CD40-CD40L共刺激分子与自身免疫性疾病

大量研究证实CD4 0分子与其配体CD4 0L结合所产生的共刺激信号在B细胞的增殖、分化、抗体的分泌和类型转换以及T细胞活化、效应性细胞因子分泌中起重要作用。近年来发现 ,CD4 0、CD4 0L异常表达与一些疾病的免疫病理密切相关。本文仅就CD4 0 CD4 0L的生物学特性、功能和在自身免疫性疾病中的致病作用及其可能的治疗策略作一综述     

129 CD40-CD40L共刺激分子与自身免疫性疾病

大量研究证实CD40分子与其配体CD40L结合所产生的共刺激信号在B细胞的增殖、分化、抗体的分泌和类型转换以及T细胞活化、效应性细胞因子分泌中起重要作用.近年来发现,CD40、CD40L异常表达与一些疾病的免疫病理密切相关.本文仅就CD40-CD40L的生物学特性、功能和在自身免疫性疾病中的致病作用及其可能的治疗策略作一综述.     

CD40—CD40L共刺激分子与自身免疫性疾病

大量研究证实CD40分子与其配体CD40L结合所产生的共刺激信号在B细胞的增殖、分化、抗体的分泌和类型转换以及T细胞活化、效应性细胞因子分泌中起重要作用。近年来发现,CD40、CD40L异常表达与一些疾病的免疫病理密切相关。本文仅就CD40－CD40L的生物学特性、功能和在自身免疫性疾病中的致病作用及其可能的治疗策略作一综述。     

孕酮对人T淋巴细胞体外活化CD69表达的作用

目的：探讨孕酮（Ｐｒｏｇｅｓｔｅｒｏｎｅ,Ｐｒｏｇ）及地塞米松（Ｄｅｘａｍｅｔｈａｓｏｎｅ,Ｄｅｘ）对人外周血Ｔ淋巴细胞体外活化ＣＤ６９表达的作用。方法：以女性健康志愿者（１０名）为研究对象,以蛋白激酶Ｃ的刺激剂佛波醇酯（Ｐｈｏｒｂｏｌ ｅｓｔｅｒ,ＰＤＢ）为Ｔ淋巴细胞的活化剂,采用双荧光染色流式细胞技术。检测ＣＤ３＾＋的Ｔ淋巴细胞表达早期活化表面分子ＣＤ６９的百分率,以观察Ｐｒｏｇ、Ｄｅｘ及Ｐｒｏ０ｇ加上Ｄｅｘ对外周血Ｔ淋巴细胞体外活化的作用。结果：在体外培养条件下,无论单独使用Ｐｒｏｇ还是Ｄｅｘ均地强低剂量ＰＤＢ刺激ＣＤ６９的表达。然而,与单独使用Ｐｒｏｇ或Ｄｅｘ的作用相比。Ｐｒｏｇ加上Ｄｅｘ明显减弱低剂量ＰＤＢ的活化ＣＤ６９的表达。结论：同时使用Ｐｒｏｇ与Ｄｅｘ可明显抑制Ｔ淋巴细胞的体外活化,提示在临床上     

共刺激分子CD40L在RA患者T细胞亚群中的异常表达

目的　探讨共刺激分子CD4 0L在类风湿关节炎 (RA)患者的T细胞亚群上的表达异常与免疫功能紊乱的关系。方法　用流式细胞仪采用直接免疫荧光法测定 4 6例RA患者和 2 0例健康对照人外周血T细胞表面标志CD3、CD4、CD8的表达情况及CD4 0L在CD4 + T和CD8+ T细胞上的表达。用IMMAGE免疫分析仪 ,速率散射比浊法测定血清中免疫球蛋白的水平。结果　RA患者CD3+ CD4 + 细胞较正常对照组显著增高 (P <0 .0 5 ) ,CD3+ CD8+ 细胞较正常对照组显著降低 (P <0 .0 5 ) ,CD4 + T细胞和CD8+ T细胞上的CD4 0L的表达都较对照组显著增高 (P <0 .0 5 ) ;血清中 3种免疫球蛋白IgG、IgA、IgM的水平均较对照组显著增高 (P <0 .0 5 )。结论　RA患者以CD4 + T细胞活化为主 ,CD4 + T细胞和CD8+ T细胞上高表达的CD4 0L为T细胞活化提供第二信号 ,促使RA患者的细胞免疫功能亢进 ,同时诱导B细胞增生 ,产生大量免疫球蛋白。CD4 0 CD4 0L途径在RA免疫功能紊乱中起了重要作用     

抗CD4抗体不同地调节CD4,45RO^＋和CD4,45RA^＋T细胞的辅助性…

观察了抗ＣＤ４抗体（ａｎｔｉ－ＣＤ４）在体外对ＣＤ４Ｔ淋巴细胞亚群ＣＤ４，４５ＲＡ＾＋和ＣＤ４，４５ＲＤ＾＋Ｔ细胞的辅助性功能及Ｔ细胞受体调节的细胞内Ｃａ＾２＋＿信号的影响，ａｎｔｉ－ＣＤ４主要是通过影响Ｔ－Ｂ淋巴细胞相互作用早期而影响ＣＤ４，４５ＲＤＴ细胞的辅助性功能，ａｎｔｉ－ＣＤ４对ＴＣＲ／ＣＤ３调节的Ｔ细胞增殖反应的抑制是由于抑制了细胞内Ｃａ＾２＋信号的传导，并且ＣＤ４５的分子结构密切相关     

CD4~+ CD28~- T淋巴细胞与自身免疫性疾病

CD4+CD28-T细胞是一个具有特殊生物学效应的细胞亚群,高频出现于某些自身免疫性疾病中,具有细胞毒样的侵蚀特性、T细胞活化的不平衡性及抗凋亡特征,与疾病的发生、发展及转归密切相关。     

重型肝炎CD4~+及CD8~+淋巴细胞亚群的检测和意义

目的:研究重型肝炎患者CD4+及CD8+淋巴细胞亚群的变化及对疾病的预后的影响。方法:收集21例重型肝炎患者及30例健康体检者作为对照组,通过流式细胞仪检测其T淋巴细胞亚群,并与临床预后进行比较。结果:重型肝炎患者T淋巴细胞亚群计数CD4+ CD8-、CD4- CD8+细胞明显低于对照组(P0.05),而CD4+/CD8+比值高于对照组(P0.05);而重症肝炎患者中死亡患者的CD4+CD8-、CD4-CD8+细胞数则较存活患者降低(P0.05),而CD4+/CD8+比值较存活者降低,但无统计学差异。结论:T淋巴细胞亚群的变化特别是CD4+ CD8+细胞数及其比值的变化对预后判断有重要参考价值。     

系统性红斑狼疮患者外周血CD4+和CD8+T细胞PD-1的表达和意义

目的 探讨程序性死亡分子1 (PD-1)在系统性红斑狼疮(SLE)患者外周血CD4+和CD8+T细胞上的表达及临床意义.方法 应用流式细胞仪检测51例SLE患者和38例健康对照者外周血T细胞亚群表面PD-1表达水平,比较SLE稳定组、活动组和健康对照组以及狼疮肾炎组和无狼疮肾炎组之间CD4+和CD8+T细胞表面PD-1表达的百分比,并分析其与临床表现及实验室检查数据的相关性.结果 SLE活动组CD4+T细胞PD-1表达水平高于健康对照组和不活动组,差异均有统计学意义(P＜0.05).SLE活动组、稳定组CD8+T细胞PD-1表达水平均高于健康对照组,差异有统计学意义(P＜0.05).狼疮肾炎患者CD4+PD-1+和CD8+PD-1+T细胞分别高于无狼疮肾炎患者(P＜0.01).SLE患者中抗dsDNA抗体、抗Sm抗体、抗核小体抗体阳性组外周血CD4+和CD8+T细胞PD-1表达水平均高于对应阴性组.SLE患者CD4+和CD8+T细胞PD-1表达百分率与SLE疾病活动度指数(SLEDAI)、尿蛋白定量呈正相关,与补体C3呈负相关.结论 SLE患者外周血CD4+和CD8+T细胞PD-1表达异常,与SLEDA1和自身抗体产生有明确的相关性.     

CD8+CD25+调节性T细胞在疾病中的研究进展

CD8⁺CD25⁺Treg具有抑制免疫反应和诱导免疫耐受作用。本文综述了CD8⁺CD25⁺Treg在恶性肿瘤、自身免疫性疾病及其他常见病如哮喘、过敏性疾病、2型糖尿病、子痫前期中的变化及相应的作用机制,CD8⁺CD25⁺Treg在不同疾病中的变化不一致,在恶性疾病中升高,而在自身免疫性疾病中降低。进一步加深对CD8⁺CD25⁺Treg的认识将为疾病的防治及预后提供依据。     

The murine homologue of the T lymphocyte CD2 antigen: molecular cloning, chromosome assignment and cell surface expression

The human T lymphocyte antigen CD2 (T11, sheep erythrocyte receptor) is expressed on all peripheral T cells and all but the most immature thymocytes. Experiments with monoclonal antibodies against CD2 suggest that CD2 is the cell surface receptor for a natural ligand involved in T cell proliferation. Clarification of the functional role of CD2 would be facilitated by the identification of CD2 in the mouse. However, antibodies that recognize the murine homologue have not been described. An alternative approach to the identification of the murine homologue was to use cross-species DNA hybridization, employing human CD2 cDNA as a probe. Clones encoding the murine homologue were isolated from a murine T helper cell cDNA library. The murine cDNA sequence encoded a predicted mature polypeptide of 322 amino acids that showed 54% identity with the predicted human sequence. As with the human polypeptide, the cytoplasmic domain was large, and rich in proline and basic residues. CD2 mRNA was expressed in murine thymus and spleen, and in the T cell line EL4. The murine CD2 gene was assigned to chromosome 3 by Southern blot analysis of mouse-hamster somatic cell hybrids. A rabbit antiserum raised against purified human CD2, precipitated from surface-labeled mouse thymocytes a glycoprotein of Mr 55,000-66,000 which decreased to Mr 35,000 on digestion with endo-beta-acetylglucosaminidase F. These sizes are consistent with those predicted for the murine CD2 antigen from the cDNA sequence.     

CD40 expression and function in murine B cell ontogeny

The CD40 antigen, a member of the nerve growth factor/tumornecrosis factor receptor family, is expressed on all matureB lymphocytes and plays a crucial role in B cell activation,T cell- dependent antigen-driven isotype switching and germinalcenter formation. We have analyzed C040 expression and functionduring mouse B cell development by examining B cell precursorsin normal mice and in transgenic animals in which B cell developmentis frozen at discrete stages. These models included RAG-2 ^-/-mice, and transgenlc littermates that express µ heavychain and/ or the bcl-2 proto-oncogene transgene. CD40 was undetectableat the pro-B cell stage, but was expressed, although at lowlevels, on pre-B cells. However, pre-B cells failed to respondto CD40 triggering either by expression of CD23 or by proliferationin the presence of lL-4. Overexpression of bcl-2 increased thedensity of CD40 expression on pre-B cells: these cells respondto CD40 ligation by expressing CD23 and by proliferating inthe presence of IL-4.     

Altered CD45 isoform expression affects lymphocyte function in CD45 Tg mice

Transgenic mice have been constructed expressing high (CD45RABC) and low (CD45R0) molecular weight CD45 isoforms on a CD45-/- background. Phenotypic analysis and in vivo challenge of these mice with influenza and lymphocytic choriomeningitis viruses shows that T cell differentiation and peripheral T cell function are related to the level of CD45 expression but not to which CD45 isoform is expressed. In contrast, B cell differentiation is not restored, irrespective of the level of expression of a single isoform. All CD45 trangenic mice have T cells with an activated phenotype and increased T cell turnover. These effects are more prominent in CD8 than CD4 cells. The transgenic mice share several properties with humans expressing variant CD45 alleles and provide a model to understand immune function in variant individuals.     

CD40 and dendritic cell function

CD40 has emerged as a key signaling pathway for the function of B cells, monocytes, and dendritic cells (DC) in the immune system, and plays a major role in inflammatory pathways of nonhemopoietic cells. CD40 is expressed by monocytes and DC and is up-regulated when DC migrate from the periphery to draining lymph nodes (DLN) in response to microbial challenge. CD154 signaling by MHC-restricted, activated CD4+ T cells induces differentiation of DC, as defined by an increased surface expression of MHC, costimulatory, and adhesion molecules. Thus, CD40 functions in the adaptive immune response as a trigger for the expression of costimulatory molecules for efficient T-cell activation. CD40 ligation of DC also has the capacity to induce high levels of the cytokine IL-12, which polarizes CD4+ T cells toward a T helper 1 (Th1) type, enhances proliferation of CD8+ T cells, and activates NK cells. CD40 may also play an important role in the decision between tolerance and immunity and the generation of regulatory CD4+ T cells that are thought to maintain peripheral self-tolerance in vivo.     

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.     

A pharmacologic study of the relationship between lymphocyte function and surface antigen expression

The relationship between functional activity and distribution of lymphocyte surface markes has not been clearly defined. We have examined the relationship between cell surface markers and function under the influence of immunosuppressant therapy. We found that after immunization with EL₄ cells, the development of the immune reponse in the BALB/c mouse was accompanied by a decrease in spleen cells which stained brightly with fluorescein-labeled monoclonal anti-Thy 1 and an increase in cells which stained with rabbit anti-mouse Ig as measured on the FACS. Low doses of azathioprine and cyclophosphamide, which affect functional activity of the cells, do not alter cell surface markers. However, at higher doses of the drugs normalization of immunization-induced marker changes were observed, and the Thy 1⁺ and Ig⁺ surface markers were maintained at levels seen in non-immunized mice. In spite of a nearly 3-fold increase in the total number of lymphocytes and an increase in the functional activity of cytotoxic T cells (Lyt2⁺) after immunization, no alteration in the percentage of Lyt 2⁺ T cells nor in the intensity of staining with FITC-labeled Lyt 2 antibody was seen. Inhibition of the immune response with immunosuppressant also failed to change the Lyt 2⁺-staining cell population. This study demonstrates that lymphocyte functional changes precede cell surface antigen changes, and that functional changes may occur without surface antigen changes. Thus cell surface markers are late indicators of functional changes.     

CD40L结构与功能的关系

CD40/CD40L是一对参与机体免疫应答的极为重要的共刺激分子,具有广泛的生物学活性。CD40L功能的发挥与其结构密切相关。现有研究表明,CD40L的活性形式为三聚体结构,其单体结构与TNF超家族其他成员有着较高的结构同源性,有着类似于三明治的结构。不同氨基酸残基结构各异,内部残基参与三聚体形成,外部残基参与与受体的结合。CD40L包括跨膜型和分泌型,二者的结构和功能均有差异。     

CD40 expression by gingival fibroblasts: correlation of phenotype with function

CD40, a member of the tumor necrosis factor-alpha receptor family, is constitutively expressed by cells of hematopoietic and non- hematopoietic origin, including fibroblasts. Signaling through this receptor molecule regulates inflammatory cytokine secretion by many cell types. Based on the recently described cytokine secretory heterogeneity of fibroblast cell subsets, we hypothesized that secretion of inflammatory cytokines by gingival fibroblast cultures may be dictated by the existence of differential proportions of cytokine- secreting subpopulations which express high levels of CD40. After examining a large number of gingival fibroblast (GF) cultures we find that the frequency of IL-6- and IL-8-secreting cells mirrors the frequency of cells expressing high levels of CD40 in these cultures. In addition, we demonstrate a direct functional relationship between CD40 expression and IL-6 or IL-8 secretion by showing that ligation of this molecule on GF, and CD40+ fibroblast subsets in particular, up- regulates secretion of these cytokines in vitro.      

Hyper-immunoglobulin M syndrome type 3 with normal CD40 cell surface expression

Mutations of the CD40 gene have been found in patients with autosomal recessive hyper-immunoglobulin M (HIGM) syndrome type 3. Five patients from four unrelated families with CD40 mutation have been reported so far. Clinical manifestations include recurrent sinopulmonary infections, Pneumocystis carinii pneumonia and Cryptosporidium parvum infection. Affected patients typically have very low levels of IgG and IgA and normal or high levels of IgM. Flow cytometry analysis of these five patients demonstrated that peripheral blood B lymphocytes lacked expression of surface CD40. Herein, we present two siblings from second-degree consanguineous Turkish parents with homozygous CD40 deletion of four nucleotides including the stop codon resulting presumably to a longer protein. Clinical and immunological profile of these patients is similar to the already reported HIGM3 patients except normal CD40 expression on B lymphocytes. This observation emphasizes the requirement of CD40 mutation analysis for definite diagnosis of HIGM3 despite normal flow cytometric expression of CD40, particularly if the immunological and clinical profile is suggestive for HIGM3.     

The roles of CD8 in cytotoxic T lymphocyte function

The CD8 glycoprotein of cytotoxic T cells is both an adhesion protein and a cosignalling receptor. These functions are regulated by signals from the T-cell antigen receptor complex (TCR-CD3), and CD8 acts to couple TCR occupancy to second messenger pathways. Here Anne O'Rourke and Matthew Mescher examine the roles of CD8 in activating the adhesion and signalling cascade initiated by antigen binding.