树突状细胞经MHC-Ⅰ类分子替代递呈途径诱导CTL产生特异性抗肿瘤作用

树突状细胞作为最有效的专职抗原递呈细胞，表面存在结合抗原的ＤＥＣ－２０５受体，随着细胞的不断成熟，对抗原俘获加工能力减弱，细胞迁移能力增强，共刺激分子表达增强，Ｔ细胞粘附能力和抗原递呈能力增强，细胞因子合成增加。树突状细胞不但可以经ＭＨＣ－Ⅱ类分子途径递呈外源性抗原Ｔ辅助细胞，而且经ＭＨＣ－Ⅰ类分子替代途径递呈抗原肽段给杀伤性Ｔ淋巴细胞，以发挥对肿瘤细胞的特异性杀伤溶解作用。     

热休克蛋白gp96与肿瘤免疫研究进展

热休克蛋白gp96作为分子伴侣参与了肿瘤抗原向MHC-I类分子途径的递呈过程,并与抗原肽形成gp96-肽复合物激活CD8 ^＋T淋巴细胞,产生抗肿瘤的特异性免疫反应.此外,还能不依赖于抗原肽通过激活NF-κB信号转导,产生细胞因子和趋化因子,诱导树突状细胞成熟等多种作用而调节非特异性免疫反应.gp96-肽复合物疫苗为肿瘤的免疫治疗提供了新的思路.     

Tat-Rac1 C-末端肽促进树突状细胞的交叉递呈

目的 研究Rac1、Rac2、Rac3、RhoA以及Cdc42的C-末端肽对树突状细胞(DC)交叉递呈的影响.方法 合成Rac1、Rac2、Rac3、RhoA及Cdc42 C末端区与人工改造的穿膜肽Tat47-57的融合肽,负载DC2.4细胞后,采用荧光显微镜及流式细胞术检测DC2.4细胞吞噬能力的变化,采用B3Z细胞检测DC2.4细胞抗原交叉递呈能力的变化.结果 负载了Tat-Rac1 C-末端肽的DC2.4细胞吞噬能力增强,并显著促进DC2.4细胞经MHC I类分子途径递呈外源性抗原的能力.结论 Tat-Rac1 C-末端肽能够有效促进DC的交叉递呈,为病毒感染和肿瘤等疾病的治疗奠定了基础.     

自噬调节抗原递呈细胞功能的研究进展

自噬是细胞内进行的一种“自我消化”的过程。在此过程中,受损的细胞结构、衰老的细胞器和变性蛋白被包裹在自噬小体中,运输到溶酶体被降解,参与细胞代谢。抗原递呈细胞（APCs）依赖自噬识别微生物,进而产生Ⅰ型干扰素。自噬不仅提供了递呈到MHC-Ⅱ类分子上的抗原肽,还参与了APC的MHC-Ⅰ类分子递呈途径。此外,自噬会降低免疫突触的稳定性。     

热休克蛋白gp96与肿瘤免疫研究进展

热休克蛋白gp96作为分子伴侣参与了肿瘤抗原向MHC-I类分子途径的递呈过程,并与抗原肽形成gp96-肽复合物激活CD8+T淋巴细胞,产生抗肿瘤的特异性免疫反应。此外,还能不依赖于抗原肽通过激活NF-κB信号转导,产生细胞因子和趋化因子,诱导树突状细胞成熟等多种作用而调节非特异性免疫反应。gp96-肽复合物疫苗为肿瘤的免疫治疗提供了新的思路。     

MHC—1类分子递呈外源性抗原诱导CTL应答的作用

ＭＨＣ－Ｉ类分子不仅能够进行内源性抗原多肽怕递呈，而且通过吞噬细胞对抗原的加工处理，与其ＭＨＣ－Ｉ类分子结合后，也能有效地递呈外源性多肽诱导ＣＲＬＳ的产生。这一抗原递呈途径可能在免疫监视中发挥着重要作用。     

072 CD1介导脂类抗原识别与递呈的研究进展

CD1分子是不同于MHC分子的另一类抗原递呈分子,是用以识别并递呈脂及糖脂类抗原而非多肽抗原给T细胞的抗原递呈系统,其编码基因非常保守,并无多态性变异,在介导抗结核感染免疫及某些自身变态反应性疾病中起非常重要作用.对其作用与机制理论深入研究将为研制新的免疫疫苗开辟新的途径.     

CDl介导脂类抗原识别与递呈的研究进展

CDl分子是不同于MHC分子的另一类抗原递呈分子，是用以识别并递呈脂及糖脂类抗原而非多肽抗原给T细胞的抗原递呈系统，其编码基因非常保守，并无多态性变异，在介导抗结核感染免疫及某些自身变态反应性疾病中起非常重要作用。对其作用与机制理论深入研究将为研制新的免疫疫苗开辟新的途径。     

CD1介导脂类抗原识别与递呈的研究进展

CD1分子是不同于MHC分子的另一类抗原递呈分子 ,是用以识别并递呈脂及糖脂类抗原而非多肽抗原给T细胞的抗原递呈系统 ,其编码基因非常保守 ,并无多态性变异 ,在介导抗结核感染免疫及某些自身变态反应性疾病中起非常重要作用。对其作用与机制理论深入研究将为研制新的免疫疫苗开辟新的途径。     

MHCⅡ类分子的伴随蛋白—Ii链

Ｉｉ链作为ＭＨＣⅡ类分子的伴随蛋白，在外源性抗原肽递呈和Ｔ、Ｂ细胞的发育与 起了重要作用。Ｉｉ链的缺陷可能导致自身免疫病的发生。     

The role of mRNA translation in direct MHC class I antigen presentation

It has been over 40 years since it was discovered that the major histocompatibility (MHC) class I molecules present peptides for the CD8 T cell-mediated immune response. The pathways for delivering and processing peptides for the MHC class I complexes have since been thoroughly studied but it is only until more recently that we start to understand the mechanisms that provide peptide material for the endogenous MHC class I pathway. Interestingly, the main source of antigenic peptide substrates does not come from the same mRNA translation mechanism that produces full length proteins but from ribosomes which products sole purpose might be to produce antigenic peptide substrates. We will discuss the latest development in this field and its implications for a better understanding of one of the corner stones for how the immune system distinguishes between self and non-self.     

Beyond the classical: Influenza virus and the elucidation of alternative MHC class II-restricted antigen processing pathways

CD4+ T cells (T(CD4+)) are activated by peptides, generally 13-17 amino acids in length, presented at the cell surface in combination with highly polymorphic MHC class II molecules. According to the classical model, these peptides are generated by endosomal digestion of internalized antigen and loaded onto MHC class II molecules in the late endosome. Historically, this "exogenous" pathway has been defined through the extensive use of purified proteins. However, the relatively recent use of clinically relevant antigens, those of influenza virus in our case, has revealed several additional pathways of peptide production, including some that are truly "endogenous", entailing synthesis of the protein within the infected cell. Indeed, some peptides appear to be created only via endogenous processing. The cell biology that underlies these alternative pathways remains poorly understood as do their relative contributions to defence against infectious agents and cancer, and the triggering of autoimmune diseases.     

Alternative pathway dysregulation in tissues drives sustained complement activation and predicts outcome across the disease course in COVID-19

Complement, a critical defence against pathogens, has been implicated as a driver of pathology in COVID-19. Complement activation products are detected in plasma and tissues and complement blockade is considered for therapy. To delineate roles of complement in immunopathogenesis, we undertook the largest comprehensive study of complement in COVID-19 to date, comprehensive profiling of 16 complement biomarkers, including key components, regulators and activation products, in 966 plasma samples from 682 hospitalized COVID-19 patients collected across the hospitalization period as part of the UK ISARIC4C (International Acute Respiratory and Emerging Infection Consortium) study. Unsupervised clustering of complement biomarkers mapped to disease severity and supervised machine learning identified marker sets in early samples that predicted peak severity. Compared to healthy controls, complement proteins and activation products (Ba, iC3b, terminal complement complex) were significantly altered in COVID-19 admission samples in all severity groups. Elevated alternative pathway activation markers (Ba and iC3b) and decreased alternative pathway regulator (properdin) in admission samples were associated with more severe disease and risk of death. Levels of most complement biomarkers were reduced in severe disease, consistent with consumption and tissue deposition. Latent class mixed modelling and cumulative incidence analysis identified the trajectory of increase of Ba to be a strong predictor of peak COVID-19 disease severity and death. The data demonstrate that early-onset, uncontrolled activation of complement, driven by sustained and progressive amplification through the alternative pathway amplification loop is a ubiquitous feature of COVID-19, further exacerbated in severe disease. These findings provide novel insights into COVID-19 immunopathogenesis and inform strategies for therapeutic intervention.     

New perspectives on mannan-binding lectin-mediated complement activation

The complement system is an important part of the innate immune system, mediating several major effector functions and modulating adaptive immune responses. Three complement activation pathways exist: the classical pathway (CP), the alternative pathway (AP), and the lectin pathway (LP). The LP is the most recently discovered, and least characterized. The CP and the LP are generally viewed as working through the generation of the C3 convertase, C4bC2b, and are here referred to as the "standard" pathways. In addition to the standard CP and LP, so-called bypass pathways have also been reported, allowing C3 activation in the absence of components otherwise believed critical. The classical bypass pathways are dependent on C1 and components of the AP. A recent study has shown the existence also of a lectin bypass pathway dependent on mannan-binding lectin (MBL) and AP components. The emerging picture of the complement system is more that of a small "scale-free" network where C3 acts as the main hub, than that of three linear pathways converging in a common terminal pathway.     

Translating costimulation blockade to the clinic: lessons learned from three pathways

Summary:  As the recognition that costimulatory signals are critical for optimal T-cell activation, proliferation, and differentiation, there has been an explosion in the study of costimulatory molecules and their roles in enhancing anti-donor T-cell responses following transplantation. Here, we focus on the bench-to-beside translation of blocking agents designed to target three critical costimulatory pathways: the CD28/CD80/CD86 pathway, the CD154/CD40 pathway, and the lymphocyte function associated antigen-1/intercellular adhesion molecule pathway. While blockade of each of these pathways proved promising in inhibiting donor-reactive T-cell responses and promoting long-term graft survival in murine models of transplantation, the progression of development of therapeutic agents to block these pathways has each taken a slightly different course. Both logistical and biological pitfalls have accompanied the translation of blockers of all three pathways into clinically applicable therapies, and the development of costimulatory blockade as a substitute for current standard-of-care calcineurin inhibitors has by no means reached completion. Collaboration between both the basic and clinical arenas will further propel the development of costimulation blockers currently in the pipeline, as well as of novel methods to target these critical pathways during transplantation.     

分子伴侣Tapasin在介导免疫反应中的作用

分子伴侣Tapasin是抗原提呈相关转运蛋白的基因产物,和MHC-Ⅰ同为免疫球蛋白超家族的成员,与MHC分子和多肽装配密切相关,是MHC-Ⅰ类分子与TAP之间的桥梁.Tapasin在抗原提呈过程中有着重要作用,因而了解其生物学特征、在介导免疫反应中的作用及与疾病的相关性具有重要意义.     

Phagocyte-induced antigen-specific activation of unprimed CD8+ T cells in vitro

The strict segregation of the major histocompatibility complex (MHC) class I and class II loading pathways has been challenged by recent reports indicating that MHC class I molecules can acquire antigen in the phagocytic pathway. We now show that this alternative peptide loading pathway can be used efficiently to generate macrophages able to activate unprimed antigen-specific cytotoxic T cells in vitro. Short peptides (8–11 residues), administered in the phagocytic pathway at nanomolar concentrations, were found to be effective in specifically activating naïve cytotoxic T lymphocytes (CTL) in vitro, but longer peptides or whole protein antigen were not. Whole protein antigen coated on beads did, however, render macrophages susceptible to lysis by an antigen-specific CTL clone. This indicates that proteolysis in the phagocytic pathway has limited capability for class I-restricted presentation. We propose a model for class I loading in the phagocytic pathway consisting of direct trafficking of nascent MHC class I from the trans-Golgi network to the phagosome, prior to appearance at the cell surface, and the use of the narrow cavity between bead and phagosomal membrane as a peptide exchange/loading compartment. Targeting immunogenic class I-binding peptide to the phagocytic pathway of macrophages facilitates presentation in association with class I. This is a useful tool for CTL response induction in vitro.     

Inhibition of alternative pathway factor D by factor B -related synthetic hexapeptides

Hexapeptides mimicking the partial amino acid sequence of factor B surrounding the bond that is cleaved by factor D have been synthesized. These peptides have been assessed for their ability to inhibit factor D enzymatic activity and for their susceptibility to serine proteases. The synthetic peptides were cleaved by bovine trypsin and Cls but not by α-thrombin and factor D. The peptides inhibited factor B cleavage and fluid-phase or cell-bound alternative pathway C3 convertase activation by factor D. Altogether, these results suggest that peptides analogous to factor B specifically inhibit factor D enzymatic activity. Thus, they constitute an interesting tool for study of alternative pathway activation and can be of use when attempting to manipulate this pathway, since factor D is an essential component for alternative pathway initiation and amplification.     

miRNA靶向RAS-MAPK通路的表观遗传性激活与肿瘤

肿瘤作为一种难治性疾病，全世界都在为其治疗寻找新靶点。高度保守的RAS-MAPK通路在生物界大多数细胞内都广泛存在，主要通过各种级联反应刺激来控制细胞增殖分化等功能。体细胞基因突变编码RAS-MAPK通路经常发生在许多肿瘤中。miRNAs作为近年来研究较多的一种基因表达调控方式，其是通过与相关靶基因3’-UTR区结合来降解mRNA或抑制翻译表达。明确miRNA调控RAS-MAPK在肿瘤发生发展中的机制，可能为肿瘤的治疗提供新靶点。