Role of infection in the pathogenesis of rheumatic diseases

Advanced immunological technology has revealed immunological abnormalities not only in some chronic and autoimmune connective tissue disorders but also in conditions like infective arthritis where infection apparently seems to play the only role. On the other hand role of infection in the pathogenesis of some connective tissue disorders has recently gained much importance from the observation of clinical, pathological and immunological similarities between these diseases and certain infectious diseases occurring in animal models. Meanwhile, knowledge gained into human leucocyte-A system and its association with certain diseases opens another angle in etiopathogenesis of certain rheumatic diseases. It has been postulated that adaptive mechanism of a microbe or the binding between the human leucocyte-A molecule and carbohydrate moiety of a microbe may set up an autoimmune reaction and in the presence of some triggering factors in the environment may lead on to disease manifestations. An attempt has been made to discuss the role of infection in the outcome of rheumatic diseases such as septic arthritis, polyarteritis nodosa, rheumatic fever, enteropathic arthritis, ankylosing spondylitis, rheumatoid arthritis and systemic lupus erythematoses in genetically susceptible individuals producing immunological abnormalities.     

Costs of immune defense: an enigma wrapped in an environmental cloak?

Host defense against parasites and pathogens has been recognized as a costly life-history trait that can generate trade-offs with other fitness components. However, universality of immunological costs and associated trade-offs remains questionable in animal–parasite systems. This discrepancy could be a result of environmental effects, which have the potential to modulate the detection of trade-offs associated with immune function. Here, attention is drawn to the role that environmental factors can play in the manifestation and detection of costs associated with immune function and resistance. Moreover, we stress the importance of considering multiple external factors, host ontogeny and estimates of immunological function in studies investigating immune-related costs in animals.     

Recurrent Herpetic Stromal Keratitis in Mice,a Model for Studying Human HSK

Herpetic eye disease, termed herpetic stromal keratitis (HSK), is a potentially blinding infection of the cornea that results in over 300,000 clinical visits each year for treatment. Between 1 and 2 percent of those patients with clinical disease will experience loss of vision of the infected cornea. The vast majority of these cases are the result of reactivation of a latent infection by herpes simplex type I virus and not due to acute disease. Interestingly, the acute infection is the model most often used to study this disease. However, it was felt that a recurrent model of HSK would be more reflective of what occurs during clinical disease. The recurrent animal models for HSK have employed both rabbits and mice. The advantage of rabbits is that they experience reactivation from latency absent any known stimulus. That said, it is difficult to explore the role that many immunological factors play in recurrent HSK because the rabbit model does not have the immunological and genetic resources that the mouse has. We chose to use the mouse model for recurrent HSK because it has the advantage of there being many resources available and also we know when reactivation will occur because reactivation is induced by exposure to UV-B light. Thus far, this model has allowed those laboratories using it to define several immunological factors that are important to this disease. It has also allowed us to test both therapeutic and vaccine efficacy.     

Tourettesyndrome免疫病因学研究进展

多发性抽动症（Tourette syndrome）是一种慢性神经精神性疾病,好发于儿童和青少年,主要表现为一个或多个部位肌肉运动性或发声性抽动,发作期持续超过一年,间歇期不超过3个月。TS的病因和发病机制至今仍未明确,目前认为其发病与免疫因素,环境心理因素,遗传因素,生物化学因素等多种因素有关,目前,A族B溶血性链球菌与Ts的发生跟发展的关系已有所报道,较多研究是关于链球茵感染的,一些免疫相关研究发现与链球菌感染有关的小儿自身免疫性神经精神疾病会引发或加重抽动症状。另外,过敏性变态反应性疾病与Ts患儿的自身免疫应答活跃的关系也有所报道。神经．内分泌一免疫网络学说认为,外周免疫系统跟中枢神经系统之间,可通过直接接触或通过产生并释放出来的生物活性因子进行信息交流。细胞因子正是两大系统间相互作用的信使,不仅可以调节免疫,而且还可以调控神经元和神经胶质细胞的功能。细胞因子与神经介质、内分泌激素共同组成机体细胞间的信号分子,参与免疫系统并激活神经递质及激素间的信息传递,与精神障碍和心理机体反应密切相关。因此,有关免疫病因学异常可能是部分易感患儿发病的机制,文章从感染免疫学,过敏性变态反应性疾病,以及细胞因子调节网络等与免疫相关的几个方面加以综述。     

Polymorphism in the rhesus macaque (Macaca mulatta) NRAMP1 gene: lack of an allelic association to tuberculosis susceptibility

Although previous tuberculosis (TB) research has suggested that underlying genetic factors influence a host's response and ability to survive Mycobacterium infection, only recently has a gene been identified, the 'natural resistance-associated macrophage protein 1' (NRAMP1) gene, which provides a degree of natural resistance to infection by some Mycobacterium species. To date, however, the role that NRAMP1 may play in resistance to Mycobacterium infection has only been examined in mouse and man. Here, we present data generated at NRAMP1 among a group of rhesus macaques (Macaca mulatta) that were euthanized because of an outbreak of Mycobacterium tuberculosis during quarantine. Data were also generated on unrelated (and healthy) rhesus macaques in order to better determine the frequency and degree of genetic polymorphism within Macaca at the NRAMP1 locus. These data represent the first study designed to examine the role that NRAMP1 may play in TB susceptibility among rhesus macaques.     

Human cytomegalovirus inhibits differentiation of monocytes into dendritic cells with the consequence of depressed immunological functions

Human cytomegalovirus (HCMV) infections in immunocompromised patients are associated with impaired immunological functions. Blood monocytes, which can differentiate into dendritic cells upon cytokine stimulation, play a central role in adequate immune reactivity and are believed to carry latent HCMV. We demonstrate here that HCMV infection of monocytes results in a block in the cytokine-induced differentiation of monocytes into functionally active CD1a-positive dendritic cells, which exhibited severely depressed immunological functions in vitro. The HCMV-infected cells exhibited a significantly reduced ability to endocytose fluorescein isothiocyanate-labeled dextran particles as well as a more than 90% reduced ability to migrate in response to the chemoattractant factors RANTES, MIP-1alpha, and MIP-3beta. Interestingly, HCMV-infected cells expressed high levels of the costimulatory molecule CD86, in contrast to the low levels of expression that was observed on uninfected monocytes and uninfected immature dendritic cells. Furthermore, HCMV-infected CD1a-negative cells were unable to induce a T-cell response. Thus, these observations suggest that HCMV infection of monocytes in vitro blocks cytokine-induced dendritic cell differentiation, and since dendritic cells play a central role in initiating immune responses, these findings suggest a powerful tactic to avoid immune recognition and to blunt the immune response at early phases of infection.     

Factors of the local immune defence of the reproductive tract in pregnant women with vaginosis

Clinico-immunological examination of 99 pregnant women with diagnosed vaginosis and 132 pregnant women without genital infection as a control group, was carried out. The immunological factors of cervical and vaginal secretions in pregnant women before and after local treatment were studied. The conclusion was made that the established changes in the cell-mediated and humoral factors of the immune resistance of the reproductive system could probably play some pathogenetic role in the development of vaginosis and its relapses in pregnant women. As found in this study, more pronounced changes in the local factors of immune protection (the signs of the functional irritation of neutrophils in combination with the prevalence of sIgA and lysozyme simultaneously with a decrease in the level of IgM and IgG in cervical slime) developed in patients with subsequent relapses of vaginosis, these changes remaining after local treatment. The defects of cell-mediated and humoral factors of cervical and humoral secretions, together with some clinical parameters, were shown to be prognostically unfavorable with respect to the relapses of vaginosis in pregnant women.     

Soluble factors with inhibitory activity against type 1 Human Immunodeficiency Virus

Soluble factors with inhibitory activity against type 1 Human Immunodeficiency Virus The pathogenesis of HIV-1 infection is a complex process that depends on multiple factors, including viral and host immune and genetic characteristics. This leads to a variable pattern of disease progression among those HIV-1-exposed individuals who become infected, while there are a number of individuals who remain healthy and HIV-1 seronegative despite being serially exposed to HIV-1. These variable outcomes of HIV-1 exposure suggest that there are mechanisms of natural resistance to HIV-1 infection. Although several genetic and adaptive immune mechanisms of resistance have been reported in some exposed seronegative and long-term non-progressor individuals, the mechanisms involved in controlling the establishment and progression of HIV-1 infection are not fully understood. Several soluble factors, such as defensins, chemokines, interferons and ribonucleases, among others, produced by cells of the immune system and epithelial tissues, have a broad anti-viral activity that might play a role as protective mechanisms during HIV-1 exposure. A better understanding of the mechanisms and role of these soluble factors during the natural resistance to HIV-1 infection may have important implications for the design of novel therapeutic strategies to combat the morbidity and mortality associated with the HIV-1 pandemic.     

Microbes and microbial toxins: paradigms for microbial-mucosal interactions. VI. Entamoeba histolytica: parasite-host interactions

The protozoan intestinal parasite Entamoeba histolytica remains a significant cause of morbidity and mortality worldwide. E. histolytica causes two major clinical syndromes, amebic colitis and amebic liver abscess. Recent advances in the development of in vitro and in vivo models of disease, new genetic approaches, the identification of key E. histolytica virulence factors, and the recognition of crucial elements of the host response to infection have led to significant insights into the pathogenesis of amebic infection. E. histolytica virulence factors include 1) a surface galactose binding lectin that mediates E. histolytica binding to host cells and may contribute to amebic resistance to complement, 2) amebapores, small peptides capable of lysing cells, which may play a role in killing intestinal epithelial cells, hepatocytes, and host defense cells, and 3) a family of secreted cysteine proteinases that play a key role in E. histolytica tissue invasion, evasion of host defenses, and parasite induction of gut inflammation. Amebae can both lyse host cells and induce their suicide through programmed cell death. The host response is also an important factor in the outcome of infection, and neutrophils may play a key role in contributing to the tissue damage seen in amebiasis and in controlling amebic infection.     

Trypanosoma cruzi: orchiectomy and dehydroepiandrosterone therapy in infected rats

The ability of gonadal hormones to influence and induce diverse immunological functions during the course of a number of parasitic infections has been extensively studied in the latest decades. Dehydroepiandrosterone and its sulfate are the most abundant steroid hormones secreted by the human adrenal cortex and are considered potent immune-activators. The effects of orchiectomy on the course of Trypanosoma cruzi infection in rats, treated and untreated with DHEA were examined, by comparing blood and cardiac parasitism, macrophage numbers, nitric oxide and IFN-γ levels. Orchiectomy enhanced resistance against infection with elevated numbers of macrophages, enhanced concentrations of NO and IFN-γ and reduced amastigote burdens in heart when compared to control animals. DHEA replacement exerted a synergistic effect, up-modulating the immune response. Male sex steroids appear to play fundamental role in determining the outcome of disease, through the regulation and modulation of the activity of the immune response.     

Illness in childhood predicts face preferences in adulthood

The value of different mate choices may depend on the local pathogen ecology and on personal infection susceptibility: when there is a high risk of infection, choosing a healthy or immunocompetent mate may be particularly important. Frequency of childhood illness may act as a cue of the ecological and immunological factors relevant to mate preferences. Consistent with this proposal, we found that childhood illness – and frequency of diarrhea in particular – was positively correlated with preferences for exaggerated sex-typical characteristics in opposite-sex, but not same-sex, faces. Moreover, this relationship was stronger among individuals with poorer current health. These data suggest that childhood illness may play a role in calibrating adult mate preferences and have implications for theories of disease-avoidance psychology, life-history strategy and cross-cultural differences in mate preferences.     

The immunohomeostatic role of hydatid cyst toxins (Echinococcus granulosus).

It is obvious that during the evolution of a host-parasite relationship, in which one animal is needing the other, while the latter is trying to expel or destroy the former, both partners tend to reach an equilibrium. In many cases they are still far off, but in hydatidosis (Echinococcus granulosus) it would appear that a lot has been achieved. As the near equilibrium is mainly related to the state of the immunological relationship, it is in fact a case of immunohomeostasis. The immunological reactions of the host involve both humoral and cellular phenomena. The nature of the humoral response varies greatly according to host species, parasite strain and several factors of the infection and analysis procedures. The cell-mediated defense mechanism involves various types of cells, but activated macrophages appear to be most important. With regards to the modes of immunoevasion, attention is paid to the barrier role of the laminated layer, the inactivation of complement and the interference with the activities of host immune cells. The role of toxic substances released by protoscoleces and cysts is especially emphasized. The toxins appear extremely vulnerable to host macrophages and play a very important role in the establishment of a hydatid cyst. However, they have only a local influence and do not jeopardize the development of concomitant immunity. Observations in experimental secondary echinococcosis led to the conclusion that the establishment of a hydatid cyst depends on the speed of the parasite's toxic effect versus the host immunological reaction. Survival of the parasite is based on the continued balancing effects of both.     

Schistosome glycoconjugates in host-parasite interplay

Schistosomes are digenetic trematodes which cause schistosomiasis, also known as bilharzia, one of the main parasitic infections in man. In tropical and subtropical areas an estimated 200 million people are infected and suffer from the debilitating effects of this chronic disease. Schistosomes live in the blood vessels and strongly modulate the immune response of their host to be able to survive the hostile environment that they are exposed to. It has become increasingly clear that glycoconjugates of schistosome larvae, adult worms and eggs play an important role in the evasion mechanisms that schistosomes utilise to withstand the immunological measures of the host. Upon infection, the host mounts innate as well as adaptive immune responses to antigenic glycan elements, setting the immunological scene characteristic for schistosomiasis. In this review we summarise the structural data now available on schistosome glycans and provide data and ideas regarding the role that these glycans play in the various aspects of the glycobiology and immunology of schistosomiasis.     

The effect of diet and time after bacterial infection on fecundity,resistance, and tolerance in Drosophila melanogaster

Mounting and maintaining an effective immune response in the face of infection can be costly. The outcome of infection depends on two host immune strategies: resistance and tolerance. Resistance limits pathogen load, while tolerance reduces the fitness impact of an infection. While resistance strategies are well studied, tolerance has received less attention, but is now considered to play a vital role in host–pathogen interactions in animals. A major challenge in ecoimmunology is to understand how some hosts maintain their fitness when infected while others succumb to infection, as well as how extrinsic, environmental factors, such as diet, affect defense. We tested whether dietary restriction through yeast (protein) limitation affects resistance, tolerance, and fecundity in Drosophila melanogaster. We predicted that protein restriction would reveal costs of infection. Because infectious diseases are not always lethal, we tested resistance and tolerance using two bacteria with low lethality: Escherichia coli and Lactococcus lactis. We then assayed fecundity and characterized bacterial infection pathology in individual flies at two acute phase time points after infection. As expected, our four fecundity measures all showed a negative effect of a low‐protein diet, but contrary to predictions, diet did not affect resistance to either bacteria species. We found evidence for diet‐induced and time‐dependent variation in host tolerance to E. coli, but not to L. lactis. Furthermore, the two bacteria species exhibited remarkably different infection profiles, and persisted within the flies for at least 7 days postinfection. Our results show that acute phase infections do not necessarily lead to fecundity costs despite high bacterial loads. The influence of intrinsic variables such as genotype are the prevailing factors that have been studied in relation to variation in host tolerance, but here we show that extrinsic factors should also be considered for their role in influencing tolerance strategies.     

Impact of climate change on parasite infection of an important pollinator depends on host genotypes

Climate change is predicted to affect host–parasite interactions, and for some hosts, parasite infection is expected to increase with rising temperatures. Global population declines of important pollinators already have been attributed to climate change and parasitism. However, the role of climate in driving parasite infection and the genetic basis for pollinator hosts to respond often remain obscure. Based on decade-long field data, we investigated the association between climate and Nosema bombi (Microsporidia) infection of buffed-tailed bumblebees (Bombus terrestris), and whether host genotypes play a role. For this, we genotyped 876 wild bumblebee queens and screened for N. bombi infection of those queens between 2000 and 2010. We recorded seven climate parameters during those 11 years and tested for correlations between climate and infection prevalence. Here we show that climatic factors drive N. bombi infection and that the impact of climate depends on mitochondrial DNA cytochrome oxidase I (COI) haplotypes of the host. Infection prevalence was correlated with climatic variables during the time when queens emerge from hibernation. Remarkably, COI haplotypes best predict this association between climatic factors and infection. In particular, two host haplotypes (“A” and “B”) displayed phenotypic plasticity in response to climatic variation: Temperature was positively correlated with infection of host haplotype B, but not haplotype A. The likelihood of infection of haplotype A was associated with moisture, conferring greater resistance to parasite infection during wetter years. In contrast, infection of haplotype B was unrelated to moisture. To the best of our knowledge, this is the first study that identifies specific host genotypes that confer differential parasite resistance under variable climatic conditions. Our results underscore the importance of mitochondrial haplotypes to ward off parasites in a changing climate. More broadly, this also suggests that COI may play a pertinent role in climate change adaptations of insect pollinators.     

浆细胞样树突状细胞在宿主抵御隐球菌肺部感染中的作用及机制研究进展

肺隐球菌病是由隐球菌感染引起的常见真菌病,由于症状的非特异性,临床上诊断较为困难。作为条件致病性真菌感染,肺隐球菌病的结局主要与宿主免疫力有关。目前肺隐球菌病免疫学发病机制研究主要局限在T细胞和巨噬细胞。近年研究表明,作为树突状细胞亚群之一的浆细胞样树突细胞,由于其激活后可以产生大量的I型干扰素并活化相关的T细胞,所以在机体抵抗病毒和细菌免疫中发挥着重要的作用。但是浆细胞样树突细胞在真菌病,尤其是在隐球菌病的发生发展中发挥的作用尚不明确。本文将介绍肺隐球菌病的临床表现、诊治及T细胞和巨噬细胞在肺隐球菌病中的免疫机制,并通过介绍肺隐球菌病和浆细胞样树突细胞及二者之间已有报道的联系,初步阐述浆细胞样树突细胞在肺隐球菌病免疫学发病机制中的相关作用。     

金蛇王营养液对老龄鼠细胞因子产生的影响

本文报导了金蛇王营养液（ＧＫＳ）对老龄鼠细胞因子产生的影响。实验表明,细胞因子分泌功能下降的老龄鼠饲喂金蛇王营养液后,ＩＬ－２和ＩＦＮ－ｒ水平明显增加。进而证明金蛇王营养液是一种良好的免疫增强剂,能增强老龄机体抗肿瘤、抗感染等作用     

Modification of foot-and-mouth disease virus O1 Caseros after serial passages in the presence of antiviral polyclonal sera.

Foot-and-mouth disease virus (FMDV) shows a remarkable antigenic variability and, like other RNA viruses, presents a high rate of mutation. It has been proposed that selection exerted by antibodies of the host could play a major role in the rapid evolution of FMDV. The present work reports the selection of FMDV antibody-resistant (Nr) populations after serial passages of a cloned FMDV O1 Caseros strain on secondary monolayers of bovine kidney cells in the presence of subneutralizing antiviral polyclonal sera (APS). After a limited number of passages, i.e., 29, under selective pressure, the virus population showed the following characteristics: (i) increased resistance to neutralization by APS (Nr), (ii) altered electrophoretic mobility of its structural viral proteins (VP1), and (iii) alterations at the RNA nucleotide sequence that codes for the major antigenic site of VP1. These acquired characteristics were detected at passage 15 and remained unmodified throughout successive passages. These results document a rapid selection and fixation of specific mutations in response to immunological pressure. In addition, the findings that (i) mutations not related to APS selection were not detected and (ii) after 29 passages at a high multiplicity of infection without immunological pressure, the RNA sequence that codes for VP1 remained unmodified clearly demonstrated that FMDV O1 Caseros presents in vitro a remarkable unexpected genetic stability.     

Dynamics in Development of Experimental Streptococcal Immunity in Mice

The interrelation between the humoral and cellular factors in the development of immunity to experimental streptococcal infection was investigated. Early resistance to infection was caused by stimulating the phagocytic cells to function efficiently in the absence of opsonins. Subsequently, the appearance of cytophilic antibodies provided further means for elimination of streptococci. Thus, in the early stages of specific antistreptococcal immunity, resistance was observed in the absence of circulating anti-M antibodies. The type-specific antibodies that appeared in the later stage did not seem to improve clearance of streptococci in the splanchnic tissues. After an intravenous lethal challenge of mice with virulent streptococci, these antibodies did not provide increased protection. The circulating anti-M antibodies were shown to play a beneficial, indeed, a crucial, role when the infection occurred in a region in which the phagocytic cells were present in a rather limited number.