免疫耐受的生理基础

免疫耐受是针对特定抗原(主要为自身抗原)的特异性不应答状态,是免疫系统稳定机体内环境的生理功能基础,其产生和维持的主要机制包括中枢耐受和外周耐受2种类型。其中,中枢耐受主要通过阴性选择的过程将自身高反应性免疫细胞进行克隆清除,其主要发生在胚胎期和新生期的动物体内;外周耐受的机制相对多样而复杂,主要包括克隆清除、克隆无能、免疫忽视状态和免疫隔离部位等多种方式。免疫耐受也会受到调节性T细胞等免疫调节细胞及分子的调控,从而保障免疫系统的正常生理状态。对免疫耐受的生理基础及其相关的进展进行了简要的介绍和总结。     

组织特异抗原异位表达与免疫耐受

诱导和维持T细胞耐受是免疫系统区分自我和非我的关键。自身免疫调节因子(autoimmune regulator,AIRE)作为转录因子,在胸腺髓质上皮细胞中可驱动一系列组织特异抗原基因的表达,从而在诱导中枢免疫耐受的过程中发挥重要作用。外周免疫耐受的机制复杂一些,清除耐受是其重要机制之一。外周淋巴结的基质细胞可表达部分组织特异抗原,递呈给T淋巴细胞,激活并最终清除它。中枢免疫耐受和外周免疫耐受机制可清除潜在的自身反应性T淋巴细胞,维持对自身组织耐受。一旦免疫耐受被打破,将发生自身免疫反应和自身免疫疾病。     

影响CD4+CD25+T细胞分化发育的细胞分子机制

免疫耐受的精髓即机体对外界病原体抗原产生免疫应答的同时对自身抗原不应答.近两年对CD4 CD25 调节性T细胞(CD4 CD25 regulatory T cell, Treg)所发挥的免疫耐受功能的研究取得了令人瞩目的长足进展,对此群细胞所具有的维持外周免疫耐受的独特地位已无可争议.但调节性T细胞的多种生物学特征特别是Treg细胞分化发育的分子机制与信号需求并不清楚,因此探索有关Treg的发生发育及其影响机制已成为近两年研究Treg细胞的热点.综述最近的相关研究数据,了解胸腺以及外周影响Treg细胞分化发育和功能产生的多种细胞分子机制,有助于进一步研究此群细胞的功能及其在抑制自身免疫性疾病、诱导移植耐受等方面的应用.     

JCB:细胞核内钙信号可改变T细胞应答,有助开发免疫抑制疗法

正组成免疫系统的免疫细胞可以区分"自己"和"非己"的蛋白分子。比如,如果我们暴露于细菌或病毒等病原体,而这些病原体表面带有外来分子,机体就会做出免疫应答。相比之下,免疫细胞会对机体自身的分子产生耐受。这种不应答状态或者称为无反应性受到一个钙控开关的调节,之前研究报道这种钙信号开关参与许多脑部功能的调控。来自海德堡大学的神经科学家和免疫学家     

调节性 T 细胞发育的一个关键转录因子 Foxp3

调节性 T 细胞是目前免疫学领域研究的热点,对于维持机体免疫耐受和免疫应答稳态具有非常重要的作用 . 对其发育和功能机制的深入认识,不但有助于了解错综复杂的免疫系统理论,而且在自身免疫性疾病、肿瘤和艾滋病的治疗以及移植耐受的诱导等方面具有广泛的应用前景 . 最近的研究发现,转录因子 Foxp3 对于调节性 T 细胞的发育具有重要的作用,是调节性 T 细胞发育的一个关键转录因子 .     

树突状细胞诱导外周免疫耐受的机制

树突状细胞既能启动免疫应答,又能诱导免疫耐受。目前对树突状细胞外周耐受方面的研究进展迅速,本文就未成熟树突状细胞、免疫抑制因子处理的树突状细胞及转基因树突状细胞在诱导外周免疫耐受中的作用作一综述,这可能是治疗自身免疫性疾病和移植排斥反应的新途径。     

肝脏固有免疫系统对肠源性感染的免疫应答与免疫耐受机制

肝特殊的解剖结构及生理特征使其成为暴露肠源性抗原的主要器官。由于肝具有独特的固有免疫系统,在正常情况下,肝分布多种致耐受的抗原提呈细胞,对持续性表达或递呈于肝的肠源性抗原物质,诱发针对该抗原的系统性免疫耐受,避免肝受到不必要的免疫损伤。当炎症发生及肝脏固有免疫系统活化时,则通过免疫效应细胞及免疫效应因子对肠源性病原体发挥强烈地免疫应答以控制感染。该过程形成机制的研究对肝功能的理解及肝性疾病的预防与治疗至关重要。本文就肝固有免疫系统对肠源性感染的免疫应答与免疫耐受形成机制作一综述。     

调节性T细胞抑制作用机制的研究进展

调节性T细胞(Treg)对维持机体免疫动态平衡具有重要作用。不仅诱导产生自身免疫耐受,防止自身免疫疾病的发生,而且能够限制免疫防御中T、B细胞过度活化,避免造成组织损伤。最近研究发现,Treg可能导致效应性免疫细胞失活,降低机体对肿瘤和病原的免疫应答。尽管Treg可能通过调节免疫细胞活化、增值和分化及效应等多环节产生抑制作用,但其抑制机制仍未清楚。本文对近几年国外研究Treg可能的抑制作用机制的进展作一综述。     

肿瘤免疫耐受——肿瘤细胞的免疫学特性

肿瘤可以看作是一种免疫性疾病,即病理性的免疫耐受疾病。正常的（生理性的）免疫耐受是人体重要的防御和维护机制,能保证免疫杀伤功能不伤害自身,也就是不会发生冤假错案。例如,免疫耐受可以保证免疫系统不识别自身细胞和抗原、防御超敏性免疫反应及自身免疫性疾病的发生、保护自身生殖细胞和成体干细胞不受周围免疫系统的干扰、保护胎儿不受母体免疫系统排斥等。病理性的免疫耐受是病原体（例如肝炎病毒）为了长期保持在宿主体内的感染状态或肿瘤细胞为了逃逸免疫的监督,     

母-胎免疫耐受机制研究现状与发展趋势

母-胎免疫耐受作为免疫学原理的唯一例外,一直是生殖免疫学界备受关注的焦点问题。一个世纪以来,人们对于母-胎免疫耐受建立和维持的机制有了越来越深入的认识。妊娠早期胎儿绒毛外滋养细胞(EVT)侵入蜕膜组织,与母体蜕膜免疫细胞(DIC)及蜕膜基质细胞(DSC)直接接触,建立精细的母-胎交互对话。在总结既往研究成果的基础上,围绕母-胎界面关键的功能细胞,基于母-胎交互对话阐明母-胎免疫耐受的建立和维持机制。其中,对以滋养细胞为中心的母-胎界面固有免疫应答、母-胎界面适应性免疫应答及穿插于其中的协同刺激信号和趋化因子等方面进行概述,以解析人早孕母-胎免疫耐受与胎盘形成机制,为反复自然流产、子痫前期、胎儿宫内生长受限等疾患的防治提供新的思路。还将为移植免疫学、肿瘤免疫学的研究提供借鉴,因此,具有重要的理论意义和实际应用价值。     

Immunological discrimination between self and non-self by precursor depletion and memory accumulation

We study processes by which T-lymphocytes "learn" to discriminate "self" from "non-self". We show that intrinsic features of the T cell activation and proliferation process are sufficient to tolerize (self) reactive T-lymphocyte clones. Self vs non-self discrimination therefore develops without any down-regulatory (e.g. suppressive) interactions. T-lymphocyte clones will expand by proliferation only if the IL2 concentration is high enough to induce a proliferation rate larger than the rate of cell decay. This concentration is the proliferation threshold. Because effector T cells are short-lived the proliferation threshold must be quite high. Such high numbers of cells producing IL2 are achieved only when sufficient (memory) precursors are activated. Self and non-self antigens differ with respect the number of (memory) precursor cells they accumulate, as a result of two processes, i.e. precursor depletion and memory accumulation, and can thus be discriminated. Precursor depletion: the dynamics of long-lived precursors can cause tolerization. In neonatal circumstances precursor influx is still low, newborn cells reacting with self antigens are immediately activated, generating (few), i.e. fewer than the proliferation threshold, effectors that decay rapidly. Thus total lymphocyte numbers remain low, yielding self tolerance. Conversely, large doses of similar antigens introduced in mature systems push "their" lymphocyte clone over the proliferation threshold because a large (accumulated) precursor population is rapidly activated. Small doses are however low zone tolerized. Memory accumulation: peripheral T-lymphocyte populations in fact consist of a mixture of virgin precursors and memory cells. If the formation process of (long-lived) memory cells is taken into account and virgin precursors are made short-lived, the proliferation threshold again accounts for self non-self discrimination. Memory cells accumulate when antigenic restimulation is low; it is low when the antigen concentration and/or the antigen affinity is low. Therefore self antigens, which are present in relatively high concentrations, fail to accumulate high affinity memory cells, and are hence tolerated. Memory cells crossreacting to self antigens with low affinity, however accumulate neonatally, pushing those clones over the proliferation threshold whenever "their" high affinity antigen enters the immune system. Thus the model generates differences in the antigenicity (i.e. memory precursor frequency) of self and non-self.(ABSTRACT TRUNCATED AT 400 WORDS)     

Autoimmunity in Coxsackievirus B3 induced myocarditis: role of estrogen in suppressing autoimmunity

Picornaviruses are small, non-enveloped, single stranded, positive sense RNA viruses which cause multiple diseases including myocarditis/dilated cardiomyopathy, type 1 diabetes, encephalitis, myositis, orchitis and hepatitis. Although picornaviruses directly kill cells, tissue injury primarily results from autoimmunity to self antigens. Viruses induce autoimmunity by: aborting deletion of self-reactive T cells during T cell ontogeny; reversing anergy of peripheral autoimmune T cells; eliminating T regulatory cells; stimulating self-reactive T cells through antigenic mimicry or cryptic epitopes; and acting as an adjuvant for self molecules released during virus infection. Most autoimmune diseases (SLE, rheumatoid arthritis, Grave's disease) predominate in females, but diseases associated with picornavirus infections predominate in males. T regulatory cells are activated in infected females because of the combined effects of estrogen and innate immunity.     

Regulatory T cells in health and disease

Regulatory T (Treg) cells have emerged as a central control point in the modulation of various immune responses, including autoimmune responses and immunity to transplants, allergens, tumors, and infectious microbes. The immune system has evolved complex processes to ensure tolerance to autoantigens while preserving the potential to mount and maintain life-long humoral and cellular immune responses against invading pathogens. In this review, we summarize research showing that naturally occurring (nTreg) and induced Treg (iTreg) cell subsets, and in particular CD4+Foxp3+ Treg cells, are critical in the control of immune responses in rodents and humans. We also discuss the cellular and molecular factors that affect CD4+Foxp3+ Treg cell development, homeostasis, and function and consequential immunity to self and non-self antigens. Recent studies have shed light in our understanding of the development of novel methods of autoimmune disease prevention and treatment via enhancing and re-establishing Treg-mediated dominant control over self-reactive T cells in animal models and humans.     

T-Cell Tolerance: Central and Peripheral

Somatic recombination of TCR genes in immature thymocytes results in some cells with useful TCR specificities, but also many with useless or potentially self-reactive specificities. Thus thymic selection mechanisms operate to shape the T-cell repertoire. Thymocytes that have a TCR with low affinity for self-peptide–MHC complexes are positively selected to further differentiate and function in adaptive immunity, whereas useless ones die by neglect. Clonal deletion and clonal diversion (Treg differentiation) are the major processes in the thymus that eliminate or control self-reactive T cells. Although these processes are thought to be efficient, they fail to control self-reactivity in all circumstances. Thus, peripheral tolerance processes exist wherein self-reactive T cells become functionally unresponsive (anergy) or are deleted after encountering self-antigens outside of the thymus. Recent advances in mechanistic studies of central and peripheral T-cell tolerance are promoting the development of therapeutic strategies to treat autoimmune disease and cancer and improve transplantation outcome.T cells recognize pathogen fragments in the context of surface MHC molecules on host cells. As such, they have the potential to do enormous damage to healthy tissue when they are not appropriately directed, that is, when they respond to self-antigens as opposed to foreign antigens. T lymphocyte tolerance is particularly important, because it impacts B-cell tolerance as well, through the requirement of T cell help in antibody responses. Thus, failure of T-cell tolerance can lead to many different autoimmune diseases. The tolerance of T cells begins as soon as a T-cell receptor is formed and expressed on the cell surface of a T-cell progenitor in the thymus. Tolerance mechanisms that operate in the thymus before the maturation and circulation of T cells are referred to as “central tolerance.” However, not all antigens that T cells need to be tolerant of are expressed in the thymus, and thus central tolerance mechanisms alone are insufficient. Fortunately, additional tolerance mechanisms exist that restrain the numbers and or function of T cells that are reactive to developmental or food antigens, which are not thymically expressed. These mechanisms act on mature circulating T cells and are referred to as “peripheral tolerance.”     

Self/non-self discrimination in angiosperm self-incompatibility

Self-incompatibility (SI) in angiosperms prevents inbreeding and promotes outcrossing to generate genetic diversity. In many angiosperms, self/non-self recognition in SI is accomplished by male-specificity and female-specificity determinants (S-determinants), encoded at the S-locus. Recent studies using genetic, molecular biological and biochemical approaches have revealed that angiosperms utilize diverse self/non-self discrimination systems, which can be classified into two fundamentally different systems, self-recognition and non-self recognition systems. The self-recognition system, adopted by Brassicaceae and Papaveraceae, depends on a specific interaction between male and female S-determinants derived from the same S-haplotype. The non-self recognition system, found in Solanaceae, depends on non-self (different S-haplotype)-specific interaction between male and female S-determinants, and the male S-determinant genes are duplicated to recognize diverse non-self female S-determinants.     

Tyrosine phosphorylation and the mechanism of signal transduction by the B-lymphocyte antigen receptor.

Lymphocytes provide a powerful defense against infectious agents with their exquisite ability to distinguish between macromolecules of the host and macromolecules of foreign invaders. This ability derives from the antigen receptors, which are created from precursor minigenes by a series of genetic-recombination reactions [1, 2] and from cellular mechanisms that inactivate lymphocytes expressing self-reactive antigen receptors [3, 4]. Central to the problem of distinguishing self from non-self is the means by which these antigen receptors recognize antigen and transmit the information of that recognition to the interior of the cell. This information ultimately leads to lymphocyte activation or inactivation, depending upon the context. In this review, I shall summarize recent advances in understanding the structural elements of the antigen receptor complex of B lymphocytes and in understanding the signal-transduction events initiated by this receptor.     

Ablation of "tolerance" and induction of diabetes by virus infection in viral antigen transgenic mice

To address the mechanisms of tolerance to extrathymic proteins, we have generated transgenic mice expressing the lymphocytic choriomeningitis viral (LCMV) glycoprotein (GP) in the beta islet cells of the pancreas. The fate of LCMV GP-specific T cells was followed by breeding the GP transgenic mice with T cell receptor transgenic mice, specific for LCMV and H-2Db. These studies suggest that "peripheral tolerance" of self-reactive T cells does not involve clonal deletion, clonal anergy, or a decrease in the density of T cell receptors or accessory molecules. Instead, this model indicates that self-reactive cytotoxic T cells may remain functionally unresponsive, owing to a lack of appropriate T cell activation. Infection of transgenic mice with LCMV readily abolishes peripheral unresponsiveness to the self LCMV GP antigen, resulting in a CD8+ T cell-mediated diabetes. These data suggest that similar mechanisms may operate in several so-called "T cell-mediated autoimmune diseases."     

Effect of physiological integration in self/non-self genotype recognition on the clonal invader Carpobrotus edulis

Aims Biological invasions represent one of the most important threats to the conservation of biodiversity; however, the mechanisms underlying successful invaders remain unsolved. Many of the most aggressive invaders show clonal growth, and capacity for clonal integration has been pointed out recently as an important trait explaining the success of invasive plants. We aim to determine the role of physiological integration in the capacity for self/non-self genotype recognition in the clonal invader Carpobrotus edulis and the implications of this capacity for the expansion of this aggressive invader.Methods We used connected and severed ramets of identical or different genotype and we determined the capacity for self/non-self recognition by comparing changes in biomass partitioning to avoid competition for resources between pairs of ramets.Important findings Physiological integration allowed self/non-self genotype recognition in the invader C. edulis. Results showed a significant effect of physiological integration on the biomass allocated to roots by genetically identical ramets: older ramets specialize in acquisition of soil-based resources and younger ramets specialize in lateral expansion. This specialization could be considered a form of division of labour, which reduce intra-genotype competition. This is the first evidence that division of labour could be interpreted as a form of self/non-self recognition between genetically identical ramets. Capacity for self/non-self discrimination could contribute to increase the colonization capacity of the aggressive invader C. edulis. This is the first study showing an association between self/non-self recognition and invasiveness in a clonal plant.     

Foreignness as a matter of degree: the relative immunogenicity of peptide/MHC ligands

The ability of T lymphocytes (T cells) to recognize and attack foreign invaders while leaving healthy cells unharmed is often analysed as a discrete self/non-self dichotomy, with each peptide/MHC ligand classified as either self or non-self. We argue that the ligand immunogenicity is more naturally treated as a continuous quantity, and show how to define and quantitate relative ligand immunogenicity. In our theory, self-tolerance is acquired through reduction of the relative immunogenicity of autoantigens, whereas xenoantigens, typically not presented during induction of deletional tolerance, retain a high degree of relative immunogenicity. Autoantigens that are not prominently presented in deletional tolerance likewise retain a high relative immunogenicity and remain essentially foreign. According to our analysis, any given autoantigen can attain a high level of relative immunogenicity, provided it is presented at sufficiently high levels. Our theory provides a quantitative tool to analyse the immunogenicity of tumour-associated neoantigens and the ætiology of autoimmune disease.