Revisiting the old link between infection and autoimmune disease with commensals and T helper 17 cells

Genetic composition and major histocompatibility complex polymorphisms unequivocally predispose to autoimmune disease, but environmental factors also play a critical role in precipitating disease in susceptible individuals. Notorious among these has been microbial infection. Older studies describing associations between microbial infection and autoimmune disease are now followed by new studies demonstrating correlations between susceptibility to autoimmune disease and commensal colonization of the intestinal tract. T helper 17 (T_H17) cells have gained a prominent role in autoimmune disease, and notably, their development within the intestine has been linked to colonization with specific commensal bacteria. Here, we consider current views on how microbes, T_H17 cells, and autoimmunity are connected. We speculate on how the intricate relationships among commensal, pathogen, and the host might ultimately determine susceptibility to autoimmune disease.     

Coordination of tolerogenic immune responses by the commensal microbiota

All mammals are born ignorant to the existence of micro-organisms. Soon after birth, however, every mammal begins a lifelong association with a multitude of microbes that lay residence on the skin, mouth, vaginal mucosa and gastrointestinal (GI) tract. Approximately 500–1000 different species of microbes have highly evolved to occupy these bodily niches, with the highest density and diversity occurring within the intestine [1]. These organisms play a vital role in mammalian nutrient breakdown and provide resistance to colonization by pathogenic micro-organisms. More recently, however, studies have demonstrated that the microbiota can have a profound and long-lasting effect on the development of our immune system both inside and outside the intestine [2]. While our immune system has evolved to recognize and eradicate foreign entities, it tolerates the symbiotic micro-organisms of the intestine. How and why this tolerance occurs has remained unclear. Here we present evidence that the commensal microbes of the intestine actively induce tolerant responses from the host that coordinate healthy immune responses. Potentially, disruption of this dialogue between the host and microbe can lead to the development of autoimmune diseases such as inflammatory bowel disease (IBD), rheumatoid arthritis (RA), or Type I diabetes (TID). As a wealth of publications have focused on the impact of the microbiota on intestinal immune responses and IBD, this chapter will focus on the extra-intestinal impacts of the microbiota from development to disease and integrate the known mechanisms by which the microbiota is able to actively communicate with its host to promote health.     

A comprehensive review of the nasal microbiome in chronic rhinosinusitis (CRS)

Chronic rhinosinusitis (CRS) has been known as a disease with strong infectious and inflammatory components for decades. The recent advancement in methods identifying microbes has helped implicate the airway microbiome in inflammatory respiratory diseases such as asthma and COPD. Such studies support a role of resident microbes in both health and disease of host tissue, especially in the case of inflammatory mucosal diseases. Identifying interactive events between microbes and elements of the immune system can help us to uncover the pathogenic mechanisms underlying CRS. Here we provide a review of the findings on the complex upper respiratory microbiome in CRS in comparison with healthy controls. Furthermore, we have reviewed the defects and alterations of the host immune system that interact with microbes and could be associated with dysbiosis in CRS.     

HLA and disease: guilt by association

It is now over forty years since the first associations between particular HLA antigens and disease susceptibility were described, and the identification of large numbers HLA‐associated diseases parallels our increased understanding of the genetic complexity of the HLA system and its extensive polymorphism. However, surprisingly and frustratingly, clear identification of the underlying mechanisms resulting in a causative role for HLA polymorphism in the molecular immunopathogenesis of individual HLA‐associated diseases remains the exception rather than the rule. This review, while not intended to be a comprehensive catalogue of HLA‐associated diseases, aims to revisit a number of well known and more recently described HLA‐associated diseases as exemplars of our current understanding of the underlying molecular mechanisms which may result in genetic disease predisposition. Such mechanisms may act as pointers for further investigations in other HLA‐associated diseases. The clinical utility of specific HLA disease associations in disease diagnosis/exclusion is also considered.     

Network analysis of human diseases using Korean nationwide claims data

ObjectiveTo investigate disease–disease associations by conducting a network analysis using Korean nationwide claims data.MethodsWe used the claims data from the Health Insurance Review and Assessment Service-National Patient Sample for the year 2011. Among the 2049 disease codes in the claims data, 1154 specific disease codes were used and combined into 795 representative disease codes. We analyzed for 381 representative codes, which had a prevalence of >0.1%. For disease code pairs of a combination of 381 representative disease codes, P values were calculated by using the χ² test and the degrees of associations were expressed as odds ratios (ORs).ResultsFor 5515 (7.62%) statistically significant disease–disease associations with a large effect size (OR > 5), we constructed a human disease network consisting of 369 nodes and 5515 edges. The human disease network shows the distribution of diseases in the disease network and the relationships between diseases or disease groups, demonstrating that diseases are associated with each other, forming a complex disease network. We reviewed 5515 disease–disease associations and classified them according to underlying mechanisms. Several disease–disease associations were identified, but the evidence of these associations is not sufficient and the mechanisms underlying these associations have not been clarified yet. Further research studies are needed to investigate these associations and their underlying mechanisms.ConclusionHuman disease network analysis using claims data enriches the understanding of human diseases and provides new insights into disease–disease associations that can be useful in future research.     

Tuberculosis and Autoimmunity

Tuberculosis remains a common and dangerous chronic bacterial infection worldwide. It is long-established that pathogenesis of many autoimmune diseases is mainly promoted by inadequate immune responses to bacterial agents, among them Mycobacterium tuberculosis. Tuberculosis is a multifaceted process having many different outcomes and complications. Autoimmunity is one of the processes characteristic of tuberculosis; the presence of autoantibodies was documented by a large amount of evidence. The role of autoantibodies in pathogenesis of tuberculosis is not quite clear and widely disputed. They are regarded as: (1) a result of imbalanced immune response being reactive in nature, (2) a critical part of TB pathogenicity, (3) a beginning of autoimmune disease, (4) a protective mechanism helping to eliminate microbes and infected cells, and (5) playing dual role, pathogenic and protective. There is no single autoimmunity-mechanism development in tuberculosis; different pathways may be suggested. It may be excessive cell death and insufficient clearance of dead cells, impaired autophagy, enhanced activation of macrophages and dendritic cells, environmental influences such as vitamin D insufficiency, and genetic polymorphism, both of Mycobacterium tuberculosis and host.     

Contemporary issues: diseases with a food vector.

Foodborne disease has become a contemporary issue. Several large, well-publicized outbreaks of foodborne disease have heightened public awareness that harmful microorganisms may be present in food and that chronic as well as acute disease may be caused by foodborne microbes. The field of food microbiology has likewise experienced a resurgence of interest. New tools, such as recombinant deoxyribonucleic acid technology and monoclonal antibody production, used to elucidate microbial virulence factors have facilitated identification of disease-causing microbes once thought to be harmless and demonstrated the complexity of individual virulence mechanisms previously considered to be well understood. Foodborne pathogens are also causing disease via some surprising food vectors, such as chopped, bottled garlic and sauteed onions. In addition to acute gastrointestinal disturbances, certain microorganisms may, through complex interactions with the human immune response, cause chronic diseases that affect several major organ systems. These microbes are serving as models in studies of molecular mimicry and genetic interrelatedness of procaryotes and eucaryotes. Other recently recognized attributes of foodborne microorganisms, such as the heat shock phenomenon and the possible nonculturability of some bacteria, may affect their ability to cause disease in humans. Because foodborne disease is a major cause of morbidity and mortality, the study of these diseases and their causative microorganisms presents a unique challenge to many professionals in the subdisciplines of microbiology, epidemiology, and clinical medicine.     

Microbial interactions in the atopic march

The human body is populated by a large number of microorganisms and exist in symbiosis with these immensely diverse communities, which are suggested to influence health and disease. The microbiota plays an essential role in the maturation and function of the immune system. The prevalence of atopic diseases has increased drastically over the past decades, and the co-occurrence of multiple allergic diseases and allergic sensitization starting in early life has gained a great deal of attention. Immune responses in different organs affected by allergic diseases (e.g. skin, intestine and lung) may be linked to microbial changes in peripheral tissues. In the current review, we provide an overview of the current understanding of microbial interactions in allergic diseases and their potential role in the atopic march.     

Environment as a critical factor for the pathogenesis and outcome of gastrointestinal disease: experimental and human inflammatory bowel disease and helicobacter-induced gastritis.

Environmental factors play an important role in the manifestation, course, and prognosis of diseases of the gastrointestinal tract such as inflammatory bowel disease (IBD) and Helicobacter pylori-induced gastritis. These two disease complexes were chosen for a discussion of the contribution of environmental factors to the disease outcome in humans and animal models. Dissecting complex diseases like IBD and Helicobacter-induced gastritis has shown that the outcome of disease depends on the allelic constellation of a host and the microbial and physical environments. Host alleles predisposing to a disease in one genomic and/or environmental milieu may not be deleterious in other constellations; on the other hand, microbes can have different effects in different hosts and under different environmental conditions. The impact of the complex interaction between host genetics and environmental factors, particularly microflora, also underlines the importance of a defined genetic background and defined environments in animal studies and is indicative of the difficulties in analyzing complex diseases in humans.     

Microbe-metabolite-host axis,two-way action in the pathogenesis and treatment of human autoimmunity

The role of microorganism in human diseases cannot be ignored. These microorganisms have evolved together with humans and worked together with body's mechanism to maintain immune and metabolic function. Emerging evidence shows that gut microbe and their metabolites open up new doors for the study of human response mechanism. The complexity and interdependence of these microbe-metabolite-host interactions are rapidly being elucidated. There are various changes of microbial levels in models or in patients of various autoimmune diseases (AIDs). In addition, the relevant metabolites involved in mechanism mainly include short-chain fatty acids (SCFAs), bile acids (BAs), and polysaccharide A (PSA). Meanwhile, the interaction between microbes and host genes is also a factor that must be considered. It has been demonstrated that human microbes are involved in the development of a variety of AIDs, including organ-specific AIDs and systemic AIDs. At the same time, microbes or related products can be used to remodel body's response to alleviate or cure diseases. This review summarizes the latest research of microbes and their related metabolites in AIDs. More importantly, it highlights novel and potential therapeutics, including fecal microbial transplantation, probiotics, prebiotics, and synbiotics. Nonetheless, exact mechanisms still remain elusive, and future research will focus on finding a specific strain that can act as a biomarker of an autoimmune disease.     

Do microbes influence the pathogenesis of allergic diseases? Building the case for Toll-like receptor ligands

The prevalence and severity of allergic diseases and other diseases of immune dysregulation are increasing in industrialized countries. One explanation for these trends is that decreased exposure to microbes, due to modern public health practices, has resulted in the loss of a main source of immune provocation, and a consequent increase in pathogenic immune responses and their associated diseases. It is now clear that molecular interactions between immunocytes and microbes are mediated largely by Toll-like receptors (TLRs) on host cells and a diversity of ligands produced by viruses, bacteria and fungi. Physiological exposures to TLR ligands are also likely to have an important yet complex role in host immune homeostasis and predisposition towards atopy.     

Paneth cells, defensins, and the commensal microbiota: a hypothesis on intimate interplay at the intestinal mucosa

Mucosal surfaces are colonized by a diverse and dynamic microbiota. Much investigation has focused on bacterial colonization of the intestine, home to the vast majority of this microbiota. Experimental evidence has highlighted that these colonizing microbes are essential to host development and homeostasis, but less is known about host factors that may regulate the composition of this ecosystem. While evidence shows that IgA has a role in shaping this microbiota, it is likely that effector molecules of the innate immune system are also involved. One hypothesis is that gene-encoded antimicrobial peptides, key elements of innate immunity throughout nature, have an essential role in this regulation. These effector molecules characteristically have activity against a broad spectrum of bacteria and other microbes. At mucosal surfaces, antimicrobial peptides may affect the numbers and/or composition of the colonizing microbiota. In humans and other mammals, defensins are a predominant class of antimicrobial peptides. In the small intestine, Paneth cells (specialized secretory epithelial cells) produce high quantities of defensins and several other antibiotic peptides and proteins. Data from murine models indicate that Paneth cell defensins play a pivotal role in defense from food and water-borne pathogens in the intestinal lumen. Recent studies in humans provide evidence that reduced Paneth cell defensin expression may be a key pathogenic factor in ileal Crohn's disease, a subgroup of inflammatory bowel disease (IBD), and changes in the colonizing microbiota may mediate this pathogenic mechanism. It is also possible that low levels of Paneth cell defensins, characteristic of normal intestinal development, may predispose premature neonates to necrotizing enterocolitis (NEC) through similar close links with the composition of the intestinal microbiota. Future studies to further define mechanisms by which defensins and other host factors regulate the composition of the intestinal microbiota will likely provide new insights into intestinal homeostasis and new therapeutic strategies for inflammatory and infectious diseases of the bowel.     

Close association between intestinal microbiota and irritable bowel syndrome

Trillions of microbes inhabiting the intestine form a complex ecological community, affecting the normal physiology and pathological susceptibility through their collective metabolic activities and interactions with the host. Increased numbers of diseases have been found to be associated with disturbances in this ecosystem. There is evidence that intestinal microflora undergoes alterations in patients with irritable bowel syndrome (IBS). IBS is a frequent functional gut disease with negative impact on the patient’s quality of life. Although the etiology and pathology of IBS remain largely unknown, it is generally accepted that the interaction between the microbiota and the host is associated with IBS. However, there are no specific or effective therapies for the treatment of IBS at present. In recent years, researchers have shown a growing interest in seeking safer and more effective alternatives for the treatment of IBS by focusing their attention on the potential role of probiotics and prebiotics. In this review, we will discuss alterations in intestinal microbiota and how these alterations may exacerbate IBS, and introduce several new IBS treatment options aiming at re-establishing a healthy and beneficial ecosystem.     

Mucosal T cells in gut homeostasis and inflammation

The antigen-rich environment of the gut interacts with a highly integrated and specialized mucosal immune system that has the challenging task of preventing invasion and the systemic spread of microbes, while avoiding excessive or unnecessary immune responses to innocuous antigens. Disruption of the mucosal barrier and/or defects in gut immune regulatory networks may lead to chronic intestinal inflammation as seen in inflammatory bowel disease. The T-cell populations of the intestine play a critical role in controlling intestinal homeostasis, and their unique phenotypes and diversities reflect the sophisticated mechanisms that have evolved to maintain the delicate balance between immune activation and tolerance at mucosal sites. In this article, we will discuss the specialized properties of mucosal T cells in the context of immune homeostasis and inflammation.     

Invasive pneumococcal disease in patients with an underlying pulmonary Disorder

Chronic pulmonary disease is a recognized risk factor for invasive pneumococcal disease (IPD). However, previous studies have often not been large enough to allow detailed analyses of less prevalent pulmonary diseases, and findings regarding case fatality have been inconsistent. We examined the associations between an underlying pulmonary disease and IPD, and the impact of these diseases on the case fatality rate. Patients with IPD ≥ 18 years of age, between 1990 and 2008, were identified in microbiological databases. The associations between IPD and the pulmonary diseases were assessed using conditional logistic regression, comparing IPD cases to ten control subjects per case, randomly selected from the general population (matched for gender, year of birth and county of residence). Adjustments were made for other co-morbidities, level of education and socio-economic status, 4085 cases of IPD and 40 353 controls were identified. A more than four-fold increased risk of IPD was seen in chronic obstructive pulmonary disease, a doubled risk in asthma and a five-fold increased risk in subjects with pulmonary fibrosis. In univariate analysis, sarcoidosis and bronchiectasis were associated with a two-fold to seven-fold increase in the risk of IPD, but there was no statistical support for the associations when adjustments for confounders were made. No increased risk was seen in subjects with a history of pneumoconiosis or allergic alveolitis. The mortality following IPD was not increased in patients with chronic obstructive pulmonary disease, asthma, pulmonary fibrosis or bronchiectasis. Several chronic pulmonary diseases increase the risk of IPD but mortality following IPD seems not to be affected.     

Multifunctional antimicrobial peptides: therapeutic targets in several human diseases

Antimicrobial peptides have emerged as promising agents against antibiotic-resistant pathogens. They represent essential components of the innate immunity and permit humans to resist infection by microbes. These gene-encoded peptides are found mainly in phagocytes and epithelial cells, showing a direct activity against a wide range of microorganisms. Their role has now broadened from that of simply endogenous antibiotics to multifunctional mediators, and their antimicrobial activity is probably not the only primary function. Although antimicrobial peptide deficiency, dysregulation, or overproduction is not known to be a direct cause of any single human disease, numerous studies have now provided compelling evidence for their involvement in the complex network of immune responses and inflammatory diseases, thereby influencing diverse processes including cytokine release, chemotaxis, angiogenesis, wound repair, and adaptive immune induction. The purpose of this review is to highlight recent literature, showing that antimicrobial peptides are associated with several human conditions including infectious and inflammatory diseases, and to discuss current clinical development of peptide-based therapeutics for future use.     

The role of neutrophils during intestinal inflammation

Polymorphonuclear leukocytes or neutrophils play a critical role in the maintenance of intestinal homeostasis. They have elegant defense mechanisms to eliminate microbes that have translocated across a single layer of mucosal epithelial cells that form a critical barrier between the gut lumen and the underlying tissue. During the inflammatory response, neutrophils also contribute to the recruitment of other immune cells and facilitate mucosal healing by releasing mediators necessary for the resolution of inflammation. Although the above responses are clearly beneficial, excessive recruitment and accumulation of activated neutrophils in the intestine under pathological conditions such as inflammatory bowel disease is associated with mucosal injury and debilitating disease symptoms. Thus, depending on the circumstances, neutrophils can be viewed as either good or bad. In this article, we summarize the beneficial and deleterious roles of neutrophils in the intestine during health and disease and provide an overview of what is known about neutrophil function in the gut.     

The relationship between vaccine refusal and self-report of atopic disease in children

BACKGROUND: In the last 3 decades, there has been an unexplained increase in the prevalence of asthma and hay fever. OBJECTIVE: We sought to determine whether there is an association between childhood vaccination and atopic diseases, and we assessed the self-reported prevalence of atopic diseases in a population that included a large number of families not vaccinating their children. METHODS: Surveys were mailed to 2964 member households of the National Vaccine Information Center, which represents people concerned about vaccine safety, to ascertain vaccination and atopic disease status. RESULTS: The data included 515 never vaccinated, 423 partially vaccinated, and 239 completely vaccinated children. In multiple regression analyses there were significant ( P < .0005) and dose-dependent negative relationships between vaccination refusal and self-reported asthma or hay fever only in children with no family history of the condition and, for asthma, in children with no exposure to antibiotics during infancy. Vaccination refusal was also significantly ( P < .005) and negatively associated with self-reported eczema and current wheeze. A sensitivity analysis indicated that substantial biases would be required to overturn the observed associations. CONCLUSION: Parents who refuse vaccinations reported less asthma and allergies in their unvaccinated children. Although this relationship was independent of measured confounders, it could be due to differences in other unmeasured lifestyle factors or systematic bias. Further research is needed to verify these results and investigate which exposures are driving the associations between vaccination refusal and allergic disease. The known benefits of vaccination currently outweigh the unproved risk of allergic disease.     

Translating genome wide association study results to associations among common diseases: In silico study with an electronic medical record

ObjectiveTo develop a map of disease associations exclusively using two publicly available genetic sources: the catalog of single nucleotide polymorphisms (SNPs) from the HapMap, and the catalog of Genome Wide Association Studies (GWAS) from the NHGRI, and to evaluate it with a large, long-standing electronic medical record (EMR).MethodsA computational model, In Silico Bayesian Integration of GWAS (IsBIG), was developed to learn associations among diseases using a Bayesian network (BN) framework, using only genetic data. The IsBIG model (I-Model) was re-trained using data from our EMR (M-Model). Separately, another clinical model (C-Model) was learned from this training dataset. The I-Model was compared with both the M-Model and the C-Model for power to discriminate a disease given other diseases using a test dataset from our EMR. Area under receiver operator characteristics curve was used as a performance measure. Direct associations between diseases in the I-Model were also searched in the PubMed database and in classes of the Human Disease Network (HDN).ResultsOn the basis of genetic information alone, the I-Model linked a third of diseases from our EMR. When compared to the M-Model, the I-Model predicted diseases given other diseases with 94% specificity, 33% sensitivity, and 80% positive predictive value. The I-Model contained 117 direct associations between diseases. Of those associations, 20 (17%) were absent from the searches of the PubMed database; one of these was present in the C-Model. Of the direct associations in the I-Model, 7 (35%) were absent from disease classes of HDN.ConclusionUsing only publicly available genetic sources we have mapped associations in GWAS to a human disease map using an in silico approach. Furthermore, we have validated this disease map using phenotypic data from our EMR. Models predicting disease associations on the basis of known genetic associations alone are specific but not sensitive. Genetic data, as it currently exists, can only explain a fraction of the risk of a disease. Our approach makes a quantitative statement about disease variation that can be explained in an EMR on the basis of genetic associations described in the GWAS.     

肠道菌群差异与健康的研究进展

正自人类微生物组计划启动以来,研究发现人体肠道内存在有1 000多种共生菌,主要包括Bacteroidetes、Firmicutes、Proteobacteria等菌门~([1]),它们寄居在肠道的不同部位,通过特有的菌群结构、菌群活动、代谢产物等来影响机体的新陈代谢,维持机体内