HBV天然免疫的研究进展

HBV入侵人体时,天然免疫首先发挥重要的作用。成人感染HBV后,常常会被自发清除,然而在出生或者年幼时期感染HBV时,病情更容易慢性化并且迁延终生。在HBV感染初期,天然免疫应答对病毒复制的抑制发挥了重要作用,HBV感染的转归取决于宿主和病毒共同作用。简述了近年来有关HBV与宿主天然免疫中发挥重要作用的细胞类型、细胞因子、信号通路及其作用机制的研究进展,并指出了其在临床治疗方面的潜在价值。     

激活肝内天然免疫治愈乙型肝炎的进展和新策略

宿主天然免疫和适应性免疫应答对HBV的清除至关重要。慢性HBV感染者体内针对HBV的天然免疫和特异性免疫应答存在缺陷,不能有效清除病毒,导致病毒持续复制和肝脏炎症。除了直接抑制HBV,针对宿主免疫的治疗策略如刺激或重塑抗病毒免疫也是实现慢性乙型肝炎患者功能性治愈的重要手段之一。肝脏是HBV感染的靶器官,因此研究HBV感染对肝内免疫微环境的影响是当前调控肝内抗病毒免疫应答的新药研发热点。主要阐述了HBV感染相关天然免疫应答的研究进展和激活肝内天然免疫应答治愈乙型肝炎的新策略。     

慢性乙型肝炎患者抗病毒治疗过程中的免疫应答特点

宿主的免疫应答是一把双刃剑,参与慢性HBV感染的肝损伤和病毒控制,核苷和核苷酸类药物及干扰素抗病毒治疗可以通过调节宿主免疫应答影响预后。简要论述了宿主免疫应答在慢性HBV感染中的作用及其在抗病毒治疗过程中的特点,指出宿主免疫功能重建在持久HBV感染控制中的重要性。     

免疫检查点对慢性HBV感染者自然杀伤细胞功能的影响

慢性HBV感染的机制尚未完全阐明，HBV可诱发宿主免疫细胞功能障碍，引起免疫失衡和功能缺陷，这可能是HBV感染慢性化的机制之一。在慢性HBV感染中，自然杀伤(NK)细胞的功能是衰竭的，可能与其细胞表面免疫检查点分子的表达上调相关，阻断免疫检查点可以恢复NK细胞的功能。本文将从HBV病原学、慢性HBV感染机制以及常见免疫检查点在慢性乙型肝炎中对NK细胞功能的影响等方面进行系统综述，旨在为慢性HBV感染的治疗提供新的思路。     

抑制性受体TIGIT与慢性HBV感染中免疫紊乱的关系

持续HBV感染改变了天然免疫细胞和获得性免疫细胞表面受体的表达,由此引发的多种免疫紊乱,可导致免疫逃逸,最终使疾病慢性化。研究表明,抑制性受体的上调是患者免疫紊乱的主要原因,阻断抑制性受体可一定程度上恢复患者的免疫功能。T淋巴细胞免疫球蛋白和免疫受体酪氨酸抑制性基序结构域(TIGIT)是目前较为关注的一种新型抑制性受体,在NK细胞和T淋巴细胞中高水平表达。研究发现,TIGIT在慢性病毒感染中发挥重要作用,现就TIGIT与慢性HBV感染中免疫紊乱的相关性研究进展进行简要综述。     

丙型肝炎慢性化的免疫机制研究进展

丙型肝炎病毒(HCV)是肝硬化和肝癌的主要原因之一,目前全球超过1.7亿人感染HCV.在HCV感染的急性阶段,宿主调动起天然免疫和适应免疫系统以达到清除病毒的目的[1].但仍有约80％急性感染者最终会慢性化.很多因素参与急性丙型肝炎慢性化的过程,本文从天然免疫,细胞免疫以及病毒免疫逃逸性突变等在慢性化机制方面的研究进展综述如下.     

白细胞介素与HBV感染的关系

HBV进入宿主体内后,多种免疫细胞及其分泌的细胞因子参与了机体的免疫应答。白细胞介素是一类对免疫应答各个环节都有重要调节作用的细胞因子,介绍了几种在乙型肝炎发生、发展及转归中作用较大的白细胞介素及其与HBV感染的相关性,分析表明对白细胞介素免疫调节机制的深入研究可为各种类型乙型肝炎的诊断和治疗提供新的依据和方法。     

乙型肝炎的病毒学和临床治疗：关键问题和最新观点

HBV感染的转归是由病毒、肝细胞和宿主免疫应答之间的相互影响决定的。在慢性乙型肝炎中，肝损伤由宿主对HBV感染与免疫清除相关的肝细胞所产生的细胞免疫应答所致。存在8种HBV基因型(A、B、C、D、E、F、G、H)和4种不同的重组型(A／D、B／C、Ba、Bj)；每一种基因型和重组     

HBV感染免疫应答和免疫治疗新进展

病毒、病毒感染的靶细胞和机体的抗病毒免疫是推动疾病进展的“三架马车”,抗HBV治疗的“爬坡假说”根据宿主免疫应答的特点,提出调节宿主免疫应答的治疗策略可用以弥补单一抗病毒治疗慢性HBV感染的不足.笔者对病毒感染的免疫应答和免疫治疗研究的新进展进行综述.     

治疗性乙型肝炎疫苗的基础与应用研究

乙型肝炎的治疗可分为两大类:一类为抗病毒治疗,另一类为免疫治疗。由于在乙型肝炎病毒(hepatitisB virus,HBV)持续性感染中,宿主免疫应答异常是主要的发病机制,正确地调动宿主的免疫应答,适当地调动宿主自身的免疫应答,使HBV感染者恢复健康是免疫治疗的目的。由于持续性HBV感染者的免疫异常情况各有不同,因此在制订免疫治疗方案时应“个样化”,既要考虑感染者体内病毒复制的程度、病毒株是     

对免疫反应介导的肝细胞损伤机制的新认识

干扰素是细胞在病毒感染或其他诱导因素作用下产生的具有广谱抗病毒、抗肿瘤、抑制细胞增殖和免疫调节作用的细胞因子[1].自1986年应用于临床以来,因其肯定的疗效已被广泛地用于临床治疗多种疾病,在肝脏疾病中的应用目前主要集中在病毒性肝炎的抗病毒治疗,目前应用最广泛的是乙型病毒性肝炎及丙型病毒性肝炎.     

Dysregulation of mucosal immune response in pathogenesis of inflammatory bowel disease

Inflammatory bowel disease(IBD)includes Crohn’s disease and ulcerative colitis.The exact etiology and pathology of IBD remain unknown.Available evidence suggests that an abnormal immune response against the microorganisms in the intestine is responsible for the disease in genetically susceptible individuals.Dysregulation of immune response in the intestine plays a critical role in the pathogenesis of IBD,involving a wide range of molecules including cytokines.On the other hand,besides T helper(Th)1 and Th2 cell immune responses,other subsets of T cells,namely Th17 and regulatory T cells,are likely associated with disease progression.Studying the interactions between various constituents of the innate and adaptive immune systems will certainly open new horizons of the knowledge about the immunologic mechanisms in IBD.     

Limited effect of adaptive immune response to control encephalitozoonosis

This study revises our understanding of the effectiveness of cell‐mediated adaptive immunity and treatment against microsporidia using molecular detection and quantification of microsporidia in immunocompetent C57Bl/6 and immunodeficient CD4^?/? and CD8^?/? mice for the first time. We demonstrate an intense dissemination of microsporidia into most organs within the first weeks post‐infection in all strains of mice, followed by a chronic infection characterized by microsporidia persistence in CD4^?/? and C57Bl/6 mice and a lethal outcome for CD8^?/? mice. Albendazole application reduces microsporidia burden in C57Bl/6 and CD4^?/? mice, whereas CD8^?/? mice experience only a temporary effect of the treatment. Surprisingly, treated CD8^?/? mice survived the entire experimental duration despite enormous microsporidia burden. On the basis of our results, we conclude that microsporidia survive despite the presence of immune mechanisms and treatments that are currently considered to be effective and therefore that CD8 T lymphocytes represent a major, but not sole effector mechanism controlling microsporidiosis. Furthermore, the survival of mice does not correspond to spore burden, which provides new insight into latent microsporidiosis from an epidemiological point of view.     

Tight mucosal compartmentation of the murine immune response to antigens of the enteric microbiota

BACKGROUND & AIMS: The normal host immune response to antigens of the enteric microbiota is poorly defined. In this study, we isolated recombinant microbial antigens from commensal bacteria and used them to probe the normal murine immune response. METHODS: A plasmid DNA expression library was generated from cecal bacteria of C3H/HeJ mice and used to express 20 recombinant intestinal bacterial proteins (rIBs). Antibody responses in serum and secretions were measured by an enzyme-linked immunosorbent assay, and CD4+ T-cell responses were measured by [3H]-thymidine incorporation. Two immunodominant commensal flagellins were also tested. RESULTS: No baseline serum immunoglobulin (Ig)G antibody or splenic CD4+ T-cell systemic response to any rIB or to either flagellin was detected in normal C3H/HeJ mice. However, there were strong systemic responses to all 20 rIBs after parenteral immunization, which were equivalent to the responses to ovalbumin. Substantial levels of intestinal IgA were detected to half the rIBs and to both commensal flagellins. Mucosal immunization with flagellin plus ovalbumin stimulated an intestinal IgA but not a serum IgG response. Antigen-pulsed dendritic cells (DCs) stimulated production of specific IgA in the absence of T-cell help via costimulation by BAFF and/or APRIL, members of the TNF family. CONCLUSIONS: The host immune response to enteric bacteria is tightly compartmentalized to the mucosa in normal mice, with systemic B cells and CD4+ T cells remaining naive rather than tolerant. We postulate that mucosal DCs play a crucial role in this compartmentation.     

Glycoprotein B7-H3 overexpression and aberrant glycosylation in oral cancer and immune response

The incidence and mortality rate of oral cancer continue to rise, partly due to the lack of effective early diagnosis and increasing environmental exposure to cancer-causing agents. To identify new markers for oral cancer, we used a sialylation probe to investigate the glycoproteins differentially expressed on oral cancer cells. Of the glycoproteins identified, B7 Homolog 3 (B7-H3) was significantly overexpressed in oral squamous cell carcinoma (OSCC), and its overexpression correlated with larger tumor size, advanced clinical stage, and low survival rate in OSCC patients. In addition, knockdown of B7-H3 suppressed tumor cell proliferation, and restoration of B7-H3 expression enhanced tumor growth. It was also found that the N-glycans of B7-H3 from Ca9-22 oral cancer cells contain the terminal α-galactose and are more diverse with higher fucosylation and better interaction with DC-SIGN [DC-specific intercellular adhesion molecule-3 (ICAM-3)–grabbing nonintegrin] and Langerin on immune cells than that from normal cells, suggesting that the glycans on B7-H3 may also play an important role in the disease.Oral cancer is the 11th most-common cancer worldwide. An estimated 300,373 new cases and 145,353 deaths from oral cavity cancer (including lip cancer) occurred worldwide in 2012 (1). According to the data in GLOBOCAN 2012 published by the World Health Organization, oral cancer incidence and mortality in men in South and Central Asia is increasing, and it has become the second most common cancer in the region. Epidemiological studies reveal the strong association between oral cancer and the use of betel quid, alcohol, and cigarettes. Cancers of buccal mucosa, tongue, and gingiva constitute the majority of oral cancer in the Asian population, and that is related to the exposure to the carcinogen in these anatomical areas (2). It is estimated that approximately 90–95% of oral cancers are squamous cell carcinoma (OSCC) (3), and oral cancer has been shown to progress from hyperplasia, to mild-to-moderate dysplasia, severe dysplasia, and carcinoma in situ (4). Surgery is the standard treatment for OSCC, but the differences in primary sites and the complex anatomy of the head and neck give rise to intricate patterns of local invasion and regional spread. This distinction makes primary tumors difficult to eradicate once they have grown large enough to spread into adjacent tissues. Radiotherapy is an integral part of primary or adjuvant treatment, and chemotherapy is used as a combination therapy in advanced OSCC (5). Despite numerous prospective trials using various combination therapies to improve locoregional control, survival rates for advanced carcinogen-associated OSCC remain dismal (6). In contrast to many other cancers in which metastasis is the primary cause of death, local recurrence is the common cause of treatment failure and death in patients with OSCC (5). Therefore, locoregional control is a key therapeutic objective (7).Glycosylation is an important biological process that occurs cotranslationally or posttranslationally on more than 50% of eukaryotic proteins and can affect protein folding, stability, solubility, and function. Aberrant glycosylation is often observed in pathological conditions such as inflammation and cancer metastasis. Altered terminal fucosylation and sialylation are believed to result from changes in expression and are associated with tumor malignancy (8). Atypical glycosylation of cell surface carbohydrates has been reported to be associated with malignant transformation of oral epithelium (9), and protein-bound sugar levels were higher in plasma and tissue samples of oral cancer patients (10). A series of studies about dysregulation of the N-glycosylation–regulating gene, DPAGT1, drives oral cancer cell discohesion by inhibiting adhesion of E-cadherin through Wnt signaling pathway were reported (11–13). It was also found that the expression of Lewis^y on EGFR promotes migration of oral cancer cells (14).To identify new markers as diagnostic and therapeutic targets for oral cancer, a sialylation probe was used to investigate the differential expression of glycoproteins in oral cancer and normal cells. Among the glycoproteins identified, receptor B7-H3 was selected for further study because it was more differentially expressed in cancer cells. B7-H3, also known as B7 homolog 3 or CD276 isoform 1, was discovered in 2001 (15) and is a 110-kDa, type I transmembrane glycoprotein with four Ig-like domains that contain a nearly exact tandem duplication of the IgV-IgC domain (4Ig-B7-H3). However, the potential binding partner of B7-H3 remains unclear (16), and the functional effect of B7-H3 on T cells is controversial (17). B7-H3 protein was also found on various cell types and organs. This broad expression pattern suggests more diverse immunological and probably nonimmunological functions of B7-H3, especially in peripheral tissues (18). Recently, B7-H3 has been found in a variety of different human cancers, including prostate (19, 20), nonsmall cell lung (NSCLC) (21), gastric (22, 23), pancreatic (24), ovarian (25), colorectal (26), urothelial cell (27), clear cell renal cell (ccRCC) (28), and hypopharyngeal (29) cancers.We are interested in understanding the expression pattern of B7-H3 in oral cancer and its possible underlying mechanisms. In this study, both the protein and the glycosylation profile of B7-H3 were investigated to explore their correlation with tumor progression with the expectation that the findings will provide more information to better understand oral cancer and improve therapies.     

Humoral immune response to tissue transglutaminase is related to epithelial cell proliferation in celiac disease

BACKGROUND & AIMS: Tissue transglutaminase (tTG) autoantibodies are markers of celiac disease, and the enzyme is required for several crucial biological processes. The aim of this study was to determine whether these autoantibodies are involved in the pathogenesis of the mucosal lesion typical of celiac disease. METHODS: Using rhodamine-conjugated phalloidin staining, we evaluated whether tTG antibodies, both commercially available and cloned from patients with celiac disease, cause cytoskeletal changes in Caco-2, MCF7, and NIH 3T3 cells. We monitored cell levels of bromodeoxyuridine incorporation to determine whether tTG autoantibodies are able to induce NIH 3T3 fibroblasts and epithelial mucosal cells into S phase. RESULTS: Treatment with tTG antibodies caused a dose-dependent increase of membrane ruffling in Caco-2, MCF7, and NIH 3T3 cells. It also dose-dependently induced G(0)-synchronized NIH 3T3 fibroblasts into S phase but did not affect the rate of apoptosis. Similarly, tTG antibodies induced S-phase entry of epithelial cells in cultured intestinal biopsy specimens from patients with celiac disease. They did not affect biopsy specimens from patients without celiac disease. CONCLUSIONS: Our results suggest that tTG autoantibodies per se, by interacting with the extracellular membrane-bound transglutaminase, may play an important role in epithelial cell proliferation in celiac disease.