti-IgE strategy has shown promising therapeutic potential in nonatopic patients with nasal polyps and asthma. These findings should lead to a clinically relevant endotyping of patients with upper and lower airway disease and to a new understanding of the role of IgE 'above atopy'.     

Invariant natural killer T (iNKT) cells in asthma: a novel insight into the pathogenesis of asthma and the therapeutic implication of glycolipid ligands for allergic diseases.

Allergic bronchial asthma is a complex inflammatory diseases originated from dysregulated immune responses in the respiratory mucosa. The inflammatory state in asthmatic lung is characterized by massive infiltration with eosinophils, lymphocytes, and mast cells in the airway mucosa leading to airway hyperseisitivity, goblet cell hyperplasia and mucus overproduction. The inflammatory process is thought to be the result of intensive T helper (Th) 2-biased immune response. Over the past several years, there has been enormous progress in understanding the mechanisms for development of Th2-biased responses after inhaled exposure to allergens and the characteristics of CD4+ T cells prominently involved in this process. Recently, a new population of T cells, invariant natural killer T (iNKT) cells has been shown to play an important role in the pathogenesis of mouse model of allergic airway inflammation. iNKT cells are one of the most potent immune modulators through a massive production of a various cytokines including IL-4 and IFN-gamma upon activation, and are involved in a variety of immunoregulations including infection, autoimmunity, and tumor surveillance. The potent pathogenic role of iNKT cells in the development of bronchial asthma is due to their ability to produce predominant Th2 cytokines in a given condition. The involvement of iNKT cells in the pathogenesis of asthma might have been underestimated in the past studies demonstrating the involvement of CD4+ T cells in asthma because of the difficulty in the detection of iNKT cells. Meanwhile, growing evidences have demonstrated that iNKT cells could be a promising target for immune-based therapies for autoimmune diseases, tumor, and infection due to the invariance of their TCR usage, the restriction to the evolutionally-conserved non-polymorphic antigen-presenting molecule CD1d, and their outstanding ability to produce both Th1- and Th2-cytokines. In this review, we will overview current understanding of the pathophysiological roles of iNKT cells in asthma. We would also discuss on possible therapeutic approaches to bronchial asthma employing glycolipid ligands for iNKT cells.