病毒感染与自身免疫病

自身免疫是机体失去对自身抗原的免疫耐受或免疫无反应性,其病因与发病机制十分复杂。已证明某些病毒感染与 些自身免疫病密切相关,并发现病毒与宿主细胞的某些基因或其蛋白了之间存在着结构类似性,因而可发生交叉免疫反应性。这种分子模拟假说得到转基因动物实验的支持。它对于进一步深入研究自身免疫病的病因,发病机制以及治疗和预防具有重要意义。     

DNA识别受体PYHIN家族及相关病毒免疫逃逸机制的研究

宿主细胞内的DNA识别受体可识别病毒核酸分子并激活细胞天然免疫反应,从而产生抗病毒效应;同时,病毒也进化出相应机制来逃避或抑制这种免疫反应。本文总结了宿主细胞内DNA识别受体PYHIN家族识别病毒核酸并激活细胞天然免疫反应的特点和分子机制,并讨论了病毒逃避宿主天然免疫应答的方式。     

噬菌体的"关闭宿主"功能

噬菌体基因组编码产生某些特殊的蛋白质分子,可与宿主菌生长、代谢的重要调控性蛋白质结合,并使其钝化,从而阻断宿主的生长与繁殖,将宿主菌大分子合成机制和能量装置转向噬菌体自身的复制与增殖。目前研究所获得的有关噬菌体“关闭宿主”功能的证据,主要涉及噬菌体编码的某些蛋白质分子与宿主菌的DNA复制及转录相关因子的相互作用,而这些蛋白质-蛋白质分子间的相互作用将为我们提供新的抗菌药物或抗菌药物作用的靶点,也有助于生物系统进化关系及蛋白质-蛋白质相互作用关系的研究。     

干扰素通路调控与自身免疫疾病

干扰素信号通路是细胞抵抗病原微生物侵染的重要防线。通过识别病源相关模式分子、激活下游通路,干扰素的表达被显著上调并分泌于细胞外,作用于自身和周围细胞,引发众多下游基因的转录激活。这些基因产物直接参与抗侵染过程或调控机体免疫反应。干扰素信号通路需要被正确调控,其异常激活会导致炎症和自身免疫疾病的发生。正确地识别“自己”和“非己”分子是首要的一步。鉴于干扰素通路所抵抗的微生物侵染中,核酸分子是重要的免疫原性分子,内源性核酸分子的代谢调控显得尤为重要。细胞编码一系列参与核酸代谢的酶,这些蛋白质功能的发挥对保持细胞核酸稳态至关重要。以单基因突变引发的自身免疫疾病Aicardi-Goutières综合征为例,目前发现9种基因可突变致病,均来自DNA代谢相关的和RNA代谢相关的基因。尽管这9种基因突变都导致干扰素通路的异常激活,但中间所依赖的参与蛋白并不相同。可见,同样症状的疾病,其致病机理也可能不同,这也将影响有效治疗方案的确定,凸显基因检测在诊治自身免疫疾病中的必要性。本综述通过阐述细胞内环境稳态对干扰素通路正确识别“自己”和“非己”的重要作用,帮助理解自身免疫疾病的发病机理。     

宿主细胞应答病毒感染的细胞信号转导研究新进展

机体如何识别以及清除入侵的病毒一直是分子免疫学研究的重点.早期的研究揭示,病毒的入侵可诱导表达大量的IFNβ,PKR等抗病毒蛋白分子.这些蛋白质分子通过多种方式造成被侵染细胞表现出特殊的状态或迅速凋亡,从而控制病毒的复制和传播,同时诱导产生大量细胞因子和趋化因子等,启动适应性免疫反应的进程.但是,该领域研究的一个重要瓶颈是对于病毒与宿主细胞相互作用的最早期信号事件了解甚微.近几年的研究工作在先天性免疫系统如何识别早期病毒的入侵方面取得了重大进展.TLR3和RIG-I/MDA5细胞信号转导通路,是最近发现的宿主细胞识别与应答病毒的重要调节机制.它们利用不同的细胞信号转导机制诱导先天性免疫反应,主要参与脊椎动物细胞识别和清除RNA病毒的原发抗感染过程,是机体先天免疫系统的一种重要反应机制,直接影响后续适应性免疫系统的作用.就这些细胞信号转导通路在先天性免疫应答中的研究进展做了概述与展望.     

基于模式识别受体和人工设计诱饵蛋白扩展植物识别特异性

病原/微生物相关分子模式(PAMPs/MAMPs)被位于宿主细胞表面的模式识别受体(PRRs)识别并激活免疫反应.这种病原相关分子模式触发的免疫反应(PTI)能够帮助植物抵抗大部分致病微生物的侵入,因此利用基因工程技术在植物中表达PRRs,以增强植物对病原微生物的免疫识别是一种非常有潜力的植物抗病性改良的策略.植物病原微生物分泌的效应蛋白通常利用多种多样的生化机制直接靶向和抑制PTI信号通路的关键组分,从而抑制PTI.一些植物进化出与效应蛋白的靶标类似的诱饵蛋白,并诱导效应蛋白的错误靶向.这种识别的结果不抑制PTI免疫反应,反而诱导效应蛋白激活的免疫反应(ETI).这种机制提示了人工设计的诱饵蛋白在特定植物中产生新的识别特异性的可能性.本综述总结了PRRs对PAMPs的识别,以及诱饵蛋白对效应蛋白监控方面的研究进展.利用转基因异源表达EFR或PBS1诱饵蛋白在实验室条件下成功扩展了植物的识别特异性,体现了对PRRs和人工设计的诱饵蛋白在植物对病原识别特异性的扩展和抗病性改良方面的潜力,突显了分离和鉴定新的PRRs和诱饵蛋白的必要性.     

柯萨奇病毒性心肌炎中γδT细胞的作用

心肌炎是一种由不同免疫病理发病机制引起组织损伤的复杂疾病。在某些但不是全部病例中,自身免疫性是主要的致病因素。病毒和肌球蛋白表位间的交叉反应性可以决定心肌炎中的体液和细胞自身免疫性。因此,宿主以及病毒的遗传学决定疾病的致病性。以γδ^＋T细胞为代表的天然免疫在决定疾病的易患性上至关重要。天然效应分子能很快地定位于感染的心肌,并可通过释放γ干扰素（Vγ4^＋细胞;BALB／c小鼠）或白细胞介素4（Vγ1^＋细胞;C5781／6小鼠）分别以卟l或Th2应答方式调节正在发生的获得性免疫应答。BALB／c小鼠中的Vγ^＋细胞能识别类似主要组织相容性复合物Ⅰ类抗原CD1d。Vγ^＋细胞的配体不明。只有在感染的肌细胞中方可见CD1d的上调,这时感染（双链RNA）和肿瘤坏死因子α都是需要的。     

泛素化修饰调控固有免疫信号通路的研究进展

宿主细胞依赖固有免疫系统识别入侵的病原微生物,经相关细胞信号转导通路,激活促炎症及抗感染的基因表达。泛素化修饰是细胞内广泛存在的蛋白质翻译后修饰机制,全方位调控宿主细胞防御病原微生物的动态过程:一方面,作为多功能的信号调节分子,在时空上精细调节免疫反应的进程,有效地清除入侵的病原体;另一方面,通过降解关键信号转导分子,限制过度免疫反应,避免造成宿主自体损伤。本文总结了泛素化修饰在Toll样受体信号通路(TLR)、RIG-I样受体信号通路(RLR)和STING介导的信号通路中的新功能,以及相关分子调控机制,并对前沿方向进行展望。     

高危型HPV E6蛋白与宿主PDZ蛋白相互作用的研究进展

病毒通过自身蛋白与宿主蛋白间的相互作用,营造一种适合于其转化、增殖的体内环境,从而引起一系列疾病的过程。人乳头瘤病毒(HPV)与某些肿瘤发病关系密切,分子机制研究表明,其表达的早期蛋白E6是HPV参与细胞恶性转化的主要蛋白。含有PDZ结构域的蛋白质是细胞内广泛存在的一类蛋白质。本文综述了人乳头瘤病毒的E6蛋白和宿主细胞的PDZ蛋白间的相互作用,讨论了这种作用引发的细胞内生化生理改变及其应用前景。     

感染及免疫相关的男性不育

男性生殖系统微生物感染及免疫疾病是导致不育的重要病因.睾丸和附睾是精子产生与成熟的器官,具有特殊的免疫环境,既可以防止精子诱导免疫反应,又能有效抵御微生物感染.然而,某些病理状态(包括微生物感染、环境毒素及组织损伤等)可能破坏睾丸免疫平衡,引发感染或自身免疫睾丸炎及附睾炎,并可导致男性不育.微生物感染还会引起前列腺炎、精囊炎与尿道炎,可干扰精子功能而影响男性生育能力.认识感染和免疫引起的男性不育机制可为预防和治疗相关疾病提供线索,本文重点综述男性生殖系统微生物感染、免疫微环境调节及免疫疾病导致男性不育的机制.     

Molecular mimicry: a mechanism for autoimmune injury.

Many mechanisms may account for immune-mediated pathology after viral infections. Although several means have been hypothesized to play a role in disease, a widely accepted mechanism for viral-induced autoimmunity is molecular mimicry. It is thought that damage could result from an immune response to similar regions shared between virus and the host. Using computer-aided analysis, many sequence homologies have been identified between virus and host antigens. Using peptides corresponding to these regions, immunologic cross-reactivity has been found. In some cases, monoclonal antibodies to peptides of these regions have been shown to directly induce or augment disease in animal models. Using this approach to identify similar regions, it is possible to associate a known autoantigen with an infectious agent in autoimmune diseases in which there is no known etiologic agent. Conversely, it would also be possible to associate a known viral constituent with an unknown host antigen. Furthermore, identification of disease-inducing regions of autoantigens or viral proteins may lead to immunotherapeutic approaches to establish tolerance or anergy to such disease-inducing regions.     

SARS-CoV-2 in patients with cancer: possible role of mimicry of human molecules by viral proteins and the resulting anti-cancer immunity

A few reports suggest that molecular mimicry can have a role in determining the more severe and deadly forms of COVID-19, inducing endothelial damage, disseminated intravascular coagulation, and multiorgan failure. Heat shock proteins/molecular chaperones can be involved in these molecular mimicry phenomena. However, tumor cells can display on their surface heat shock proteins/molecular chaperones that are mimicked by SARS-CoV-2 molecules (including the Spike protein), similarly to what happens in other bacterial or viral infections. Since molecular mimicry between SARS-CoV-2 and tumoral proteins can elicit an immune reaction in which antibodies or cytotoxic cells produced against the virus cross-react with the tumor cells, we want to prompt clinical studies to evaluate the impact of SARS-CoV-2 infection on prognosis and follow up of various forms of tumors. These topics, including a brief historical overview, are discussed in this paper.     

IMMUNE EVASION AND THE EVOLUTION OF MOLECULAR MIMICRY IN PARASITES

Parasites that are molecular mimics express proteins which resemble host proteins. This resemblance facilitates immune evasion because the immune molecules with the specificity to react with the parasite also cross‐react with the host's own proteins, and these lymphocytes are rare. Given this advantage, why are not most parasites molecular mimics? Here we explore potential factors that can select against molecular mimicry in parasites and thereby limit its occurrence. We consider two hypotheses: (1) molecular mimics are more likely to induce autoimmunity in their hosts, and hosts with autoimmunity generate fewer new infections (the “costly autoimmunity hypothesis”); and (2) molecular mimicry compromises protein functioning, lowering the within‐host replication rate and leading to fewer new infections (the “mimicry trade‐off hypothesis”). Our analysis shows that although both hypotheses may select against molecular mimicry in parasites, unique hallmarks of protein expression identify whether selection is due to the costly autoimmunity hypothesis or the mimicry trade‐off hypothesis. We show that understanding the relevant selective forces is necessary to predict how different medical interventions will affect the proportion of hosts that experience the different infection types, and that if parasite evolution is ignored, interventions aimed at reducing infection‐induced autoimmunity may ultimately fail.     

Molecular mimicry--hypothesis or reality?

A number of observations support molecular mimicry as a possible pathogenetic mechanism in diseases such as acute rheumatic fever, reactive arthritis after enteric infection or associated with Reiter''s syndrome, myasthenia gravis, or even in rheumatoid arthritis. Molecular mimicry can be defined as a sharing of epitopes in linear or 3-dimensional presentation on disparate proteins from entirely different sources--for instance, group A streptococcal membranes and human cardiac myosin. How exposure to or infection with organisms sharing molecular similarity with antigens of the human host can evade tolerance and actually induce a self-reacting humoral or cellular immune response is still not clear; however, a large body of evidence has now been accumulated that documents apparent molecular mimicry mechanisms in these disorders. In some diseases, the molecular mimicry appears to involve human target organs and specific components of the infectious organism, whereas in others the host HLA cell surface molecules appear to share antigens with presumed bacterial or viral initiators of disease.     

Autoimmunity due to molecular mimicry as a cause of neurological disease

One hypothesis that couples infection with autoimmune disease is molecular mimicry. Molecular mimicry is characterized by an immune response to an environmental agent that cross-reacts with a host antigen, resulting in disease. This hypothesis has been implicated in the pathogenesis of diabetes, lupus and multiple sclerosis (MS). There is limited direct evidence linking causative agents with pathogenic immune reactions in these diseases. Our study establishes a clear link between viral infection, autoimmunity and neurological disease in humans. As a model for molecular mimicry, we studied patients with human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a disease that can be indistinguishable from MS (refs. 5,6,7). HAM/TSP patients develop antibodies to neurons. We hypothesized these antibodies would identify a central nervous system (CNS) autoantigen. Immunoglobulin G isolated from HAM/TSP patients identified heterogeneous nuclear ribonuclear protein-A1 (hnRNP-A1) as the autoantigen. Antibodies to hnRNP-A1 cross-reacted with HTLV-1-tax, the immune response to which is associated with HAM/TSP (refs. 5,9). Immunoglobulin G specifically stained human Betz cells, whose axons are preferentially damaged. Infusion of autoantibodies in brain sections inhibited neuronal firing, indicative of their pathogenic nature. These data demonstrate the importance of molecular mimicry between an infecting agent and hnRNP-A1 in autoimmune disease of the CNS.     

Viral mimicry of the complement system

The complement system is a potent innate immune mechanism consisting of cascades of proteins which are designed to fight against and annul intrusion of all the foreign pathogens. Although viruses are smaller in size and have relatively simple structure, they are not immune to complement attack. Thus, activation of the complement system can lead to neutralization of cell-free viruses, phagocytosis of C3b-coated viral particles, lysis of virus-infected cells, and generation of inflammatory and specific immune responses. However, to combat host responses and succeed as pathogens, viruses not only have developed/adopted mechanisms to control complement, but also have turned these interactions to their own advantage. Important examples include poxviruses, herpesviruses, retroviruses, paramyxoviruses and picornaviruses. In this review, we provide information on the various complement evasion strategies that viruses have developed to thwart the complement attack of the host. A special emphasis is given on the interactions between the viral proteins that are involved in molecular mimicry and the complement system.     

Human 60-kDa heat shock protein is a target autoantigen of T cells derived from atherosclerotic plaques

Epidemiological studies suggest the potential importance of an inflammatory component in atherosclerosis and support the hypothesis that immune responses to Ags of pathogens cross-react with homologous host proteins due to molecular mimicry. Protein candidates involved may be the stress-induced proteins known as heat shock proteins (HSP). In this study, we report that atherosclerotic plaques harbor in vivo-activated CD4(+) T cells that recognize the human 60-kDa HSP. Such in vivo-activated 60-kDa HSP-specific T cells are not detectable in the peripheral blood. In patients with positive serology and PCR for Chlamydia pneumoniae DNA, but not in patients negative for both, most of plaque-derived T cells specific for human 60-kDa HSP also recognized the C. pneumoniae 60-kDa HSP. We characterized the submolecular specificity of such 60-kDa HSP-specific plaque-derived T cells and identified both the self- and cross-reactive epitopes of that autoantigen. On challenge with human 60-kDa HSP, most of the plaque-derived T cells expressed Th type 1 functions, including cytotoxicity and help for monocyte tissue factor production. We suggest that arterial endothelial cells, undergoing classical atherosclerosis risk factors and conditioned by Th type 1 cytokines, express self 60-kDa HSP, which becomes target for both autoreactive T cells and cross-reactive T cells to microbial 60-kDa HSP via a mechanism of molecular mimicry. This hypothesis is in agreement with the notion that immunization with HSP exacerbates atherosclerosis, whereas immunosuppression and T cell depletion prevent the formation of arteriosclerotic lesions in experimental animals.     

Genome-wide identification of molecular mimicry candidates in parasites

Among the many strategies employed by parasites for immune evasion and host manipulation, one of the most fascinating is molecular mimicry. With genome sequences available for host and parasite, mimicry of linear amino acid epitopes can be investigated by comparative genomics. Here we developed an in silico pipeline for genome-wide identification of molecular mimicry candidate proteins or epitopes. The predicted proteome of a given parasite was broken down into overlapping fragments, each of which was screened for close hits in the human proteome. Control searches were carried out against unrelated, free-living eukaryotes to eliminate the generally conserved proteins, and with randomized versions of the parasite proteins to get an estimate of statistical significance. This simple but computation-intensive approach yielded interesting candidates from human-pathogenic parasites. From Plasmodium falciparum, it returned a 14 amino acid motif in several of the PfEMP1 variants identical to part of the heparin-binding domain in the immunosuppressive serum protein vitronectin. And in Brugia malayi, fragments were detected that matched to periphilin-1, a protein of cell-cell junctions involved in barrier formation. All the results are publicly available by means of mimicDB, a searchable online database for molecular mimicry candidates from pathogens. To our knowledge, this is the first genome-wide survey for molecular mimicry proteins in parasites. The strategy can be adopted to any pair of host and pathogen, once appropriate negative control organisms are chosen. MimicDB provides a host of new starting points to gain insights into the molecular nature of host-pathogen interactions.     

How microbes utilize host ubiquitination

Activity, abundance and localization of eukaryotic proteins can be regulated through covalent attachment of ubiquitin and ubiquitin-like moieties. Ubiquitination is important in various aspects of immunity. Pathogens utilize host ubiquitination for the suppression of immune signalling and reprogramming host processes to promote microbial life. They deliver so-called effector molecules into host cells, which functionally or structurally resemble components of the host ubiquitination machinery utilizing this enzymatic process or they secrete molecules to inhibit ubiquitin-mediated degradation. Since prokaryotic pathogens lack a classical ubiquitination system, effector mimicry of components of the ubiquitin machinery could be achieved through gene flow. Horizontal gene transfer allows pathogenic bacteria to access ubiquitination enzymes from a potential host, while lateral gene transfer recruits components from another pathogen providing spread within the microbial community. Additionally, convergent evolution can shape bacterial proteins to acquire ubiquitination functions.     

Evidence for selective incorporation of host immunoglobulin by strobilocerci of Taenia taeniaeformis

Strobilocerci of Taenia taeniaeformis were obtained from laboratory rats 90 days after experimental infection. Cyst fluid, whole parasite homogenate, and rat serum each were fractionated by SDS-PAGE, immobilized on nitrocellulose by western blot, and probed with conjugated goat anti-rat IgG. Reactive bands with relative mobilities corresponding to rat IgG were found in all 3 samples. Additional bands in cyst fluid and parasite homogenate may represent enzymatic degradation of IgG. The pattern of reactive bands in the homogenate discounts the nonspecific adsorption of host molecules onto the tegument and suggests selective incorporation of serum proteins. The presence of an IgG-like molecule of atypical molecular weight is consistent with either molecular mimicry or enzymatic cleavage of IgG bound to the tegument. The relevance of serum protein utilization by the parasite to evasion of the host immune response is discussed.