CD40-CD40L功能与疾病的研究进展

CD40与CD40L的相互作用不仅在细胞免疫和 体液免疫中起作用,而且在疾病的发病机制和临床治疗中起重要作用。     

CD40／CD40L介导信号的免疫调节作用

Ｂ细胞的ＣＤ４０分子与活化Ｔ细胞的ＣＤ４０配体（ＣＤ４０Ｌ）结合可调节Ｂ细胞生长分化、克隆转换、Ｉｇ分泌、阻断Ｂ细胞凋亡和导Ｆａｓ表面分隔表达等,直接参与调节体液免疫。ＣＤ４０与ＣＤ４０Ｌ结合也影响细胞免疫功能,诱导Ｔｈ１和Ｔｈ２细胞因子产生《ＣＤ４０和ＣＤ４０Ｌ连接ＴＲＡＦ蛋白多聚化,从而调节基因的转录。ＣＤ４０介导的信号传导过程与蛋白酷氨酸酶、蛋白酪氨酸磷酸化有等有关。     

CD40/CD40L信号系统与子痫前期的关系

子痫前期是病理产科中常见的疾病,是导致孕产妇和围生儿死亡的主要原因,其具体病因目前尚未完全阐明,大多数学者认为主要与氧化应激导致的血管内皮细胞损伤,胎盘浅着床,免疫平衡的破坏等因素有关,其中内皮细胞损伤导致的内皮细胞生理功能失衡是其病因学研究的热点.CD40/CD40L是一对互补的肿瘤坏死因子和肿瘤坏子因子受体超家族跨膜糖蛋白,相互作用可以促进内皮细胞、平滑肌细胞表达和释放细胞因子、组织因子、金属蛋白酶、粘附分子,这些物质间接或直接的参与了炎症反应和免疫调节,导致内皮细胞损伤.因此,CD40/CD40L相互作用在炎症反应和免疫失调中亦起着关键作用,可能是子痫前期的病因之一,以CD40/CD40L为靶点为子痫前期的诊断和治疗提供了新的思路和方向.本文拟对CD40/CD40L信号系统与子痫前期的关系做一综述.     

不同剂量瑞舒伐他汀对ACI患者外周血淋巴细胞OX40L表达及血清OX40L和hs-CRP水平的影响

目的:探讨不同剂量瑞舒伐他汀对急性动脉硬化脑梗死(ACI)病人外周血淋巴细胞OX40L及血清OX40L和hs-CRP水平的影响.方法:选择40名动脉硬化性脑梗死病人,随机分为瑞舒伐他汀20 mg治疗组(A组)和瑞舒伐他汀10 mg治疗组(B组),应用QRT-PCR及酶联免疫吸附试验(ELISA)法分别检测外周血淋巴细胞OX40L及血清OX40L和hs-CRP的水平.结果:A组与B组外周血淋巴细胞OX40L下降幅度比较(P＜0.01)及血清sOX40L和CRP水平治疗后有明显降低(P＜0.05),A组与B组比较A组降低更加明显,有统计学意义.结论:动脉硬化性脑梗死病人急性期服用瑞舒伐他汀20 mg能更明显的降低患者外周血淋巴细胞OX40L及血清OX40L和CRP的水平,提示动脉粥样硬化性脑梗死病人早期服用较大剂量的他汀药物治疗效果可能更好.     

自身免疫与动脉粥样硬化斑块

自身免疫可能促成动脉粥样硬化,这一观点已得到多数人的认可。动脉粥样硬化病程中产生的表位如氧化修饰的低密度脂蛋白(oxLDL)已被看作是自身免疫的攻击目标。但Binder等最近提出,自身免疫对动脉粥样硬化有保护作用(文章发表在Nat Med 2003年第6期),其证据如下：在小鼠模型中,抗oxLDL的自然自身抗体(命名为T15)不导致动脉粥样硬化的发生,而是减轻疾病的程度。     

编码流感病毒血凝素基因和CD40L的核酸疫苗抗小鼠流感研究

为了检测表达CD40L的质粒能否作为核酸疫苗佐剂提高A/PR8/34流感病毒血凝素(HA)DNA疫苗的免疫应答,构建了表达鼠CD40L的质粒,并将它与A型流感病毒的 HA DNA疫苗用电击的方法共同免疫BALB/C小鼠(各30μg),免疫两次,间隔三周,第二次免疫后1周,用致死量流感病毒A/PR8/34攻击.发现与单独免疫30μg HA相比,血清中抗HA的IgG抗体量明显提高,且以IgG2a抗体提高为主,小鼠体重减轻非常少且体重恢复加快.实验结果显示,CD40L能作为流感病毒核酸疫苗佐剂,提高小鼠抗流感病毒攻击的能力.     

编码流感病毒血凝素基因和CD40L的核酸疫苗抗小鼠流感研究

为了检测表达CD40L的质粒能台作为核酸疫苗佐剂提高A／PR8／34流感病毒血凝素(HA)DNA疫苗的免疫应答,构建了表达鼠CD40L的质粒,行将它与A型流感病毒的HADNA疫苗用电击的方法共同免疫BALB／C小鼠(各30μg),免疫两次,间隔三周,第二次免疫后1周,用致死量流感病毒A／PR8／34攻击。发现与单独免疫30μgHA相比,血清中抗HA的IgG抗体节明显提高,且以IgG2a抗体提高为主,小鼠体重减轻非常少且体重恢复加快。实验结果显示,CD40L能作为流感病毒核酸疫苗佐剂,提高小鼠抗流感病毒攻击的能力。     

幽门螺杆菌感染与胃癌共刺激分子OX40和 OX40L表达的相关性

目的 研究幽门螺杆菌(H. pylori)感染与胃癌共刺激分子OX40、OX40L表达的相关性。 方法 收集本院2017年1月至2019年1月进行胃癌手术的68例患者为研究对象。采用Giemsa染色和PCR方法检测胃癌组织H. pylori感染情况。应用免疫组织化学法检测胃癌和癌旁组织中共刺激分子OX40、OX40L的表达,并分析共刺激分子OX40、OX40L表达与胃癌组织H. pylori感染的相关性。分析OX40、OX40L表达与胃癌患者临床病理特征的关系。采用二元Logistic回归分析胃癌组织H. pylori感染的影响因素。 结果 胃癌组织中OX40、OX40L阳性表达率显著高于癌旁组织(均P0.05),而与胃癌肿块大小相关(P结论 H. pylori感染可能与胃癌组织中OX40、OX40L异常表达相关,可为探究H. pylori致癌机制提供一定参考。     

鸡源CD40L基因克隆、蛋白表达及生物活性检测

为获得鸡源CD40L (chCD40L)蛋白,以鸡脾细胞制备cDNA并以之为模板扩增chCD40L基因,构建pFastBac-chCD40L供体重组质粒,转化感受态细胞DH 10Bac,通过筛选及鉴定获得Bacmid-chCD40L重组质粒,转入真核表达系统sf9昆虫细胞进行蛋白表达与纯化,获得His-chCD40L蛋...     

动脉粥样硬化易损斑块形成和破裂的研究进展

动脉粥样硬化能导致斑块形成。随着疾病的进展,斑块发展和破裂会引起致死性冠状动脉血栓形成,表现为急性冠脉综合征。斑块破裂后,斑块内具有高度成血栓性的物质暴露在血液中,导致血栓形成。斑块破裂主要发生于薄帽纤维斑块。此外,未破裂的斑块也可以形成血栓。然而,斑块破裂的机制仍不太清楚。本文将讨论动脉粥样硬化斑块发生和发展机制、斑块是如何参与危及生命的血栓形成等问题。     

Involvement of CD40-CD40L signaling in postischemic lung injury

Our studies show that ischemia-reperfusion (I/R) in the isolated rat lung causes retention of lymphocytes, which is associated with increased microvascular permeability, as determined by quantitative measurement of the microvascular filtration coefficient (K(f,c)). Immunoneutralization of either CD40 or CD40L, cell surface proteins important in lymphocyte-endothelial cell proinflammatory events, results in significantly lower postischemic K(f,c) values. Antagonism of CD40-CD40L signaling also results in attenuation of I/R-elicited macrophage inflammatory protein-2 production. Rat lymphocytes activated ex vivo with phorbol 12-myristate, 13-acetate increased K(f,c) in isolated lungs independently of I/R, and this increase was prevented by pretreating lungs with anti-CD40. In addition to lymphocyte involvement via CD40-CD40L interactions, our studies also show that I/R injury is potentiated by antagonism of IL-10 produced locally within the postischemic lung, whereas exogenous, rat recombinant IL-10 provided protection against I/R-induced microvascular damage. Thus acute lymphocyte involvement in lung I/R injury involves CD40-CD40L signaling mechanisms, and these events may be influenced by local IL-10 generation.     

Immunological synapse formation licenses CD40-CD40L accumulations at T-APC contact sites

The maintenance of tolerance is likely to rely on the ability of a T cell to polarize surface molecules providing "help" to only specific APCs. The formation of a mature immunological synapse leads to concentration of the TCR at the APC interface. In this study, we show that the CD40-CD154 receptor-ligand pair is also highly concentrated into a central region of the synapse on mouse lymphocytes only after the formation of the TCR/CD3 c-SMAC. Concentration of this ligand was strictly dependent on TCR recognition, the binding of ICAM-1 to T cell integrins and the presence of an intact cytoskeleton in the T cells. This may provide a novel explanation for the specificity of T cell help directing the help signal to the site of Ag receptor signal. It may also serve as a site for these molecular aggregates to coassociate and/or internalize alongside other signaling receptors.     

The expression of CD40-CD40L and activities of matrix metalloproteinases in atherosclerotic rats

This study investigated the expression of CD40, CD40 ligand (CD40L) and matrix metalloproteinases (MMPs) in dietary-induced atherosclerosis in rats. Wister rats were fed with high cholesterol diet (As group, n = 6) or with normal diet (N group, n = 6). Blood cells that express CD40 and CD40L were sorted by flow cytometry, the MMP-2 and MMP-9 were measured by zymography method. The morphological locations of MMP-2 and MMP-9 in the aorta were studied with immunohistochemistry and by microscopy. The results showed that the expression of CD40, CD40L and matrix metalloproteinase were higher in As group than those in control group. The MMP-2 and MMP-9 were positive in As group but negative in control group by immunohistochemistry study. Our results suggest that the expression of CD40 and CD40L in the blood cells and the activities of MMP-2 and MMP-9 in plasma were higher in As group than those in Normal group, indicating that they may contribute to the formation of atherosclerosis.     

CD40-CD40 ligand-independent activation of CD8+ T cells can trigger allograft rejection

In experimental transplantation, blockade of CD40-CD40 ligand (CD40L) interactions has proved effective at permitting long-term graft survival and has recently been approved for clinical evaluation. We show that CD4+ T cell-mediated rejection is prevented by anti-CD40L mAb therapy but that CD8+ T cells remain fully functional. Furthermore, blocking CD40L interactions has no effect on CD8+ T cell activation, proliferation, differentiation, homing to the target allograft, or cytokine production. We conclude that CD40L is not an important costimulatory molecule for CD8+ T cell activation and that following transplantation donor APC can activate recipient CD8+ T cells directly without first being primed by CD4+ T cells.     

CD40-CD40 ligand interactions in oxidative stress, inflammation and vascular disease

CD40 ligand (CD40L) and its receptor CD40 participate in numerous inflammatory pathways that contribute to multiple pathophysiological processes. A role for CD40-CD40L interactions has been identified in atherosclerosis, and such interactions are known to destabilize atherosclerotic plaques by inducing the expression of cytokines, chemokines, growth factors, matrix metalloproteinases and pro-coagulant factors. The CD40-CD40L interaction has also been implicated in immune system disorders. Recent studies have suggested that CD40-CD40L interactions regulate oxidative stress and affect various signaling pathways in both the immunological and cardiovascular systems. Here, we discuss the emerging role of CD40-CD40L-mediated processes in oxidative stress, inflammatory pathways and vascular diseases. Understanding the roles and regulation of CD40-CD40L-mediated oxidative signaling in immune and non-immune cells could facilitate the development of therapeutics targeting diverse inflammatory diseases.     

CD40-CD40L interactions promote neuronal death in a model of neurodegeneration due to mild impairment of oxidative metabolism

Abnormalities in oxidative processes, region-selective neuron loss, inflammation and diminished activity of thiamine-dependent enzymes characterize age-related neurodegenerative diseases. Thiamine deficiency (TD) models the selective neurodegeneration that accompanies mild impairment of oxidative metabolism. As in human neurodegenerative diseases, alterations in multiple cell types accompany the TD-induced neurodegeneration. The current studies demonstrate that CD40 and CD40 ligand (CD40L), two co-stimulatory immune molecules, are involved in TD-induced selective neuronal death. TD induced CD40 immunoreactivity in microglia and CD40L immunoreactivity in astrocytes. Both CD40-positive microglia and CD40L-positive astrocytes increased during the progressive TD-induced neuronal death. In early stages of TD, targeted deletion of CD40 diminished the number of CD40L-positive astrocytes and reduced neuronal death by 35%. The number of CD40L-positive astrocytes increased whenever the number of NeuN-positive neurons decreased. In early stages of TD, deletion of CD40L diminished CD40-positive microglia and reduced the neuronal death by 64%. In advanced phases of TD, neither CD40 nor CD40L deletion protected against neuronal death. The data show for the first time that TD induces expression of CD40 by the microglia and CD40L by astrocytes. The results indicate that CD40-CD40L interactions promote neuronal death in early stages of TD, but that at later phases the protective effects of the diminished CD40 or CD40L are over-ridden by other mechanisms.     

RNAi-mediated CD40-CD154 interruption promotes tolerance in autoimmune arthritis

Introduction

We have previously demonstrated that ex vivo inhibition of costimulatory molecules on antigen-pulsed dendritic cells (DCs) can be useful for induction of antigen-specific immune deviation and suppression of autoimmune arthritis in the collagen induced arthritis (CIA) model. The current study evaluated a practical method of immune modulation through temporary systemic inhibition of the costimulatory molecule CD40.

Methods

Mice with collagen II (CII)-induced arthritis (CIA) were administered siRNA targeting the CD40 molecule. Therapeutic effects were evaluated by clinical symptoms, histopathology, Ag-specific T cell and B cell immune responses.

Results

Systemic administration of CD40-targeting siRNA can inhibit antigen-specific T cell response to collagen II, as well as prevent pathogenesis of disease in both a pre- and post-immunization manner in the CIA model. Disease amelioration was associated with suppression of Th1 cytokines, attenuation of antibody production, and upregulation of T regulatory cells.

Conclusions

These studies support the feasibility of transient gene silencing at a systemic level as a mechanism of resetting autoreactive immunity.     

The role of CD40-CD154 interaction in cell immunoregulation

CD40, a member of the nerve growth factor/tumor necrosis factor receptor superfamily, and its ligand, CD154, play essential roles in cell immune responses. The results of many studies have indicated that CD40-CD154 interaction can upregulate costimulatory molecules, activate antigen-presenting cells (APCs), influence T-cell priming and T-cell-mediated effector functions as well as participate in the pathogenic processing of chronic inflammatory diseases, such as autoimmune diabetes, graft rejection, atherosclerosis, and cancer. Ligation of CD40 on cancer cells was also found to produce a direct growth-inhibitory effect through cell cycle blockage and/or apoptosis with no overt side effects on normal cells and treatment with CD154 can heighten tumor rejection immune response as well. However, systemic treatment with CD154 has some potential risks. Therefore, searching for efficient and safe strategies of CD154-based cancer therapy has been a hot topic in human cancer research. This review focuses on the latest discovered functions of CD40-CD154 interaction in cell immune responses and on the new findings of CD154-based human cancer therapy.     

The CD40-CD154 interaction in B cell-T cell liaisons

The CD40 receptor is expressed constitutively on B lymphocytes, for which it provides important signals regulating clonal expansion, antibody production and isotype switching, as well as the development of humoral memory. The major source of CD154, the ligand for CD40, is activated T lymphocytes. Interactions between CD40 and CD154 provide a number of signals that play important roles in regulating the complex and multifactorial interactions between these two major cell types of the adaptive immune response. Understanding both the biological effects of this receptor-ligand interaction, as well as how CD40 signaling pathways are controlled, adds to our detailed picture of the complex interplay between B and T cells.