Infectome: A platform to trace infectious triggers of autoimmunity

The “exposome” is a term recently used to describe all environmental factors, both exogenous and endogenous, which we are exposed to in a lifetime. It represents an important tool in the study of autoimmunity, complementing classical immunological research tools and cutting-edge genome wide association studies (GWAS). Recently, environmental wide association studies (EWAS) investigated the effect of environment in the development of diseases. Environmental triggers are largely subdivided into infectious and non-infectious agents. In this review, we introduce the concept of the “infectome”, which is the part of the exposome referring to the collection of an individual's exposures to infectious agents. The infectome directly relates to geoepidemiological, serological and molecular evidence of the co-occurrence of several infectious agents associated with autoimmune diseases that may provide hints for the triggering factors responsible for the pathogenesis of autoimmunity. We discuss the implications that the investigation of the infectome may have for the understanding of microbial/host interactions in autoimmune diseases with long, pre-clinical phases. It may also contribute to the concept of the human body as a superorganism where the microbiome is part of the whole organism, as can be seen with mitochondria which existed as microbes prior to becoming organelles in eukaryotic cells of multicellular organisms over time. A similar argument can now be made in regard to normal intestinal flora, living in symbiosis within the host. We also provide practical examples as to how we can characterise and measure the totality of a disease-specific infectome, based on the experimental approaches employed from the “immunome” and “microbiome” projects.     

Redox proteomics and the dynamic molecular landscape of the aging brain

It is well established that the risk to develop neurodegenerative disorders increases with chronological aging. Accumulating studies contributed to characterize the age-dependent changes either at gene and protein expression level which, taken together, show that aging of the human brain results from the combination of the normal decline of multiple biological functions with environmental factors that contribute to defining disease risk of late-life brain disorders. Finding the “way out” of the labyrinth of such complex molecular interactions may help to fill the gap between “normal” brain aging and development of age-dependent diseases. To this purpose, proteomics studies are a powerful tool to better understand where to set the boundary line of healthy aging and age-related disease by analyzing the variation of protein expression levels and the major post translational modifications that determine “protein” physio/pathological fate. Increasing attention has been focused on oxidative modifications due to the crucial role of oxidative stress in aging, in addition to the fact that this type of modification is irreversible and may alter protein function. Redox proteomics studies contributed to decipher the complexity of brain aging by identifying the proteins that were increasingly oxidized and eventually dysfunctional as a function of age.The purpose of this review is to summarize the most important findings obtained by applying proteomics approaches to murine models of aging with also a brief overview of some human studies, in particular those related to dementia.     

The mosaic of environment involvement in autoimmunity: The abrogation of viral latency by stress,a non-infectious environmental agent,is an intrinsic prerequisite prelude before viruses can rank as infectious environmental agents that trigger autoimmune diseases

An autoimmune disease (AD), organ-specific or systemic, results from an aberrant response in which the protective immune system normally schooled to recognize and destroy invading infectious agents (viruses, etc.) instead fails to distinguish self-antigens and proceeds to attack and destroy the host's organs. There can be familial aggregation in which a single AD may occur in members of a family, or a single family may be afflicted with multiple ADs. Finally, sometimes multiple ADs co-occur in a single individual: the kaleidoscope of autoimmunity. Autoimmunity is a multifactorial process in which genetic, hormonal, immunological and environmental factors act in concert to materialize the mosaic of autoimmunity phenomenon. A genetically primed individual may yet not develop an AD: the contribution by an environmental factor (non-infectious or infectious) is essential for completion of the act. Of the non-infectious factors, stress plays a determinative step in autoimmunity in that it abrogates viral latency and thereby ordains the viruses to qualify as infectious environmental factors that trigger ADs. This is note-worthy as viruses rank first as the most important environmental triggers of ADs. Furthermore, all these viruses experience going through latency. Hence the hypothesis: “The abrogation of viral latency by stress, a non-infectious environmental agent, is an intrinsic prerequisite prelude before viruses can rank as infectious environmental agents that trigger autoimmune diseases”. There is collaboration here between non-infectious- and infectious-agent to achieve the cause of autoimmunity. We say viral latency and stress have a covenant: continued perpetration of autoimmunity is dependent on the intervention by stress to reactivate latent infections.     

Autoantigens: Novel forms and presentation to the immune system

Abstract

It is clear that lupus autoimmunity is marked by a variety of abnormalities, including those found at a macroscopic scale, cells and tissues, as well as more microenvironmental influences, originating at the individual cell surface through to the nucleus. The convergence of genetic, epigenetic, and perhaps environmental influences all lead to the overt clinical expression of disease, reflected by the presences of autoantibodies and tissue pathology. This review will address several specific areas that fall among the non-genetic factors that contribute to lupus autoimmunity and related syndromes. In particular, we will discuss the importance of understanding various protein post-translational modifications (PTMs), mechanisms that mediate the ability of “modified self” to trigger autoimmunity, and how these PTMs influence lupus diagnosis. Finally, we will discuss altered pathways of autoantigen presentation that may contribute to the perpetuation of chronic autoimmune disease.     

Using exposomics to assess cumulative risks and promote health

Under the exposome paradigm all nongenetic factors contributing to disease are considered to be ‘environmental’ including chemicals, drugs, infectious agents, and psychosocial stress. We can consider these collectively as environmental stressors. Exposomics is the comprehensive analysis of exposure to all environmental stressors and should yield a more thorough understanding of chronic disease development. We can operationalize exposomics by studying all the small molecules in the body and their influence on biological pathways that lead to impaired health. Here, we describe methods by which this may be achieved and discuss the application of exposomics to cumulative risk assessment in vulnerable populations. Since the goal of cumulative risk assessment is to analyze, characterize, and quantify the combined risks to health from exposures to multiple agents or stressors, it seems that exposomics is perfectly poised to advance this important area of environmental health science. We should therefore support development of tools for exposomic analysis and begin to engage impacted communities in participatory exposome research. A first step may be to apply exposomics to vulnerable populations already studied by more conventional cumulative risk approaches. We further propose that recent migrants, low socioeconomic groups with high environmental chemical exposures, and pregnant women should be high priority populations for study by exposomics. Moreover, exposomics allows us to study interactions between chronic stress and environmental chemicals that disrupt stress response pathways (i.e., ‘stressogens’). Exploring the impact of early life exposures and maternal stress may be an interesting and accessible topic for investigation by exposomics using biobanked samples. Environ. Mol. Mutagen. 56:715–723, 2015. © 2015 Wiley Periodicals, Inc.     

PBC triggers in water reservoirs, coal mining areas and waste disposal sites: from Newcastle to New York

Various environmental factors have been proposed as triggers of primary biliary cirrhosis (PBC), a progressive autoimmune cholestatic liver disease which is characterised by the destruction of the small intrahepatic bile ducts. Support for their pathogenic role in PBC is provided by epidemiological studies reporting familial clustering and clusters of the disease within a given geographical area. The seminal study by Triger reporting that the great majority of PBC cases in the English city of Sheffield drank water from a specific water reservoir, has been followed by studies reporting disease 'hot spots' within a restricted geographic region of the former coal mining area of Newcastle. The New York study reporting an increased risk and significant clustering of PBC cases near toxic federal waste disposal sites has added strength to the notion that environmental factors, possibly in the form of infectious agents or toxic/chemical environmental factors in areas of contaminated land, water or polluted air may play a key role in the development of the disease. This review discusses the findings of reports investigating environmental factors which may contribute to the cause of primary biliary cirrhosis.     

Gene-environment interactions in the aetiology of systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a disease that displays a multitude of symptoms and a vast array of autoantibodies. The disease course may vary substantially between patients. The current understanding of SLE aetiology includes environmental factors acting on a genetically prone individual during an undetermined time period resulting in autoimmunity and finally surpassing that individual's disease threshold. Genetic differences and environmental factors may interact specifically in the pathogenetic processes and may influence disease development and modify the disease course. Identification of these factors and their interactions in the pathogenesis of SLE is vital in understanding the disease and may contribute to identify new treatment targets and perhaps also aid in disease prevention. However, there are several problems that need to be overcome, such as the protracted time frame of environmental influence, time dependent epigenetic alterations and the possibility that different pathogenetic pathways may result in a similar disease phenotype. This is mirrored by the relatively few studies that suggest specific gene-environment interactions. These include an association between SLE diagnosis and glutation S-transferase gene variants combined with occupational sun exposure as well as variants of the N-acetyl transferase gene in combination with either aromatic amine exposure or hydralazine. With increased knowledge on SLE pathogenesis, the role of environmental factors and their genetic interactions may be further elucidated.     

Type 1 diabetes in mice and men: gene expression profiling to investigate disease pathogenesis

Type 1 diabetes (T1D) is a complex polygenic disease that is triggered by various environmental factors in genetically susceptible individuals. The emphasis placed on genome-wide association studies to explain the genetics of T1D has failed to advance our understanding of T1D pathogenesis or identify biomarkers of disease progression or therapeutic targets. Using the nonobese diabetic (NOD) mouse model of T1D and the non-disease prone congenic NOD.B10 mice, our laboratory demonstrated striking tissue-specific and age-dependent changes in gene expression during disease progression. We established a “roadmap” of differential gene expression and used this to identify candidate genes in mice (and human orthologs) that play a role in disease pathology. Here, we describe two genes, Deformed epidermal autoregulatory factor 1 (Deaf1) and Adenosine A1 receptor (Adora1), that are differentially expressed and alternatively spliced in the pancreatic lymph nodes or islets of NOD mice and T1D patients to form dominant-negative non-functional isoforms. Loss of Deaf1 function leads to reduced peripheral tissue antigen expression in lymph node stromal cells and may contribute to a breakdown in peripheral tolerance, while reduced Adora1 function results in an early intrinsic alpha cell defect that may explain the hyperglucagonemia and resulting beta cell stress observed prior to the onset of diabetes. Remarkably, both genes were also alternatively spliced in the same tissues of auto-antibody positive prediabetic patients, and these splicing events resulted in similar downstream effects as those seen in NOD mice. These findings demonstrate the value of gene expression profiling in studying disease pathogenesis in T1D.     

Thinking bigger: How early‐life environmental exposures shape the gut microbiome and influence the development of asthma and allergic disease

Imbalance, or dysbiosis, of the gut microbiome of infants has been linked to an increased risk of asthma and allergic diseases. Most studies to date have provided a wealth of data showing correlations between early‐life risk factors for disease and changes in the structure of the gut microbiome that disrupt normal immunoregulation. These studies have typically focused on one specific risk factor, such as mode of delivery or early‐life antibiotic use. Such “micro‐level” exposures have a considerable impact on affected individuals but not necessarily the whole population. In this review, we place these mechanisms under a larger lens that takes into account the influence of upstream “macro‐level” environmental factors such as air pollution and the built environment. While these exposures likely have a smaller impact on the microbiome at an individual level, their ubiquitous nature confers them with a large influence at the population level. We focus on features of the indoor and outdoor human‐made environment, their microbiomes and the research challenges inherent in integrating the built environment microbiomes with the early‐life gut microbiome. We argue that an exposome perspective integrating internal and external microbiomes with macro‐level environmental factors can provide a more comprehensive framework to define how environmental exposures can shape the gut microbiome and influence the development of allergic disease.     

Impact of host genetics on susceptibility to human Chlamydia trachomatis disease

Evidence that host genetic factors play a major role in susceptibility or resistance to many infectious diseases is increasing, due to major advances in genetic epidemiological methodology. Recent human genome mapping information and the identification of a large number of candidate genes provide the tools for such studies. The information obtained is important for understanding the pathogenesis of disease and for the design of preventive and therapeutic strategies. In the study of Chlamydia trachomatis disease pathogenesis, much research focuses on how bacterial factors modulate the immune response and thus contribute to the disease process. It is likely, however, that host factors also play a role, and therefore susceptibility to disease is the result of an environmental effect set against a background of genetic factors. This review outlines the evidence for the contribution of host genetic factors to susceptibility to C. trachomatis disease in humans.     

Molecular mimicry in multiple sclerosis

Two main etiological components are considered important in human autoimmune diseases including multiple sclerosis (MS), first the immunogenetic background and second environmental factors. Among the latter, infectious organisms are probably the most relevant, and epidemiological studies in MS firmly support that viral infections often precede disease exacerbations or the onset of MS. Infectious agents can contribute to disease development or phenotypic expression in different ways. Our focus will be directed on molecular mimicry, i.e. antigenic similarity between structural epitopes or peptide sequences from infectious organisms with those found in self proteins of the host. The intriguing concept of molecular mimicry has evolved substantially since its introduction over 20 years ago. We will summarize the most important developments and discuss puzzling questions, which remain open despite many claims that molecular mimicry is involved in the development of human autoimmune disease after infections or vaccinations.     

The diagnosis and classification of undifferentiated connective tissue diseases

The term undifferentiated connective tissue disease (UCTD) refers to unclassifiable systemic autoimmune diseases which share clinical and serological manifestations with definite connective tissue diseases (CTDs) but not fulfilling any of the existing classification criteria. In this review we will go through the more recent evidence on UCTD and we will discuss in what extent the availability of new criteria for the CTDs could interfere with the “UCTD concept”. The development of criteria able to identify early phases of defined CTD, may help in the differentiation of stable UCTD form their early stages and may offer a valuable guide to the treating physician to set up appropriate follow up schedules as well as therapeutic protocols. This simplified subset of CTD could offer a model to study clinic pathological correlations as well as the role of possible environmental factors in the development of autoimmunity.     

Gene–environment interactions in the aetiology of systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a disease that displays a multitude of symptoms and a vast array of autoantibodies. The disease course may vary substantially between patients. The current understanding of SLE aetiology includes environmental factors acting on a genetically prone individual during an undetermined time period resulting in autoimmunity and finally surpassing that individual's disease threshold. Genetic differences and environmental factors may interact specifically in the pathogenetic processes and may influence disease development and modify the disease course. Identification of these factors and their interactions in the pathogenesis of SLE is vital in understanding the disease and may contribute to identify new treatment targets and perhaps also aid in disease prevention. However, there are several problems that need to be overcome, such as the protracted time frame of environmental influence, time dependent epigenetic alterations and the possibility that different pathogenetic pathways may result in a similar disease phenotype. This is mirrored by the relatively few studies that suggest specific gene-environment interactions. These include an association between SLE diagnosis and glutathion S-transferase gene variants combined with occupational sun exposure as well as variants of the N-acetyl transferase gene in combination with either aromatic amine exposure or hydralazine. With increased knowledge on SLE pathogenesis, the role of environmental factors and their genetic interactions may be further elucidated.     

HIV epidemics driven by late disease stage transmission

How infectious a person is when infected with HIV depends on what stage of the disease the person is in. We use 3 stages, which we call primary, asymptomatic, and symptomatic. It is important to have a systematic method for computing all 3 infectivities so that the measurements are comparable. Using robust modeling, we provide high-resolution estimates of semen infectivity by HIV disease stage. We find that the infectivity of the symptomatic stage is far higher, hence more potent, than the values that prior studies have used when modeling HIV transmission dynamics. The stage infectivity rates for semen are 0.024, 0.002, and 0.299 for the primary, asymptomatic, and symptomatic stages, respectively. Implications of our infectivity estimates and modeling for understanding heterosexual epidemics such as that in sub-Saharan African are explored.     

Importance of gene–environment interactions in the etiology of selected birth defects

It is generally understood that both genetic and environmental factors contribute to the highly complex etiology of structural birth defects, including neural tube defects, oral clefts and congenital heart defects, by disrupting highly regulated embryonic developmental processes. The intrauterine environment of the developing embryo/fetus is determined by maternal factors such as health/disease status, lifestyle, medication, exposure to environmental teratogens, as well as the maternal genotype. Certain genetic characteristics of the embryo/fetus also predispose it to developmental abnormalities. Epidemiologic and animal studies conducted over the last few decades have suggested that the interplay between genes and environmental factors underlies the etiological heterogeneity of these defects. It is now widely believed that the study of gene–environment interactions will lead to better understanding of the biological mechanisms and pathological processes that contribute to the development of complex birth defects. It is only through such an understanding that more efficient measures will be developed to prevent these severe, costly and often deadly defects. In this review, we attempt to summarize the complex clinical and experimental literature on current hypotheses of interactions between several select environmental factors and those genetic pathways in which they are most likely to have significant modifying effects. These include maternal folate nutritional status, maternal diabetes/obesity-related conditions, and maternal exposure to selected medications and environmental contaminants. Our goal is to highlight the potential gene–environment interactions affecting early embryogenesis that deserve comprehensive study.     

Autoimmunity and pathophysiology

Several matters concerning the term “Autoimmunity” have arisen the last two decades. Most researchers agree that a degree of natural autoimmunity in the absence of disease is needed for the development of effective immune responses against infectious agents or cancer cells. Individuals, however, with suitable genetic background and after exposure to certain environmental triggers (such as UV radiation, bacteria, viruses, etc) may develop an exaggerated immune response against self leading to the development of several autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus etc.In this context, a the meeting on “Autoimmunity: Physiological and Pathophysiological Aspects” was held on May in Athens, Greece aiming to bring together and discuss different points of view of the principal investigators that have contributed in the development of this field during the last years. Several aspects of both natural and pathological autoimmunity as well as the possible links between these two states are presented by leading authorities of the field in this special issue.     

Smoking, citrullination and genetic variability in the immunopathogenesis of rheumatoid arthritis

This review describes how studies on interactions between genetic variants, and environmental factors, mainly smoking, contribute to the understanding of how autoimmunity to post-translationally (citrullinated) proteins/peptides may occur and potentially contribute to certain subsets of rheumatoid arthritis. A main message is that studies on specific immune mechanisms in a complex and heterogeneous disease like RA should be undertaken with the help of results from genetic epidemiology. By those means, it may be possible to identify subsets of RA in a way that in the end allows development and testing of precise and subset-specific interventions against environment as well as genetically defined molecular pathways, in particular those that regulate specific immune responses.     

Prion Disease: A Tale of Folds and Strains

Research on prions, the infectious agents of devastating neurological diseases in humans and animals, has been in the forefront of developing the concept of protein aggregation diseases. Prion diseases are distinguished from other neurodegenerative diseases by three peculiarities. First, prion diseases, in addition to being sporadic or genetic like all other neurodegenerative diseases, are infectious diseases. Animal models were developed early on (a long time before the advent of transgenic technology), and this has made possible the discovery of the prion protein as the infectious agent. Second, human prion diseases have true equivalents in animals, such as scrapie, which has been the subject of experimental research for many years. Variant Creutzfeldt–Jakob disease (vCJD) is a zoonosis caused by bovine spongiform encephalopathy (BSE) prions. Third, they show a wide variety of phenotypes in humans and animals, much wider than the variants of any other sporadic or genetic neurodegenerative disease. It has now become firmly established that particular PrP^Sc isoforms are closely related to specific human prion strains. The variety of human prion diseases, still an enigma in its own right, is a focus of this article. Recently, a series of experiments has shown that the concept of aberrant protein folding and templating, first developed for prions, may apply to a variety of neurodegenerative diseases. In the wake of these discoveries, the term prion has come to be used for Aβ, α‐synuclein, tau and possibly others. The self‐propagation of alternative conformations seems to be the common denominator of these “prions,” which in future, in order to avoid confusion, may have to be specified either as “neurodegenerative prions” or “infectious prions.”     

自身免疫性疾病发病机制新进展

自身免疫性疾病(AD)是一种免疫紊乱状态,机体正常的保护性免疫应答不能区分自身抗原和外源性抗原转而攻击人体正常的组织和细胞,因而会出现一系列的异常症状.目前国际上对AD有了很多新的认识,基因和环境的共同作用增加了发病倾向人群的患病风险,而环境因素是多方面的,有学者针对人体内外的环境暴露提出了暴露组学的概念,暴露组学涵盖了除人体外的各种外界因素.根据目前的研究进展,拟从暴露组学、微生物组学及感染组学等多个方面详细阐述AD发病机理提出了致病假说,为进一步研究提供理论依据.     

Life history, maintenance, and the early origins of immune function.

There is compelling evidence to suggest that early environments are important determinants of immune function over the life course. While current research focuses on proximate mechanisms and clinical implications, an adaptationist perspective may contribute a theoretical basis for explaining, rather than merely describing, the long-term impact of early environments. Life history theory in particular, with its emphasis on the life cycle and investment in maintenance effort-of which immune function is a central component-provides a predictive framework for identifying prenatal and early postnatal factors that are likely to shape immunity. Key life history issues at these stages include avoiding death from infectious disease, investing in immune defenses that are appropriate for the local disease ecology, and optimizing competing demands for investment in immune function and growth. A series of hypotheses derived from these issues are proposed and evaluated with data from ongoing research in the Philippines and Bolivia. Ecologically-informed research on immunity is in its earliest stages, and life history theory has the potential to make important contributions to our understanding of the development and function of this critical physiological system.