支气管哮喘的免疫治疗

CD4 T淋巴细胞可根据其产生的细胞因子的不同分为Th1和Th2两大类，Th1/Th2平衡对于哮喘的发生和发展具有重要的作用，通过免疫治疗调节Th1／Th2细胞平衡是哮喘治疗的一个途径。     

白细胞介素33在炎症性肠病中作用的研究进展

白细胞介素33(interleukin-33,IL-33)是新近发现的IL-1家族的细胞因子,在自身免疫性疾病的发生和发展中起到重要的作用.它广泛表达于各种细胞,如上皮细胞,间质细胞及炎症细胞.在抗胃肠道寄生虫感染过程中,IL-33能够发挥前炎症因子的作用诱导Th2型免疫应答.而且,在组织损伤时,IL-33可作为信号分子,启动免疫系统.近年来,有报道炎症性肠病患者的肠黏膜组织中的IL-33过量表达.本文对IL-33在炎症性肠病中作用进行综述.     

嗜酸性粒细胞的凋亡及对哮喘的意义

嗜酸性粒细胞（EOS）在支气管哮喘中起到重要作用，是参与哮喘气道炎症关键的效应细胞，其募集入肺并释放损伤性介质是气道炎症的中心环节。而在支气管哮喘炎症消退过程中，细胞凋亡是炎性细胞消除的主要方式。     

白介素-16与支气管哮喘关系的研究

白介素—16(IL—16)作为一种淋巴细胞趋化因子，参与了哮喘发病的早期调节，通过与细胞表面的CD4分子结合引起CD4^ 细胞、嗜酸性粒细胞和单核细胞的趋化性活动并在活化中发挥重要作用，参与哮喘气道炎症形成．     

发现白介素三元复合物晶体结构

白细胞介素是淋巴细胞、单核细胞以及其他非单核细胞等产生的细胞因子，在细胞间相互作用、免疫调节、造血过程以及炎症反应中起到重要作用。其中的白细胞介素4（IL-4）、白细胞介素13（IL-13）对于T细胞介导的体液免疫应答非常关键。与过敏和哮喘等疾病相关。在这一过程中，白细胞介素通过共同受体的3种不同组合发挥其作用。     

IL-17、IL-6对DSS诱导的小鼠慢性结肠炎结肠癌模型的调控作用的初步研究

IL-17是Th17细胞产生的诱导炎症反应的早期启动因子,IL-6是活化的T细胞和成纤维细胞产生的一种多效的促炎性细胞因子,都参与溃疡性结肠炎结肠癌的发生发展过程.通过DSS诱导小鼠慢性结肠癌模型,利用IL-17及IL-6基因敲除小鼠,分析了IL-17、IL-6在肠癌模型中对肿瘤的形成,对机体免疫反应过程中主要T细胞亚型及细胞因子的影响.结果显示,敲除IL-17能加重慢性肠炎诱导的结肠癌.这种加剧作用并不是通过影响T细胞的激活,而是可能通过上调CD8+T细胞的IFN-γ加重慢性肠炎进而促进肠癌的发生.敲除IL-6对肠癌表型影响不显著,但对T细胞的功能的影响与IL-17类似.该工作为深入探讨IL-17、IL-6对慢性结肠癌发生的调控机制奠定了一定的基础.     

太极拳锻炼对免疫平衡影响及其机制研究进展

通过整理与分析国内外文献,分析了太极拳锻炼影响CD4+/CD8+细胞平衡与T1/T2平衡的作用与机制.研究认为,太极拳锻炼可引起CD4+细胞数量与CD4+/CD8+细胞比值升高,该变化可能与MDC数量的增高促进了Th细胞的分化过程有关;太极拳锻炼可提升Th1细胞数量与Th1/Th2细胞比例以及Ⅰ型细胞因子IFN-γ,IL-2含量与IFN-γ/IL-4比值,诱发T1/T2平衡向T1方向漂移.该变化的机制可能是Treg数量的增高抑制了Th细胞的分化过程,从而降低了IL-4对Th1细胞分化的交互抑制作用.     

CD40在支气管哮喘患者外周血嗜酸性粒细胞的表达

探讨过敏哮喘患者和正常人外周血嗜酸性粒细胞（EOS）表达CD40的差异,采集10例过敏性哮喘患者和8例正常对照者静脉血用于纯化EOS,以流细胞仪检测CD40在EOS表达的表达,EOS胞浆中的CD40蛋白则以铭疫细胞化学方法显示,结果表明,哮喘患者EOS表面存在CD40表达,但CD40并不表达于正常人EOS的表面,无论是哮喘患者还是正常人,其EOS的胞浆均可检测到CD40蛋白,人EOS均能合成和储存CD40,CD40分子可以移行到哮喘患者EOS的表达而不能移行到正常人EOS的表面,揭示CD40在哮喘的发病机理中具有某种作用。     

Th17细胞调节宿主免疫应答功能研究进展

T细胞诱导的特异性免疫应答是机体血液淋巴细胞特异性免疫应答的重要组成部分,Th17细胞作为第3类因子可区分于体液中其他辅助T细胞.基于此,论述了Th17细胞系在对抗胞外寄生和胞内寄生细菌以及真菌感染中的作用.一系列研究表明,Th17细胞系能够紧密联系固有免疫和特异性免疫,使机体产生强烈的感染炎症反应.Th17细胞系既能...     

细胞周期调控蛋白Cdkn2a对于CD8~+T细胞中IL-10表达调控机制的初步研究

IL-10是一种典型的抑制性炎症因子,在机体免疫反应中发挥着重要的作用,探明该因子的表达调控机制对于阐释免疫应答在炎症反应、肿瘤发生发展等过程中的作用机制均具有重要意义.在前期工作的基础上,利用IL-10转基因报告小鼠10BiT,对细胞周期调控蛋白Cdkn2a在IL-10分泌型CD8+T细胞中调控IL-10表达的机制进行了初步探讨.结果显示,Cdkn2a对于CD8+T细胞中IL-10的表达调控与细胞分裂无关,而是可能作用于IL-4信号通路的下游来发挥作用.该工作为深入探讨Cdkn2a对IL-10的表达调控机制奠定了初步的基础.     

Hassall's corpuscles instruct dendritic cells to induce CD4+CD25+ regulatory T cells in human thymus

Hassall's corpuscles-first described in the human thymus over 150 years ago-are groups of epithelial cells within the thymic medulla. The physical nature of these structures differs between mammalian species. Although Hassall's corpuscles have been proposed to act in both the removal of apoptotic thymocytes and the maturation of developing thymocytes within the thymus, the function of Hassall's corpuscles has remained an enigma. Here we report that human Hassall's corpuscles express thymic stromal lymphopoietin (TSLP). Human TSLP activates thymic CD11c-positive dendritic cells to express high levels of CD80 and CD86. These TSLP-conditioned dendritic cells are then able to induce the proliferation and differentiation of CD4(+)CD8(-)CD25(-) thymic T cells into CD4(+)CD25(+)FOXP3(+) (forkhead box P3) regulatory T cells. This induction depends on peptide-major histocompatibility complex class II interactions, and the presence of CD80 and CD86, as well as interleukin 2. Immunohistochemistry studies reveal that CD25(+)CTLA4(+) (cytotoxic T-lymphocyte-associated protein 4) regulatory T cells associate in the thymic medulla with activated or mature dendritic cells and TSLP-expressing Hassall's corpuscles. These findings suggest that Hassall's corpuscles have a critical role in dendritic-cell-mediated secondary positive selection of medium-to-high affinity self-reactive T cells, leading to the generation of CD4(+)CD25(+) regulatory T cells within the thymus.     

Toll-like receptor 3 promotes cross-priming to virus-infected cells

Cross-presentation of cell-associated antigens plays an important role in regulating CD8+ T cell responses to proteins that are not expressed by antigen-presenting cells (APCs). Dendritic cells are the principal cross-presenting APCs in vivo and much progress has been made in elucidating the pathways that allow dendritic cells to capture and process cellular material. However, little is known about the signals that determine whether such presentation ultimately results in a cytotoxic T cell (CTL) response (cross-priming) or in CD8+ T cell inactivation (cross-tolerance). Here we describe a mechanism that promotes cross-priming during viral infections. We show that murine CD8alpha+ dendritic cells are activated by double-stranded (ds)RNA present in virally infected cells but absent from uninfected cells. Dendritic cell activation requires phagocytosis of infected material, followed by signalling through the dsRNA receptor, toll-like receptor 3 (TLR3). Immunization with virus-infected cells or cells containing synthetic dsRNA leads to a striking increase in CTL cross-priming against cell-associated antigens, which is largely dependent on TLR3 expression by antigen-presenting cells. Thus, TLR3 may have evolved to permit cross-priming of CTLs against viruses that do not directly infect dendritic cells.     

CD21 is a ligand for CD23 and regulates IgE production.

The molecule CD23, a low-affinity receptor for IgE (Fc epsilon R2), is a type II transmembrane molecule expressed on many haemopoietic cell types. CD23 has pleiotropic roles in the control of lymphocyte behaviour, suggesting that CD23 may interact with another ligand in addition to IgE. To identify such a CD23 ligand, we expressed and purified full-length recombinant CD23, incorporated it into fluorescent liposomes and used these as a probe. We report here that fluorescent liposomes carrying CD23 interact specifically with the cell-surface protein CD21, identified as the receptor for Epstein-Barr virus and the complement receptor-2 on B cells, some T cells and follicular dendritic cells. In addition, fluorescent CD23-liposomes were shown to bind to hamster kidney cells (BHK-21) transfected with CD21 complementary DNA. The interaction between fluorescent CD23-liposomes and B cells or CD21-transfected BHK-21 cells was specifically inhibited by anti-CD21 and anti-CD23 monoclonal antibodies. Western blotting analysis revealed that 14C-labelled liposomes carrying CD23, in contrast to anti-CD21 antibodies, reacted with a subtype of CD21 molecules. Triggering of CD21 either with an anti-CD21 antibody or with recombinant soluble CD23 was shown to increase specifically interleukin-4-induced IgE production from blood mononuclear cells. These results demonstrate that the cell-surface protein CD21 is a ligand for CD23 and that the pairing of these molecules may participate in the control of IgE production.     

Structure of domain 1 of rat T lymphocyte CD2 antigen.

The CD2 antigen is largely restricted to cells of the T-lymphocyte lineage and has been established as an important adhesion molecule in interactions between human T lymphocytes and accessory cells. In the adhesion reaction, CD2 on T cells binds to LFA-3 on other cells, with binding through domain 1 of CD2. CD2 can also be a target for the delivery of mitogenic signals to T lymphocytes cultured with combinations of anti-CD2 antibodies. Two predictions that are contradictory have been made for the structure of CD2 domain 1. One suggests an immunoglobulin (Ig) fold, on the basis of sequence patterns conserved in the Ig-superfamily (IgSF), whilst the other proposes a pattern of alternating alpha-helices and beta-strands, on the basis of secondary structure predictions. Thus CD2 domain 1 is an important test case for the validity of IgSF assignments based on sequence patterns. We report here the expression of domain 1 of rat CD2 in an Escherichia coli expression system and have determined a low-resolution solution structure by NMR spectroscopy.     

Chemokines enhance immunity by guiding naive CD8+ T cells to sites of CD4+ T cell-dendritic cell interaction

CD8+ T cells have a crucial role in resistance to pathogens and can kill malignant cells; however, some critical functions of these lymphocytes depend on helper activity provided by a distinct population of CD4+ T cells. Cooperation between these lymphocyte subsets involves recognition of antigens co-presented by the same dendritic cell, but the frequencies of such antigen-bearing cells early in an infection and of the relevant naive T cells are both low. This suggests that an active mechanism facilitates the necessary cell-cell associations. Here we demonstrate that after immunization but before antigen recognition, naive CD8+ T cells in immunogen-draining lymph nodes upregulate the chemokine receptor CCR5, permitting these cells to be attracted to sites of antigen-specific dendritic cell-CD4+ T cell interaction where the cognate chemokines CCL3 and CCL4 (also known as MIP-1alpha and MIP-1beta) are produced. Interference with this actively guided recruitment markedly reduces the ability of CD4+ T cells to promote memory CD8+ T-cell generation, indicating that an orchestrated series of differentiation events drives nonrandom cell-cell interactions within lymph nodes, optimizing CD8+ T-cell immune responses involving the few antigen-specific precursors present in the naive repertoire.     

Epithelial-cell-intrinsic IKK-beta expression regulates intestinal immune homeostasis

Intestinal epithelial cells (IECs) provide a primary physical barrier against commensal and pathogenic microorganisms in the gastrointestinal (GI) tract, but the influence of IECs on the development and regulation of immunity to infection is unknown. Here we show that IEC-intrinsic IkappaB kinase (IKK)-beta-dependent gene expression is a critical regulator of responses of dendritic cells and CD4+ T cells in the GI tract. Mice with an IEC-specific deletion of IKK-beta show a reduced expression of the epithelial-cell-restricted cytokine thymic stromal lymphopoietin in the intestine and, after infection with the gut-dwelling parasite Trichuris, fail to develop a pathogen-specific CD4+ T helper type 2 (T(H)2) response and are unable to eradicate infection. Further, these animals show exacerbated production of dendritic-cell-derived interleukin-12/23p40 and tumour necrosis factor-alpha, increased levels of CD4+ T-cell-derived interferon-gamma and interleukin-17, and develop severe intestinal inflammation. Blockade of proinflammatory cytokines during Trichuris infection ablates the requirement for IKK-beta in IECs to promote CD4+ T(H)2 cell-dependent immunity, identifying an essential function for IECs in tissue-specific conditioning of dendritic cells and limiting type 1 cytokine production in the GI tract. These results indicate that the balance of IKK-beta-dependent gene expression in the intestinal epithelium is crucial in intestinal immune homeostasis by promoting mucosal immunity and limiting chronic inflammation.     

Molecular identification of a danger signal that alerts the immune system to dying cells

In infections, microbial components provide signals that alert the immune system to danger and promote the generation of immunity. In the absence of such signals, there is often no immune response or tolerance may develop. This has led to the concept that the immune system responds only to antigens perceived to be associated with a dangerous situation such as infection. Danger signals are thought to act by stimulating dendritic cells to mature so that they can present foreign antigens and stimulate T lymphocytes. Dying mammalian cells have also been found to release danger signals of unknown identity. Here we show that uric acid is a principal endogenous danger signal released from injured cells. Uric acid stimulates dendritic cell maturation and, when co-injected with antigen in vivo, significantly enhances the generation of responses from CD8+ T cells. Eliminating uric acid in vivo inhibits the immune response to antigens associated with injured cells, but not to antigens presented by activated dendritic cells. Our findings provide a molecular link between cell injury and immunity and have important implications for vaccines, autoimmunity and inflammation.     

Positive selection of CD4+ T cells mediated by MHC class II-bearing stromal cell in the thymic cortex

T lymphocytes differentiate in the thymus, where functionally immature, CD4+CD8+ (double positive) thymocytes develop into functionally mature CD4+ helper cells and CD8+ cytotoxic (single positive) T cells. The thymus is the site where self-reactive T cells are negatively selected (clonally deleted) and where T cells with the capacity to recognize foreign antigens in association with self-proteins encoded by the major histocompatibility complex (MHC) are positively selected. The net result of these developmental pathways is a T-cell repertoire that is both self-tolerant and self-restricted. One unresolved issue is the identity of the thymic stromal cells that mediate the negative and positive selection of the T-cell repertoire. Previous work has pointed to a bone-marrow-derived macrophage or dendritic cell as the inducer of tolerance, whereas a radiation-resistant, deoxyguanosine-resistant thymic cell seems to mediate the positive selection of self-MHC restricted T cells. Thymic stromal cells in the cortex interact with the T-cell antigen receptor on thymocytes. Using several strains of transgenic mice that express the class II MHC molecule I-E in specific regions of the thymus, we show directly that the positive selection of T cells is mediated by an I-E-bearing cell in the thymic cortex.     

Delta is the Cx-gene product in the gamma/delta antigen receptor of dendritic epidermal cells

Most T cells bear an antigen receptor that is a protein of a disulphide-linked heterodimer composed of an alpha chain and a beta chain associated with the non-polymorphic CD3 (T3) complex. A small subpopulation of thymic and peripheral T cells, as well as Thy-1+dendritic epidermal cells (dEC), express an alternative CD3-associated dimeric receptor composed of the product of the T-cell antigen receptor (TCR) gamma gene and a fourth chain, designated delta. Recently a new murine TCR constant-region gene, designated Cx, has been cloned and proposed as a candidate for the C delta gene. We have previously demonstrated that murine Thy-1+ dEC cell lines express a CD3-associated disulphide-linked heterodimer composed of a relative molecular mass Mr 41,000 (41K) gamma chain and a 50K delta chain. We have further analysed the receptor of one of these cloned dEC lines, 7-17.1, by endoglycosidase treatment of the isolated gamma and delta chains. The gamma chain was found to contain two N-linked oligosaccharide residues, consistent with the expression of a chain encoded by the V gamma 3 and C gamma 1 gene segments. The delta chain contains at least three N-linked oligosaccharides and has a core size of 38K. Northern blot analysis indicated the presence of abundant Cx messenger RNA in 7-17.1 cells. Immunoprecipitation with two antisera to peptides comprising distinct regions of the Cx sequence indicates that the delta chain is encoded by the Cx gene.