调节性B细胞与自身免疫病研究进展

调节性B细胞（Breg）是一群可以降低炎症诱导免疫耐受的B细胞新亚群。Breg主要通过分泌白细胞介素10（IL-10）、肿瘤生长因子-β（TGF-β）等细胞因子或者与其他细胞相互作用来发挥免疫调节作用。Breg可以抑制效应T细胞增殖及炎症因子分泌并支持调节T细胞（Treg）的分化从而抑制自身免疫性疾病的发生或缓解病情。本文主要讨论Breg的表型、免疫学功能和Breg分化的分子机制以及在几种人类自身免疫性疾病中的作用。     

A20的免疫调节作用及其临床意义

A20最初是作为肿瘤坏死因子α(TNFα)诱导蛋白3(TNFA IP3)而鉴定的,它是炎症信号传导的中心调节因子———NF-κB抑制因子,在天然免疫和过继性免疫调节中发挥了重要作用。近期研究提示,A20是一个肿瘤抑制因子。A20缺失与炎症介导的自身免疫性疾病和淋巴细胞肿瘤的发生发展关系密切。近期有关A20在免疫细胞中的表达特点和生物学功能,在天然免疫、体液和细胞免疫中的调节作用,在淋巴细胞肿瘤中缺失情况以及在自身免疫性疾病中的异常表达等等的研究进展提示:有必要深入认识A20的临床意义和探讨其在诱导免疫耐受、肿瘤免疫调节治疗和抗病毒治疗等方面的应用价值。     

肿瘤坏死因子及其在肝病诊断中的应用

肿瘤坏死因子（TNF）是一类由激活的巨噬细胞、淋巴细胞等分泌的细胞因子,具有广泛的生物学活性。近年来,随着对TNF研究的不断深入,发现TNF在机体的细胞功能调节、免疫和炎症反应中起着重要作用。本文就TNF及其在肝病诊断中的应用概述如下。ITN’F的来源它是一种由内毒素激活的巨噬细胞产生的,仅对癌细胞有杀伤作用而对正常细胞无毒性的非种属特异性活性因子。TNF主要有两种：TNF－a（由活化的单核巨噬细胞产生）又称恶病质素;TNF－p（由活化的T细胞产生）又称淋巴毒素。最近又将自然杀伤细胞（NK）产生的NK细胞因子称之为…     

炎性细胞因子与脑缺血

0引言炎性细胞因子是一组由淋巴细胞、单核-巨噬细胞和血管内皮细胞等产生的免疫活性分子,包括白介素-1(IL-1),白介素-6(IL-6)和肿瘤坏死因子(TNF)等。它们共同参与机体免疫反应、应激反应和炎症调节。最近实验发现,在凝血和血管内皮损伤中也有重要作用,尤其是在脑缺血中的表达及作用已成为目前卒中研究的热点之一。1炎性细胞因子的生物学特性1.1TNF的生物特性根据来源不同,TNF分为TNF-a和TNF-β。TNF-a是活化的单核-巨噬细胞分泌的可溶性细胞肽,由157个氨基酸组成,分子量为17u。TNF-β是活化的淋巴细胞产生的淋巴毒素,由171个氨…     

P38 MAPK信号通路:炎性肠病治疗的新靶

细胞外刺激可通过细胞内信号传导途径介导细胞功能，包括细胞的基因表达、细胞增殖和死亡或凋亡、炎症反应和免疫反应等。细胞外刺激可主要通过两种细胞内信号传导途径调节细胞的基因转录，一是通过一系列磷酸化酶磷酸化激活下游分子的级联反应，激活胞核中的核转录因子，调节细胞的基因转录；二是通过受体-配体途径激活胞浆内的核转录因子，激活后的核转录因子通过转位进入核内调节细胞的基因表达。^1MAPK信号传导途径可通过前一途径调节细胞的基因表达。在免疫介导的炎症反应中发挥重要作用，本文就P38MAPK信号传导通路与IBD的关系及P38MAPK抑制剂在IBD中的应用研究进行综述。     

IL-33及其受体ST2在抗病毒和抗肿瘤免疫应答中的意义

白细胞介素33(IL-33)是白细胞介素1家族的新成员。先前研究表明,IL-33主要参与TH2型免疫应答,在变态反应、炎症、感染、自身免疫性疾病和心肺疾病等领域起重要作用。最新研究发现,IL-33还可通过干扰素γ(IFN-γ)、肿瘤坏死因子α(TNF-α)等多种细胞因子或作为免疫佐剂活化CD4+、CD8+T细胞,促进TH1型免疫应答,在细胞介导的抗病毒和抗肿瘤免疫中发挥重要作用。本文就近年来IL-33在抗肿瘤和抗病毒免疫应答中的相关研究作一综述。     

NALP3炎性体及相关肿瘤性疾病发病机制的研究进展

NALP3(NACHT-LRR-PYD-containing proteins 3 inflammasome)是NOD样受体(NOD-like receptors,NLRs)蛋白家族中典型代表,有调节机体免疫及调控炎症反应的作用,通过促进多种炎性介质(如IL-1β、IL-6、TNF-α等)释放可增加自身免疫性疾病及非感染性疾病的发生风险,近年来有许多研究表明NALP3炎性体还与肿瘤的发生、逃逸及转移有关,使之成为肿瘤性疾病研究的新热点。本文主要针对NALP3炎性体的结构、激活方式及相关肿瘤疾病做一综述。     

共刺激分子与类风湿关节炎

共刺激/抑制分子为T细胞提供正性和负性信号,调控T细胞的活化、增殖、分化和功能成熟,在T细胞的动态平衡中起重要的作用[1].它们的表达失衡可能导致免疫性疾病的发生:①共刺激分子如CD28,可诱导共刺激分子(ICOS)的上调,有持续活化T细胞的能力;②负调节因子如细胞毒性T细胞相关抗原4 (CTLA-4),程序性死亡蛋白1 (PD-1)的表达紊乱以及这些分子的可溶形式的功能拮抗导致免疫耐受的失调.虽然类风湿关节炎(RA)等常见的自身免疫性疾病的发病机制尚未明确,但是近1/4个世纪的实验研究证明了共刺激/抑制信号参与了自身免疫性疾病的免疫调节紊乱.最近发现共刺激/抑制分子的可溶形式在一些自身免疫性疾病中特异地表达,可能成为新的免疫学标记.而以共刺激信号通路为靶,也为RA的治疗提供了新的思路.本文现就共刺激/抑制分子在RA的发病机制中的研究以及临床应用前景作一综述,着重追踪了可溶性共刺激分子在RA等自身免疫性疾病中的新发现.     

白细胞介素10在膀胱肿瘤中的研究进展

白细胞介素10(IL-10)是一种多细胞源、多功能的细胞因子,调节细胞的生长与分化,参与炎性反应和免疫反应;主要是能够抑制活化的T细胞产生细胞因子,因此曾称为细胞因子合成抑制因子(CSIF),从而抑制细胞免疫应答,是目前公认的炎症与免疫抑制因子。近年来,对IL-10免疫抑制作用在肿瘤方面的研究已成为抗癌热点;特别是对膀胱肿瘤发病机制的探索已经为膀胱癌的治疗提供了较好的研究前景。本文就IL-10在膀胱肿瘤方面的研究作一综述。     

白细胞介素-27研究进展

细胞因子介导的免疫反应在许多疾病的发病机制中均发挥着关键性作用。白细胞介素-27（IL-27）是近期新发现的隶属于IL-6/IL-12家族的细胞因子,它通过不同的作用机制参与自身免疫性疾病、炎症及肿瘤等多种疾病的发生、发展及转归。许多研究证明,在缺乏IL-27的免疫疾病中,多种炎症因子高表达,从而产生严重的炎症反应。然而,IL-27还能促进Th1细胞的分化,具有一定的促炎作用。因此,IL-27具有免疫抑制和促炎双重作用。本文主要从IL-27在自身免疫性疾病、感染和肿瘤等疾病中发挥的作用及近期研究进展方面加以阐述。     

Gene polymorphisms of interleukins 1 and 10 in infectious and autoimmune diseases

Cytokines are proteins that regulate immune and inflammatory reactions as well as haematopoiesis. This group of molecules is very heterogeneous including, for example, several interleukins (IL), tumour necrosis factors (TNF) and colony-stimulating factors (CSF). The cytokines participating in the regulation of the inflammatory response are IL-1, IL-1 receptor antagonist (IL-1RA), IL-6, IL-10 and TNF. Functionally they can be divided into proinflammatory (IL-1, IL-6, TNF) and anti-inflammatory (IL-1RA, IL-10) molecules. There is evidence that the inflammatory response must be finely tuned: too strong a response causes the various adverse effects associated with infectious and autoimmune diseases, while a weak inflammatory response attenuates the subsequent immune response. It has now been demonstrated that several of the cytokine genes are polymorphic. In this review we describe the polymorphisms of the two inflammatory cytokines, IL-1 and IL-10, and their significance in various diseases of autoimmune or inflammatory nature.     

Mice transgenic for BAFF develop lymphocytic disorders along with autoimmune manifestations

The cause of many autoimmune and inflammatory diseases is unresolved, although dysregulated production of tumor necrosis factor (TNF) family members appears to be important in many cases. BAFF, a new member of the TNF family, binds to B cells and costimulates their growth in vitro. Mice transgenic for BAFF have vastly increased numbers of mature B and effector T cells, and develop autoimmune-like manifestations such as the presence of high levels of rheumatoid factors, circulating immune complexes, anti-DNA autoantibodies, and immunoglobulin deposition in the kidneys. This phenotype is reminiscent of certain human autoimmune disorders and suggests that dysregulation of BAFF expression may be a critical element in the chain of events leading to autoimmunity.     

Manipulation of cytokines in the management of patients with inflammatory bowel disease

In recent years, new concepts have been formulated for the therapeutic management of the intractable forms of Crohn's disease and ulcerative colitis, the two major forms of inflammatory bowel disease. These advances are based largely on new insights into the immune-inflammatory events occurring in the gut of these patients. Analysis of the types of immune response ongoing in the inflamed intestine has revealed that in Crohn's disease there is predominantly a T-helper cell type 1 response, with exaggerated production of interleukin (IL)-12 and interferon (IFN)-gamma, whereas in ulcerative colitis the lesion seems more of an antibody-mediated hypersensitivity reaction. Despite these differences, downstream inflammatory events are the same in both conditions. In both Crohn's disease and ulcerative colitis mucosa, IL-1gamma, IL-6, IL-8 and tumour necrosis factor (TNF)-alpha are produced in excess, and the production of free radicals accompanying the influx of nonspecific inflammatory cells into the mucosa is above the normal range. Strategies aimed at inhibiting T-cell responses are therefore more relevant in Crohn's disease, whereas, in theory at least, inhibition of downstream inflammatory processes should be therapeutic in both Crohn's disease and ulcerative colitis. This review seeks to summarize studies in which anticytokine antibodies, cytokines or cytokine-modifying agents have been used in the treatment of either Crohn's disease or ulcerative colitis.     

IL-17/IL-17 receptor system in autoimmune disease: mechanisms and therapeutic potential

IL-17 (interleukin-17), a hallmark cytokine of Th17 (T-helper 17) cells, plays critical roles in host defence against bacterial and fungal infections, as well as in the pathogenesis of autoimmune diseases. The present review focuses on current knowledge of the regulation, functional mechanisms and targeting strategies of IL-17 in the context of inflammatory autoimmune diseases. Evidence shows that IL-17 is highly up-regulated at sites of inflammatory tissues of autoimmune diseases and amplifies the inflammation through synergy with other cytokines, such as TNF (tumour necrosis factor) α. Although IL-17 was originally thought to be produced mainly by Th17 cells, a newly defined T-cell subset with a specific differentiation programme and tight regulation, several other cell types (especially innate immune cells) are also found as important sources for IL-17 production. Although IL-17 activates common downstream signalling, including NF-κB (nuclear factor κB), MAPKs (mitogen-activated protein kinases), C/EBPs (CCAAT/enhancer-binding proteins) and mRNA stability, the immediate receptor signalling has been shown to be quite unique and tightly regulated. Mouse genetic studies have demonstrated a critical role for IL-17 in the pathogenesis of variety of inflammatory autoimmune diseases, such as RA (rheumatoid arthritis) and MS (multiple sclerosis). Importantly, promising results have been shown in initial clinical trials of monoclonal antibodies against IL-17 or its receptor (IL-17R) to block IL-17-mediated function in treating autoimmune patients with psoriasis, RA and MS. Therefore targeting IL-17/IL-17R, IL-17-producing pathways or IL-17-mediated signalling pathways can be considered for future therapy in autoimmune diseases.     

Cytokine-induced immune deviation as a therapy for inflammatory autoimmune disease

The properties and outcome of an immune response are best predicted by the lymphokine phenotype of the responding T cells. Cytokines produced by CD4+ T helper type 1 (Th1) T cells mediate delayed type hypersensitivity (DTH) and inflammatory responses, whereas cytokines produced by Th2 T cells mediate helper T cell functions for antibody production. To determine whether induction of Th2-like cells would modulate an inflammatory response, interleukin 4 (IL-4) was administered to animals with experimental allergic encephalomyelitis (EAE), a prototypic autoimmune disease produced by Th1-like T cells specific for myelin basic protein (MBP). IL-4 treatment resulted in amelioration of clinical disease, the induction of MBP-specific Th2 cells, diminished demyelination, and inhibition of the synthesis of inflammatory cytokines in the central nervous system (CNS). Modulation of an immune response from one dominated by excessive activity of Th1- like T cells to one dominated by the protective cytokines produced by Th2-like T cells may have applicability to the therapy of certain human autoimmune diseases.     

Targeting BAFF: immunomodulation for autoimmune diseases and lymphomas

In an effort to develop more effective treatments for inflammatory diseases, immunologists have targeted numerous molecular pathways, but with limited success. Notable exceptions are anti-TNF agents, which have proved efficacious in a proportion of rheumatoid arthritis (RA) patients. Another TNF family member, termed BAFF ("B cell-activating factor belonging to the TNF family"), plays a central role in autoimmune diseases, as well as in B cell maturation, survival, and T cell activation. Agents that block BAFF have proven to be highly effective in the treatment of certain autoimmune conditions in mice. In addition, phase II data in human clinical trials for RA appear very promising. BAFF is also a survival factor for certain B cell lymphomas. Despite the relatively recent identification of BAFF, this molecule has provided considerable new insight into B cell homeostasis and immune function, and represents an important new molecular target for treatment of autoimmune diseases and lymphomas.     

白介素-35在炎症及自身免疫性疾病中的免疫学效应及临床意义

白介素（IL）-35是新近发现的IL-12家族抑制性细胞因子,在T细胞、B细胞免疫应答及传播性免疫耐受过程中发挥重要调控作用。目前尚未发现IL-35具备促炎效应。新近,炎症及自身免疫性疾病的相关基础及临床研究揭示了IL-35的病理生理学意义及其对疾病发生、发展及转归的重大影响。IL-35有望成为炎症及自身免疫性疾病诊断、监测及判断预后的重要免疫学指标,也是潜在的调控、治疗靶点。对IL-35表达及调控的深入研究,将为临床诊治炎症及自身免疫性疾病提供崭新的思路及方向。     

Tumor necrosis factor (TNF) receptor shedding controls thresholds of innate immune activation that balance opposing TNF functions in infectious and inflammatory diseases

Tumor necrosis factor (TNF) is a potent cytokine exerting critical functions in the activation and regulation of immune and inflammatory responses. Due to its pleiotropic activities, the amplitude and duration of TNF function must be tightly regulated. One of the mechanisms that may have evolved to modulate TNF function is the proteolytic cleavage of its cell surface receptors. In humans, mutations affecting shedding of the p55TNF receptor (R) have been linked with the development of the TNFR-associated periodic syndromes, disorders characterized by recurrent fever attacks and localized inflammation. Here we show that knock-in mice expressing a mutated nonsheddable p55TNFR develop Toll-like receptor-dependent innate immune hyperreactivity, which renders their immune system more efficient at controlling intracellular bacterial infections. Notably, gain of function for antibacterial host defenses ensues at the cost of disbalanced inflammatory reactions that lead to pathology. Mutant mice exhibit spontaneous hepatitis, enhanced susceptibility to endotoxic shock, exacerbated TNF-dependent arthritis, and experimental autoimmune encephalomyelitis. These results introduce a new concept for receptor shedding as a mechanism setting up thresholds of cytokine function to balance resistance and susceptibility to disease. Assessment of p55TNFR shedding may thus be of prognostic value in infectious, inflammatory, and autoimmune diseases.     

2017年消化系统疾病主要临床进展

2017年国内外胃肠病学相关学会及专家制订或更新了诸多消化领域的指南及共识意见,其中国内消化系统疾病相关学组结合我国疾病的发病特点,制订了许多切合我国国情的临床共识,为临床工作的开展带来极大便利。本文主要从幽门螺杆菌感染、胃食管反流病、Barrett食管、炎症性肠病、病毒性肝炎、自身免疫性肝病及胰腺等疾病入手,全面详实的介绍消化领域疾病的国内外诊治进展,以期为消化内科医生诊疗疾病提供帮助。