Tracing environmental markers of autoimmunity: introducing the infectome

We recently introduced the concept of the infectome as a means of studying all infectious factors which contribute to the development of autoimmune disease. It forms the infectious part of the exposome, which collates all environmental factors contributing to the development of disease and studies the sum total of burden which leads to the loss of adaptive mechanisms in the body. These studies complement genome-wide association studies, which establish the genetic predisposition to disease. The infectome is a component which spans the whole life and may begin at the earliest stages right up to the time when the first symptoms manifest, and may thus contribute to the understanding of the pathogenesis of autoimmunity at the prodromal/asymptomatic stages. We provide practical examples and research tools as to how we can investigate disease-specific infectomes, using laboratory approaches employed from projects studying the “immunome” and “microbiome”. It is envisioned that an understanding of the infectome and the environmental factors that affect it will allow for earlier patient-specific intervention by clinicians, through the possible treatment of infectious agents as well as other compounding factors, and hence slowing or preventing disease development.     

Unraveling the soul of autoimmune diseases: pathogenesis, diagnosis and treatment adding dowels to the puzzle

The pathogenesis of autoimmune diseases (ADs) is characterized by a complex interaction between genetic, immune defects, environmental and hormonal factors. The concept of “mosaic of autoimmunity” deals with the multi-factorial origin and diversity of expression of ADs in humans. Genetic leads to a predisposition in developing an autoimmune syndrome, but the presence of an external or endogenous environmental factor, recently called “exposome,” is essential in triggering the immune response. Infections as well as the expositions to different other external environmental agents have been identified as potential trigger for ADs. A new syndrome, namely the autoimmune/inflammatory syndrome induced by adjuvants, has recently been defined alluding to the key role of adjuvant in inducing an immune-mediated condition. Aluminum and silicone, respectively found in vaccines and breast implants, are the most commonly known adjuvants charged with development of autoimmune conditions. Similarly to playing chess, unraveling the pathogenesis of autoimmune diseases with every new discovery is adding a move to the game aiming at checkmating ADs.     

Diary

Autoimmunity encompasses a wide spectrum of diseases from organ-specific diseases like Hashimoto thyroiditis, to systemic diseases such as systemic lupus erythematosus. These diseases are characterized by inflammation and the production of a wide range of autoantibodies directed against multiple autoantigens. Although their etiology is still poorly understood, genetic, immunological, hormonal, and environmental factors are major predisposing and triggering factors. These multiple factors, like pieces in a mosaic, may interplay in different forms, leading to the expression of various autoimmune manifestations and diseases. This phenomenon, which has been referred by us as the “mosaic of autoimmunity”, illuminates the diversity of autoimmune manifestations among susceptible individuals. From this theoretical framework we conducted a wide search of the literature, on the prevalence of thyroid autoimmunity, the commonest of the autoimmune conditions, among other autoimmune diseases, and discuss the possible clinical significance of this association.     

Multiple sclerosis,the microbiome,TLR2, and the hygiene hypothesis

The pathophysiology of autoimmune diseases such as Multiple Sclerosis (MS) involves a complex interaction between genetic and environmental factors. Studies of monozygotic twins suggest a significant role for environmental factors in susceptibility to MS. Numerous studies, driven by the “Hygiene Hypothesis,” have focused on the role of environmental factors in allergic and autoimmune diseases. The hygiene hypothesis postulates that individuals living in environments that are too “clean” lack the requisite exposure to “immune-tolerizing” microbial products, resulting in poorly regulated immune systems and increased immune-mediated diseases. Interestingly, few studies have linked MS with the hygiene hypothesis. Similarly, although numerous studies have examined the role of the microbiome in autoimmune diseases, there has been no consistent documentation of disease-specific alterations in the MS microbiome. In this review, we present evidence that integrating the hygiene hypothesis and the microbiome allows for the identification of novel pathophysiologic mechanisms in MS.Our central hypothesis is that the microbiome in MS represents a “defective environment” that fails to provide normal levels of “TLR2-tolerizing” bacterial products to the systemic immune system. Consistent with the hygiene hypothesis, we posit that this defective microbiome function results in abnormally regulated systemic innate immune TLR2 responses that play a critical role in both the inflammatory and defective remyelinative aspects of MS. We have completed proof of concept studies that support the inflammatory, remyelinating, and human immune response components of this paradigm. Our studies suggest that induction of TLR2 tolerance may represent a novel approach to treating MS, inhibiting autoimmune inflammation while simultaneously facilitating remyelination.     

Infection, vaccines and other environmental triggers of autoimmunity

The etiology of autoimmune diseases is still not clear but genetic, immunological, hormonal and environmental factors are considered to be important triggers. Most often autoimmunity is not followed by clinical symptoms unless an additional event such as an environmental factor favors an overt expression.Many environmental factors are known to affect the immune system and may play a role as triggers of the autoimmune mosaic.Infections: bacterial, viral and parasitic infections are known to induce and exacerbate autoimmune diseases, mainly by the mechanism of molecular mimicry. This was studied for some syndromes as for the association between SLE and EBV infection, pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection and more. Vaccines, in several reports were found to be temporally followed by a new onset of autoimmune diseases. The same mechanisms that act in infectious invasion of the host, apply equally to the host response to vaccination. It has been accepted for diphtheria and tetanus toxoid, polio and measles vaccines and GBS. Also this theory has been accepted for MMR vaccination and development of autoimmune thrombocytopenia, MS has been associated with HBV vaccination.Occupational and other chemical exposures are considered as triggers for autoimmunity. A debate still exists about the role of silicone implants in induction of scleroderma like disease.Not only foreign chemicals and agents have been associated with induction of autoimmunity, but also an intrinsic hormonal exposure, such as estrogens. This might explain the sexual dimorphism in autoimmunity.Better understanding of these environmental risk factors will likely lead to explanation of the mechanisms of onset and progression of autoimmune diseases and may lead to effective preventive involvement in specific high-risk groups.So by diagnosing a new patient with autoimmune disease a wide anamnesis work should be done.     

Infection,vaccines and other environmental triggers of autoimmunity

The etiology of autoimmune diseases is still not clear but genetic, immunological, hormonal and environmental factors are considered to be important triggers. Most often autoimmunity is not followed by clinical symptoms unless an additional event such as an environmental factor favors an overt expression.

Many environmental factors are known to affect the immune system and may play a role as triggers of the autoimmune mosaic.

Infections: bacterial, viral and parasitic infections are known to induce and exacerbate autoimmune diseases, mainly by the mechanism of molecular mimicry. This was studied for some syndromes as for the association between SLE and EBV infection, pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection and more. Vaccines, in several reports were found to be temporally followed by a new onset of autoimmune diseases. The same mechanisms that act in infectious invasion of the host, apply equally to the host response to vaccination. It has been accepted for diphtheria and tetanus toxoid, polio and measles vaccines and GBS. Also this theory has been accepted for MMR vaccination and development of autoimmune thrombocytopenia, MS has been associated with HBV vaccination.

Occupational and other chemical exposures are considered as triggers for autoimmunity. A debate still exists about the role of silicone implants in induction of scleroderma like disease.

Not only foreign chemicals and agents have been associated with induction of autoimmunity, but also an intrinsic hormonal exposure, such as estrogens. This might explain the sexual dimorphism in autoimmunity.

Better understanding of these environmental risk factors will likely lead to explanation of the mechanisms of onset and progression of autoimmune diseases and may lead to effective preventive involvement in specific high-risk groups.

So by diagnosing a new patient with autoimmune disease a wide anamnesis work should be done.     

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.     

The role of infections in autoimmune disease

Autoimmunity occurs when the immune system recognizes and attacks host tissue. In addition to genetic factors, environmental triggers (in particular viruses, bacteria and other infectious pathogens) are thought to play a major role in the development of autoimmune diseases. In this review, we (i) describe the ways in which an infectious agent can initiate or exacerbate autoimmunity; (ii) discuss the evidence linking certain infectious agents to autoimmune diseases in humans; and (iii) describe the animal models used to study the link between infection and autoimmunity.     

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.     

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.     

The Role of Exposomes in the Pathophysiology of Autoimmune Diseases II: Pathogens

In our continuing examination of the role of exposomes in autoimmune disease, we use this review to focus on pathogens. Infections are major contributors to the pathophysiology of autoimmune diseases through various mechanisms, foremost being molecular mimicry, when the structural similarity between the pathogen and a human tissue antigen leads to autoimmune reactivity and even autoimmune disease. The three best examples of this are oral pathogens, SARS-CoV-2, and the herpesviruses. Oral pathogens reach the gut, disturb the microbiota, increase gut permeability, cause local inflammation, and generate autoantigens, leading to systemic inflammation, multiple autoimmune reactivities, and systemic autoimmunity. The COVID-19 pandemic put the spotlight on SARS-CoV-2, which has been called “the autoimmune virus.” We explore in detail the evidence supporting this. We also describe how viruses, in particular herpesviruses, have a role in the induction of many different autoimmune diseases, detailing the various mechanisms involved. Lastly, we discuss the microbiome and the beneficial microbiota that populate it. We look at the role of the gut microbiome in autoimmune disorders, because of its role in regulating the immune system. Dysbiosis of the microbiota in the gut microbiome can lead to multiple autoimmune disorders. We conclude that understanding the precise roles and relationships shared by all these factors that comprise the exposome and identifying early events and root causes of these disorders can help us to develop more targeted therapeutic protocols for the management of this worldwide epidemic of autoimmunity.     

Coexistence of thyroid autoimmunity with other autoimmune diseases: friend or foe? Additional aspects on the mosaic of autoimmunity

Autoimmunity encompasses a wide spectrum of diseases from organ-specific diseases like Hashimoto thyroiditis, to systemic diseases such as systemic lupus erythematosus. These diseases are characterized by inflammation and the production of a wide range of autoantibodies directed against multiple autoantigens. Although their etiology is still poorly understood, genetic, immunological, hormonal, and environmental factors are major predisposing and triggering factors. These multiple factors, like pieces in a mosaic, may interplay in different forms, leading to the expression of various autoimmune manifestations and diseases. This phenomenon, which has been referred by us as the "mosaic of autoimmunity", illuminates the diversity of autoimmune manifestations among susceptible individuals. From this theoretical framework we conducted a wide search of the literature, on the prevalence of thyroid autoimmunity, the commonest of the autoimmune conditions, among other autoimmune diseases, and discuss the possible clinical significance of this association.     

Environmental pathways to autoimmune diseases: the cases of primary biliary cirrhosis and multiple sclerosis

The pathways leading to autoimmunity remain enigmatic despite numerous lines of experimental inquiry and epidemiological evidence. The mechanisms leading to the initiation and perpetuation of specific diseases such as primary biliary cirrhosis (PBC) or multiple sclerosis (MS) remain largely enigmatic, although it is established that a combination of genetic predisposition and environmental stimulation is required. The growing number of genome-wide association studies and the largely incomplete concordance for autoimmune diseases in monozygotic twins concur to support the role of the environment (including infectious agents and chemicals) in the breakdown of tolerance leading to autoimmunity through different mechanisms. In the present article we illustrate the current hypotheses related to an environmental impact on the onset of PBC and MS as two representative conditions investigated with complementary approaches. Indeed, while a role of post-translational antigen modifications has been proposed for MS, this field remain unexplored in PBC where, conversely, most evidence is gathered from geoepidemiology and experimental data on xenobiotics or infectious agents.     

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.     

Antigen-presenting cell activation: a link between infection and autoimmunity?

The onset of autoimmune diseases such as type I diabetes and multiple sclerosis is often thought to be associated with infection. This has led to studies of molecular mimicry between infectious agents and the self-antigens associated with autoimmunity. Despite many claims, however, a single causative infectious agent for autoimmunity has not been found. An alternative possibility is that many infectious agents are capable of non-specifically enhancing the likelihood of an autoimmune attack. Here we show how infectious agents may activate antigen-presenting cells leading to the activation of autoreactive T cells by otherwise innocuous antigens. The mechanism of activation involves upregulation of co-stimulatory molecules on the antigen-presenting cell resulting in a lowering of the threshold required for activation. These results help explain how diverse infectious agents could cause autoimmune disease in susceptible individuals.     

Hygiene hypothesis and autoimmune diseases: A narrative review of clinical evidences and mechanisms

Since the start of the “modern era”, characterized by the increase in urbanization, a progressive attention to hygiene and autoimmune conditions has considerably grown. Although these diseases are often multifactorial, it was demonstrated that environment factors such as pollution, diet and lifestyles may play a crucial role together with genetic signature. Our research, based on the newest and most significant literature of this topic, highlights that the progressive depletion of microbes and parasites due to increased socioeconomic improvement, may lead to a derangement of immunoregulatory mechanisms. Moreover, special attention was given to the complex interplay between microbial agents, as gut microbiome, diet and vitamin D supplementation with the aim of identifying promising future therapeutic options. In conclusion, autoimmunity cannot be limited to hygiene-hypothesis, but from the point of view of precision medicine, this theory represents a fundamental element together with the study of genomics, the microbiome and proteomics, in order to understand the complex functioning of the immune system.     

The Concept of Type-1 and Type-2 Helper T Cells and Their Cytokines in Humans

In both mice and humans, functionally distinct helper T (Th)-cell subsets, known as Th1 and Th2 cells, are characterized by the patterns of cytokines they produce. These two polarized forms of the specific cellular immune response provide a useful model for explaining not only the different types of protection, but also the pathogenic mechanisms of several immunopathological disorders. The development of polarized Th1 or Th2 responses depends on either environmental factors, including dose of antigen, nature of immunogen and cytokines (IL-12 and interferons or IL-4) at the time of antigen presentation, or other undefined factors in the individual genetic background, mainly at level of the so-called “natural immunity”. Th1-dominated responses are potentially effective in eradicating infectious agents, including those hidden within the host cells. When the Th1 response is poorly effective or exhaustively prolonged, it may result in host damage. In contrast, Th2 responses are apparently insufficient to protect against the majority of infectious agents, but can provide some protection against parasites. Th2 cells are able to make unpleasant the life of parasites in the host and tend to limit potentially harmful Th1-mediated responses. Thus, Th2 cells may be regarded as a part of down-regulatory (or suppressor) mechanism for exaggerated and/or inappropriate Th1 responses. The Th1/Th2 paradigm applied to the study of chronic inflammatory disorders or autoimmune diseases allowed to understand that a number of diseases are mediated by Th1 cells, the two clearest examples being multiple sclerosis and thyroid autoimmunity. In other disorders, Th1/Th2 polarization is less prominent, or rather Th2 responses tend to predominate, such as in systemic lupus erythematosus, progressive systemic sclerosis or allergic diseases. It is of note that in experimental models in animals, a number of diseases can be prevented by switching immune responses from Th1 to Th2 or from Th2 to Th1. Moreover, the Th1/Th2 concept suggests that modulation of the relative contribution of Th1-or Th2-type cytokines makes possible to regulate the balance between protection and immunopathology, as well as the development and/or the severity of some immunologic disorders.     

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.     

Epigenetics in human autoimmunity

Epigenetic mechanisms are essential for normal development and function of the immune system. Similarly, a failure to maintain epigenetic homeostasis in the immune response due to factors including environmental influences, leads to aberrant gene expression, contributing to immune dysfunction and in some cases the development of autoimmunity in genetically predisposed individuals. This is exemplified by systemic lupus erythematosus, where environmentally induced epigenetic changes contribute to disease pathogenesis in those genetically predisposed. Similar interactions between genetically determined susceptibility and environmental factors are implicated in other systemic autoimmune diseases such as rheumatoid arthritis and scleroderma, as well as in organ specific autoimmunity. The skin is exposed to a wide variety of environmental agents, including UV radiation, and is prone to the development of autoimmune conditions such as atopic dermatitis, psoriasis and some forms of vitiligo, depending on environmental and genetic influences. Herein we review how disruption of epigenetic mechanisms can alter immune function using lupus as an example, and summarize how similar mechanisms may contribute to other human autoimmune rheumatic and skin diseases.     

Epigenetics in human autoimmunity. Epigenetics in autoimmunity - DNA methylation in systemic lupus erythematosus and beyond

Epigenetic mechanisms are essential for normal development and function of the immune system. Similarly, a failure to maintain epigenetic homeostasis in the immune response due to factors including environmental influences, leads to aberrant gene expression, contributing to immune dysfunction and in some cases the development of autoimmunity in genetically predisposed individuals. This is exemplified by systemic lupus erythematosus, where environmentally induced epigenetic changes contribute to disease pathogenesis in those genetically predisposed. Similar interactions between genetically determined susceptibility and environmental factors are implicated in other systemic autoimmune diseases such as rheumatoid arthritis and scleroderma, as well as in organ specific autoimmunity. The skin is exposed to a wide variety of environmental agents, including UV radiation, and is prone to the development of autoimmune conditions such as atopic dermatitis, psoriasis and some forms of vitiligo, depending on environmental and genetic influences. Herein we review how disruption of epigenetic mechanisms can alter immune function using lupus as an example, and summarize how similar mechanisms may contribute to other human autoimmune rheumatic and skin diseases.