key: cord-0720649-46e6qae9
authors: Bogdanos, Dimitrios P.; Smyk, Daniel S.; Invernizzi, Pietro; Rigopoulou, Eirini I.; Blank, Miri; Pouria, Shideh; Shoenfeld, Yehuda
title: Infectome: A platform to trace infectious triggers of autoimmunity
date: 2012-12-22
journal: Autoimmun Rev
DOI: 10.1016/j.autrev.2012.12.005
sha: 1f0ab2bee5fde00f2e1a9a2abd5bc05267d23f7d
doc_id: 720649
cord_uid: 46e6qae9

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.

It is widely accepted that the vast majority of diseases develop from the interaction between genes and the environment [1] [2] [3] . This concept has formed the basis for studying the pathogenesis of many diseases including autoimmune diseases [1, 2, 4] . There are now almost 100 categories of autoimmune diseases, both organ specific or systemic in nature. Although individual autoimmune diseases are relatively rare in any population that has been investigated so far, projected data estimate that approximately 5-20% of North Americans are affected by at least one autoimmune disease [5] . Some of the best known autoimmune diseases are type 1 diabetes, rheumatoid arthritis, multiple sclerosis, Grave's disease, Hashimoto's thyroiditis, myasthenia gravis, systemic lupus erythematosus, Sjögren's syndrome, scleroderma and autoimmune liver diseases such as autoimmune hepatitis, primary sclerosing cholangitis, and primary biliary cirrhosis (PBC) [5] . The observation that many autoimmune diseases may affect one individual, has led to the concept of the Mosaic of Autoimmunity [6] [7] [8] [9] [10] [11] [12] [13] .

The study of genetic and epigenetic factors linking to autoimmunity is the focus of ongoing research [14] . Also, the exact signalling cascades that govern the perpetuation of inflammatory processes responsible for tissue destruction are poorly understood [15] . In recent years, genome wide association studies (GWAS) have identified numerous gene-disease associations, many of which include autoimmune diseases [2] . Although these associations are connected to genetic susceptibility, the genetic 'dosage' or number of associated genes required for disease development is not well defined [16] . Although GWAS have been instrumental in unlocking a pathogenetic starting point, exposure to environmental factors is also likely to contribute to the actual development of most diseases, and work with genetics in the induction of autoimmune disease [1, 2, 17] . For example, smoking has been indicated to increase the risk of developing MS in individuals with HLA-DRB1*1501 [18] . Epidemiological studies using toxicological, microbiological, biochemical, and immunological testing are important in order to identify these environmental agents, which include infectious organisms, xenobiotics, chemical compounds, heavy metals from prostheses and dental materials, radiation, vaccines, and foods to name but a few [1, [19] [20] [21] [22] . Heavy metals and vaccinations have also been implicated in the pathogenesis of autoimmune (auto-inflammatory) syndrome induced by adjuvants (ASIA) [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] . In fact, siliconosis, Gulf war syndrome (GWS), macrophagic myofasciitis syndrome (MMF) and post-vaccination phenomena were linked with past exposure to adjuvants.

Since GWAS underlined the view that multiple genes are needed to induce autoimmunity [2] , it is also likely that several environmental triggers either complement or substitute each other to provoke immune mediated processes which then lead to autoimmunity. The additive effects of these triggers, and their interaction with susceptible genes, remain poorly defined.

In recent years, the concept of an "exposome" has been introduced, as a means of collating, and possibly measuring the effects of environmental factors. The exposome takes into account all internal and external stimuli associated with a disease, and provides a potentially quantifiable way for the evaluation of environmental factors (Fig. 1) . This review will examine the role of the exposome in relation to major exemplary autoimmune disease where genetics and environment most likely play key roles in pathogenesis. The role of the "infectome" as the infectious component of the microbiome/ exposome that takes part (directly or indirectly) in the development of autoimmunity will also be introduced (Fig. 2 ).

The exposome: what is it, and how do we measure it?

The exposome represents the totality of all environmental exposures, both exogenous and endogenous, which begins from conception, and extends throughout our lives [33] [34] [35] [36] [37] . This differs from previous epidemiological studies, which have largely concentrated on the external environment, and specifically to air, water, soil and food [35] . In contrast to approaches limited to external triggers, the study of the exposome needs to address endogenous factors directly or indirectly related to the environment [36, 37] . Endogenous sources include by-products of inflammation, lipid peroxidation, as well as oxidative stress [35] . Some of these components may act as nucleophiles or electrophiles, and as such, would be capable of DNA and protein modification [38] . Indeed, bacterial alterations in glycosylation patterns of immunoglobulins have been noted in several studies [39] [40] [41] . The collation of all these exposures may provide a fingerprint of a particular disease, which would likely complement data from GWAS [38] .

The predominant problems in examining environmental exposures are the difficulties of quantification and normalisation as well as the determination of exposure sequences. This information is required, as alterations induced by one environmental agent may be necessary for a subsequent exposure to have its effect [2] . Moreover, environmental exposures within a population, as well as within an individual, are greatly varied. Given the myriad of causative possibilities in one individual, it may be useful clinically to look at causes within an individual in terms of exposure, sequence of exposure, hierarchy of exposure events, genetic and other risk factors that initiate or provoke exposure to various stimuli. Examined individually, these pieces may comprise the jigsaw puzzle that is loss of immunological tolerance, development of autoimmune disease and progression of Fig. 1 . From exposome to infectome via microbiome. "Exposome" describes all environmental factors which we are exposed to in a lifetime, both exogenous and endogenous, infectious and non-infectious. Environmental exposures are basically subdivided into infectious and non-infectious agents. The concept of "infectome" that we introduce, describes the part of the exposome which refers to the collection of an individual's exposures to infectious agents participating in the pathogenesis of autoimmune disease. The infectome can be considered a part of "microbiome", the collection of the microbial products which the human body is exposed to at a given time.

clinically over disease and its complications. Although great variability may be seen from patient to patient, the overall collation of well-defined disease-related exposures individually may provide a picture of disease development in that patient. The exposome provides a potential platform by which these exposures may be measured. It has been suggested that their by-products in an individual, such as DNA and protein modification, can serve as biomarkers that are potentially measurable [38] in the blood or body fluids of patients [3, [36] [37] [38] via technologies such as liquid chromatography-tandem mass spectrometry (LC-MS/MS) [42] , DNA adducts [43] , functional measurements of antioxidant capacity, and breath analysis [34] .

Rappaport suggests two methods in which the exposome may be measured: the 'bottom-up' method measures chemicals in air, water and the external environment, but is limited in that it does not take into account the actual uptake of those substances nor the internal environment of a subject [35] . As an alternative, the 'top-down' method measures biomarkers in the patient's blood, however, this method does not indicate a potential source of the toxicant. It is likely that both complementary methods, in conjunction with refined questionnaires, will define the exposome in individuals, and larger populations [35] [36] [37] . Frequent sampling could demonstrate changes of these markers over time, especially during critical phases in the development of a disease [35] . A study by Pleil and colleagues [34] indicates that breath analysis for particular biomarkers is capable of identifying whether one has been exposed, what the dosage was, how rapidly the body is eliminating the toxicant, as well as possibly identifying the short and long term effects [34] . Finally, a recent study by Patel and colleagues [44] has provided evidence that the exposome can indeed be measured and characterised. That study conducted an environmental-wide association study (EWAS) on type 2 diabetes mellitus, where epidemiological data was comprehensively interpreted in a manner similar to GWAS [44] . Associations were found with 37 environmental factors, including organochlorine, pesticides, nutrients/vitamins, polychlorinated biphenyls, and dioxins [44] . Other studies have shown a potential crossreactivity between antigens within the pancreatic islet cells and cow's milk casein in siblings of type 1 diabetics [45] , and multiple sclerosis's myelin oligodendrocyte glycoprotein with milk butyrophilin [46] , highlighting the potential role for food antigens as triggers of autoimmune disease. Similar approaches can be used in future studies on the role of the exposome in the development of autoimmune diseases, especially those which develop in genetically susceptible individuals several years or decades following the initial insult.

One major obstacle to the complete analysis of all these triggers is their heterogeneity. It is unlikely to cover all such components by homogeneous technology platforms, as all human biomarker measurements are subject to inter-and intra-subject variance. This includes the composition of the received data into one model, which appears to be a Sisyphean task even in the age of ultra-fast computing. Therefore, the break-down of this multiversity of components into easier accessible, homogeneous realms of markers seems to be a reasonable next step. Techniques that can be utilised to detect infectious agents like multi-parametric immunoassays for antibodies of various isotypes specific to bacterial or viral antigens, urine and stool cultures and polymerase chain reaction (PCR) can be considered to be robust and integrateable [36] . Routine screening to detect the presence of an infectious causative agent is used clinically in a small scale and for individual microbial agents on an everyday basis [36] .

Infectious and non-infectious environmental agents have long been considered important for the development of autoimmunity [4, [47] [48] [49] [50] [51] . The list of non-infectious environmental factors which can trigger autoimmunity is vast, and includes tobacco smoke, pharmaceuticals, oestrogens, ultraviolet radiation, silica solvents, dietary components, heavy metals, dental materials, vaccines, and collagen/ silicone implants (Table 1) [47, . Infectious triggers implicated in autoimmunity are also numerous and include bacteria, viruses, parasites and fungi. An infection burden corresponding to geoepidemiological and serological evidence of the co-occurrence of anti-infectious agents has been observed and it is of interest that such an infection burden may differ from one autoimmune disease to another [4, 81, 82 ]. An analogous, autoantibody burden in nonautoimmune individuals during infection with various agents, further points towards the close relation of exposure to several infectious agents and the development of autoantibody reactivities [83] . From our point of view, it is helpful to define this subgroup of triggers as the "infectome" which is the part of the exposome referring to the collection of an individual's infectious exposures which are associated with disease, and in our case specific autoimmune diseases. It may also demonstrate the alteration in disease states, which are affected by alterations of the flora within the microbiome. Examples include Tracing infectious triggers of autoimmunity: the infectome from A to Z. Infectious agents participating in a series of events critical for the initiation of autoimmunity and the development of autoimmune disease can be traced at various time points. The traces of these infectious agents may help us to understand the extent of their involvement in the loss of immunological breakdown and/or the maintenance of autoreactive immune responses leading to self destruction. Infections, at times different of those responsible for the chain reaction of events that led to autoimmune disease, may participate in the remission/relapse clinical patterns seen after the onset of the disease. treatment with antibiotics [84, 85] , or exposure to toxic metals, silicone or other xenobiotics [30, 86, 87] . These exposures may very well alter the disease course or progression, by altering the flora within the microbiome, or by increasing the likelihood of infection with a disease causing infection. They may also increase the burden of oxidative stress. While the hygiene hypothesis underlines the protective role played by infections [88] [89] [90] [91] [92] , clinical and experimental data in animal models implicate infections in the development of autoimmunity and autoimmune disease [4] . One of the best-studied examples of infection-induced autoimmunity is that of acute rheumatic fever presenting several weeks after infection with Streptococcus pyogenes. It is now well established that molecular mimicry between the bacterial M-protein and human lysoganglioside is responsible for the loss of immunological tolerance, and the development of autoimmunity in genetically susceptible individuals [93] . Other examples include the associations between Helicobacter pylori and autoimmune gastritis [94] , as well as between Trypanosoma cruzi and Chagas' cardiomyopathy [95] , and Mycoplasma with rheumatoid arthritis [96] .

Although experimental models of autoimmune diseases and studies like those mentioned above provide data to support the role played by a single infectious trigger, the prevailing idea is that a multitude of infections from birth, in our term the infectome, contributes to the induction of autoimmunity [4] . In fact, Rolf Zinkernagel's hypothesis is that the increasing predisposition to autoimmune disease in the developing world may be due to the overall host-infection balance, beginning as early as the transfer of maternal antibodies via the placenta or via breast milk in the gastrointestinal tract. The question which then arises is how one can identify those specific infectious agents responsible for the initiation of an autoimmune disease. Studies in animals have provided some clues, but their resemblance to the human setting is poor in most cases.

Ideally, investigations have to be carried out in affected individuals. However, when work is performed on biological material obtained from patients with a given autoimmune disease, it is difficult to single out disease-triggering microbes. Undoubtedly, information from the collection of the microbial genes in a particular region (such as the gut or the oral cavity), also known as "microbiome", can provide important hints for those potentially involved in the development of or protection against autoimmunity. However, this by itself cannot differentiate those with a pathogenic potential from the non-harmful ones, the latter representing the great majority. In fact, most of the isolated microbes have little to do with the initiation of immune-mediated inflammatory processes leading to a given disease. Moreover, induction of autoimmunity by viruses or bacteria is probably done by a 'hit-and-run' mechanism when the causative agent has been cleared from circulation by the time of diagnosis. Tracking down each individual's exposure to infectious agents as well as anti-microbial immune responses may be important for the establishment of a causative link between infection and autoimmunity.

Studies attempting to investigate the role of the "infectome" in the induction or remission/relapse state of autoimmune disease may need to focus on autoimmune diseases such as multiple sclerosis or rheumatoid arthritis, as patients with these diseases experience frequent remissions and relapses as well as fluctuations in disease activities that are poorly understood. Systemic lupus erythematosus, multiple sclerosis and rheumatoid arthritis are three of the best studied diseases so far for which specific viral agents have been considered to be important for the development of the disease and the breakdown of immunological tolerance [4] . As well, exposure to metals and various other chemical components have also been linked with these two conditions, and it would be interesting to see how these exposures alter the presence of infectious agents. It may be the case that exposure to certain xenobiotics increases susceptibility to disease causing microorganisms, or possibly eliminates organisms that are determined to be protective.

Arguably, the ideal clinical setting for the study of the role of the "infectome" in autoimmunity would involve typical autoimmune diseases with long prodromal stages [97] . Serial testing of biological material from individuals who progress from an asymptomatic subclinical phase to clinical disease would be optimal for the study of the "infectome". Examples of this include systemic lupus erythematosus (SLE), multiple sclerosis (MS) and primary biliary cirrhosis (PBC) to name a few. All of those are characterised by highly specific antibodies that may appear years or even decades before the onset of symptoms [98] [99] [100] . These diseases also have long prodromal stages and their course highly varies among individuals. Relapse and remission states can be seen, but the reasons for this remain unknown. The characteristic features of these diseases and their reported pathogenic relationship with infectious agents make them ideal candidates for the study of the infectome.

Systemic lupus erythematosus (SLE) is often characterised by a prodromal stage of antibody positivity (predominantly anti-Sm and anti-Ro) with no symptomatology [101, 102] . A recent study has also found that a significant proportion of first degree relatives of SLE patients are positive for several autoantibodies, namely ANA (mostly anti-dsDNA), anti-Ro/SSA, and many other specificities [103] [104] [105] . In fact, ANA titre ≥ 1:160, anti-dsDNA, anti-Ro/SSA and anti-chromatin may have a high predictive value for SLE diagnosis [103] . The reasons underlying the development of and/or the progression to clinical disease, as well as the mechanisms underlying disease flares, remain elusive [19] . However, several infectious agents have been implicated including EBV, cytomegalovirus (CMV) and parvovirus B19 [48, 101, 102, [104] [105] [106] [107] [108] [109] [110] . These features make SLE an ideal model for the [353, [356] [357] [358] [359] [360] [361] [362] infectome, given the strong evidence for an infectious trigger, in addition to its unpredictable clinical course. EBV appears to have an association with SLE, with variations and susceptibility based on demographical and genetic characteristics [111] . Harley and colleagues [101] propose a progression of EBV infection followed by Epstein-Barr virus nuclear antigen 1 (EBNA-1) antibody production, which predisposes to the development of cross-reactive autoantibodies, with progression to clinical SLE. Harley and James [102] indicated that the first lupus specific antibodies are directed against EBNA-1, which interestingly also binds lupus specific antigens such as Sm and Ro. As with many implicated viruses, the exact mechanisms in which they induce autoimmunity are not yet clear. However, one group which has indicated molecular mimicry as a mechanism with regard to EBV and SLE, notes similarities between the EBV peptide PPPGRRP and the PPPGMRPP peptide of Sm [109] . That same group tested 196 ANA positive adult SLE patients, and two age, race, and sex matched controls per patient, for evidence of previous infection with EBV, CMV, herpes simplex virus-1 (HSV-1), HSV-2, and varicella zoster virus (VZV) by ELISA [109] . Among the SLE patients, 195 out of 196 had previous EBV infection compared to 370 controls [109] . No differences were found in regard to the rate of infection with other viruses [109] . A study by Wang et al. [112] found that the EBV-encoded latent membrane protein 2A induced a heightened sensitivity to toll-like receptor (TLR) ligand stimulation, which increased proliferation of anti-Sm B-cells, and/or increased antibody secreting cell differentiation.

Parvovirus B19 has also been found to be associated with SLE, although the evidence is not as clear cut as that of EBV. The group of Bengtsson [106] tested 99 SLE patients and 99 age and sex matched controls for parvovirus IgG antibodies. No evidence of parvovirus B19 was found in SLE compared to controls, and in one analysis, the controls had a higher positivity than the SLE group [106] . As the symptoms of SLE and parvovirus B19 infection may be similar, a prospective study involving 42 patients with acute parvovirus B19 infection attempted to determine whether the symptoms persisted, and whether infection contributed to the development of SLE [110] . Clinical and laboratory investigations were performed at 1, 2, 6, 12, and 24 months from initial infection. Arthralgias persisted for 2-6 months in three female patients, for greater than two years in one female, but resolved in the remaining cases within 2 weeks [110] . One female with persistent arthralgia over two years was ANA positive and had hypercomplementaemia, but did not fulfil the diagnostic criteria for SLE or RA [110] . Despite the lack of evidence linking parvovirus B19 to the induction of SLE, one case report of a 26 year old female with SLE, who had a disease flare-up following parvovirus B19 infection, suggests that parvovirus B19 causes disease flares in SLE patients [107] .

As with parvovirus B19, the evidence linking CMV to SLE is scarce. Hrycek and colleagues found that 100% of female SLE patients have evidence of CMV infection, compared to 75% of controls [108] . As well, another study had found that the CMV pp65 antigen triggers humoral immunity in SLE patients and autoimmune prone mice [113] . The lack of evidence linking particular viruses to SLE does not infer non-involvement, but reflects the difficulty of detecting infectious organisms, which may be transient, in these patients. It is likely that diagnosis of SLE and/or SLE flares occurs after an infection. The infectome serves as a model in such cases. At-risk patients, such as first degree relatives of SLE patients, who are found to be positive for autoantibodies, may be screened at regular intervals. Likewise, SLE patients may be screened, and changes in clinical course, such as flares, may be correlated with infection. Several other diseases with a well defined connection such as that of H. pylori-induced idiopathic thrombocytopenic purpura could be explored. These methods are useful in that they not only indicate the who and when, but also provide a more narrowed-down list of organisms to evaluate in regard to the mechanism in which they induce autoimmunity.

Multiple sclerosis (MS) serves as another example in which the infectome model may be applied. MS is a chronic autoimmune neurological syndrome characterised by chronic inflammation, demyelination and gliosis in the central nervous system (CNS) [114, 115] . It is characterised by periods of relapse and remission [114, 115] , the reasons for which are not understood. Current evidence suggests that the risk for acquiring MS is spread over a long period of time, and is not limited to childhood or early adult life [116] [117] [118] .

The most prevalent form of the syndrome is the so called relapsingremitting MS, characterised by flares whereby pre-existing symptoms become more severe, or new symptoms develop [119] . These flares are followed by phases of complete or partial recovery and their duration is highly variably among affected individuals. A considerable proportion of these patients acquire progressive disability with or without disease relapses (secondary progressive MS). Another form of MS is characterised by a stable progression of the disease with worsening of the symptomatology over the course of the disease. This form is also known as primary progressive MS (PPMS). Two further forms of the disease are also found with totally contradictory outcomes. The benign form of MS usually presents with minimal or mild progression of disability, and is clinically characterised by full recovery of sporadic sensory episodes [119] . On the other hand, the Marburg variant of MS is characterised by rapidly progressive disease which leads to accumulating disability and eventually to death. The mechanisms responsible for the development of clinically distinct disease phenotypes are poorly understood [119] .

The pathological hallmark of MS is inflammatory lesions (areas of demyelination) in the CNS composed of mononuclear cell infiltrates in the perivascular spaces that develop into plaques [114, 120] . These mononuclear cells are largely composed of T and B lymphocytes, plasma cells, macrophages and microglia [114, 120] . Positive staining for IgG is found in the peripheral regions of the plaques [114, 120] . Additionally, approximately 90% of MS patients show intrathecal IgG synthesis in the cerebrospinal fluid (CSF) [114] .

Environmental and genetic components are clearly involved in the aetiology of MS, with geographical and twin data indicating a greater environmental component [114, 115, 121, 122] . However, identical twins are 100 times more likely to develop MS if their co-twin is affected, whereas non-twin siblings are 20 times more likely [123, 124] . Genetic and GWAS have implicated several alleles, with the strongest association being with HLA-DRB1*1501 [125] . Seven GWAS studies have been conducted, which included nearly 10,000 MS patients and 15,000 controls [115] . Implicated genes include IL7R, IL12RA, CLEC16, and CD226 [126, 127] . Nonetheless, implicated genes have only demonstrated an odds ratio of less than 1.3 [115] , and MS twins only demonstrate a 30% concordance [114] , indicating more of an environmental influence in the disease pathogenesis.

Non-infectious and infectious components have been implicated to be involved in the development of MS. Within the group of non-infectious agents, vitamin D is of particular interest, not only in MS but also in several other autoimmune diseases [115, [128] [129] [130] [131] [132] [133] [134] [135] [136] [137] [138] [139] [140] . Vitamin D appears to play a role in the modulation of pro-inflammatory pathways and T cell regulation [115] . Increased distance from the equator has been correlated with low vitamin D, and interestingly, MS rates increase as distance from the equator increases [114] . As well, populations with increased dietary vitamin D intake have lower rates of MS [115] . An Australian study found a decreased risk of a first demyelinating event in those with increased sun exposure, who also had increased levels of serum vitamin D [141] . This has also been found in other studies [142] . As well, the effect of month of birth on MS development was more apparent in familial MS groupings, suggesting an influence on prenatal vitamin D levels, as well as an interaction between genes and environment [115] . Like many conditions, smoking has also been associated with MS development, and a recent meta-analysis overwhelmingly associated smoking with MS [143] . Gene-environment interactions have been suggested in regard to smoking and the presence of HLA-DRB1*15 with the absence of HLA-A*02 [144] . Smokers with this genetic combination appeared to have an increased risk of developing MS [144] . Whether this is due to the effect of the nitrosamines or the heavy metals in cigarette smoke is not clear. There is limited evidence for the role of heavy metals in some patients with MS [145] . Infectious agents investigated in regard to MS have included bacteria and viruses (Table 3 ) [114, 115, 121, 122, 146, 147] , and implicated viruses include EBV [114, 115, 121, 122] and human herpes virus 6 (HHV6). The relapseremittance pattern of the human herpes virus 6 (HHV6) is similar to the clinical pattern of MS [115] and HHV6 reservoirs have been found in CNS tissue [148, 149] , in addition to the CSF and serum of MS patients [150, 151] . Molecular mimicry has been indicated, as sequence homology has been found between myelin basic protein and HHV6 encoded U24, and cross-reactive T cells responding to both protein types are found to be elevated in MS patients [152] . Varicella zoster virus, torque teno virus, retroviruses, coronaviruses and JC virus have also been implicated, but with limited evidence [114, 115, 121, 122] . Reactivity to several viral peptides was found [153] , which has led to the speculation that continual exposure to a variety of viruses can lead to T cell expansion reactive against highly conserved proteins, including self-peptides.

An infectome for the above conditions (and others) may clarify questions regarding aetiology, but may also identify the cause of certain disease characteristics, such as variable presentation and progression among PBC patients, disease flares in patients with SLE, or relapse-remittance among MS patients. As such, these conditions serve as models for an infectomal analysis.

PBC can be used as a model disease to investigate the role of the exposome, and indeed of the infectome [154] , as A) it is an autoimmune disease and it is not as rare as many other such diseases, B) it has a long silent phase in which well-established biomarkers can be determined in high-risk populations, C) it presents with subgroups of patients who have differing disease progressions and/or concomitant other autoimmune diseases, D) it is not treated with immunosuppessive drugs that might deteriorate the immunological assessment of the infectome, and E) there is growing evidence in support of genetic, environmental, and infectious factors involved in the pathogenesis of the disease such as recurrent urinary tract infection (UTI), cigarette smoke, and oestrogen deficiency [155] [156] [157] [158] [159] [160] [161] [162] [163] . A plethora of experimental and clinical data clearly indicate that the disease is indeed autoimmune in nature [98, 159, . Infectious agents and xenobiotics mimicking or modifying the core epitopic region of PDC-E2, the major autoantigen in PBC, appear to induce immunemediated destruction of the bile ducts. As PBC affects the liver, access to the affected organ for research purposes is possible at the time of diagnosis via liver biopsy, and over the course of the disease from early to advanced stages. This is not possible in diseases such as diabetes mellitus type I.

In line with the already discussed ideal situation of a long prodromal period, PBC has a long pre-clinical phase, characterised by an asymptomatic period with evidence of autoimmune markers in the form of autoantibodies, followed by biochemical evidence of liver damage and finally clinically-evident disease. The progression from asymptomatic to symptomatic PBC may take years or decades. Virtually, all patients with PBC have high-titre anti-mitochondrial antibodies (AMA) at the time of diagnosis [99, 175, . Also, the presence of AMA is predictive of eventual disease development [211] . PBC patients with disease-specific anti-nuclear autoantibodies (ANA) appear to have more advanced disease and poorer prognosis [212] [213] [214] [215] [216] [217] [218] [219] [220] [221] [222] [223] [224] [225] [226] [227] . Individuals at the highest risk of developing PBC are family members of PBC patients. [228] [229] [230] [231] [232] [233] [234] . The vast majority of patients with PBC experience concomitant autoimmune diseases such as Sicca syndrome, autoimmune thyroiditis, rheumatoid arthritis, autoimmune hepatitis and systemic sclerosis. The reasons behind the fast pace of progression seen in some patients with PBC are unknown, and attempts to predefine those individuals which will progress faster than others have been largely unsuccessful.

PBC does not appear to respond to immunosuppressive treatment, making the disease perfect to study the involvement of infectious agents over the course of the disease without the need to consider the effects of immunosuppressive therapy on relapse/remission states. PBC patients are instead treated with ursodeoxycholic acid (UDCA) at adequate doses of 13-15 mg/kg/day [235, 236] . It is not clear as to whether UDCA has immunomodulatory properties or not.

A number of environmental factors have been implicated in PBC by 'bottom-up' approaches in various epidemiological studies examining associated risk factors [155] [156] [157] [158] including numerous xenobiotics and infectious agents [159] [160] [161] [162] 237] . Animal models have further supported this notion [159, [238] [239] [240] [241] [242] . The genetics of PBC appear to include HLA [243, 244] , non-HLA [245] [246] [247] [248] [249] [250] [251] and sex-linked Saccharomyces cerevisiae [420] genes [252] [253] [254] . Particular allelic associations may be indirectly relevant to the pathogenesis of the disease, as they may influence the penetrance of infectious agents. For example HLA-DRB1*11 and HLA-DRB1*13 have a negative association with PBC, and are protective for several viruses that affect the liver, such as hepatitis B and C. The lack of HLA alleles protective for PBC, which are associated with resistance to specific pathogens, may lead to susceptibility to infection responsible for the induction of the disease [244, 255] . These findings underline the urgent need to investigate the infectome in parallel with GWAS. An infection burden involving EBV, CMV and Toxoplasma has been recently reported in patients with PBC. However, the list of pathogens involved in PBC is vast, with some such as Escherichia coli, having a relatively strong evidence base (Table 2) [164, 182, 252, . Molecular mimicry has been considered a likely mechanism that could account for the initiation of liver autoimmune diseases, including PBC [164, 182, [256] [257] [258] [259] [260] 264, 274, 275, [279] [280] [281] [282] [283] [284] [285] .

Much as the exposome reflects the collation of all exposures, an infectome may reflect all those bacterial, viral, or parasitic exposures which may contribute to the development of an autoimmune disease.

The study of the infectome needs to be customised taking into account the disease to be investigated. The type of the sample to be collected largely depends on the disease under investigation.

A generic, step-wise approach of infectome analysis at presentation would be the following:

under investigation. Ideally, this could be performed at birth, or at the baseline when the individual/patient presents for the first time in the clinic. This information is important in order to sub-group the individual into high or low risk. 2) Collect urine, oro-nasal swabs, saliva, faecal material, and blood (for isolation of plasma, serum, and peripheral blood mononuclear cells -PBMCs). 3) Regular follow-up (once yearly) with collection of samples; 4) Meticulous recording of clinical data and collection of samples are needed when anti-infective treatment is applied for incidental/casual infections at the pre-clinical stages of the disease, as this may affect the final outcome of the underlying processes. 5) Store samples until patient has laboratory and/or clinical features related to the disease; 6) Analysis of collected samples for infectious agents with a known association with the disease, and "out of the box" analysis using multiplex technology for other infectious agents (see section "How to screen?" below). The analysis will provide information regarding the infection burdens at various-time points; 7) Associations are analysed, providing evidence for known/unknown infectious agents in the development of symptomatic disease. 8) Continuous analysis over the course of the disease, as it may reveal a close link between a specific agent and the clinical phenotypes of the disease.

The study of the role of infectious agents in the development of an autoimmune disease, whether RA, SLE, MS or PBC, may reveal which agents are involved in the development of the disease as well as other concomitant autoimmune diseases. It is likely that the combination of particular genes and particular infectious exposures is responsible for the development of an autoimmune disease, with or without a particular concomitant autoimmune disease. In other words, there may be several infectomes for SLE, some of which define SLE with a particular concomitant autoimmune disease. This of course applies to other autoimmune diseases.

The recently described microbiome concept can be separated from that of the infectome. The microbiome defines the collection of microbial genes in a particular region, such as the gut, inguinal crease, oral cavity, or virtually any body site [286] [287] [288] [289] [290] [291] [292] [293] [294] [295] . The microbiome may be reflective of the normal or pathological profile of organisms. For example, the microbiome of the gut has been analysed in healthy individuals [288] [289] [290] [291] 294] , which identified three distinct profiles or clusters, known as enterotypes [287, 293] . Similar studies have been performed for the oral cavity as well [286, 295] . The microbiome may also be applied to a disease-affected body site, such as the gastrointestinal tract in children with irritable bowel syndrome (IBS) [292] . A study by Saulnier and colleagues [292] obtained 71 faecal samples from 22 children with IBS and 22 healthy children, all aged 7-12 years. These samples were analysed by 16S rRNA gene sequencing, which showed an elevated percentage of γ-proteobacteria in the gut flora of children with IBS, with Haemophilus parainfluenza being a prominent component [292] .

So how does the infectome differ from this? First, the infectome relates to those infectious organisms which are associated with the disease in question, as opposed to a totality of all organisms, both pathological and non-pathological within the human microbiome. Second, the infectome reflects all sites of infection, as opposed to one body site usually represented by the microbiome. As well, microbiome studies to date have largely concentrated on bacterial species, whereas the infectome takes into account all pathological bacteria, viruses, parasites, and fungi. The infectome is not limited to the affected site or organ but includes biological fluids as well as sampling of various body-sites including the oral cavity. Some argue that the organisms of the human microbiome do not usually induce antigen specific systemic humoral and cellular immune responses provoking local or systemic inflammatory response, while others believe that these organisms may not be directly pathogenic, but create a dysbiosis of the gut flora and participate in the induction of autoimmunity. This is a key difference between the microbiome and the infectome as the former appreciates the direct or indirect effect of immune responses against infectious agents as pivotal for the initiation of autoaggression and immune-mediated, self-targeting pathology. For the infectome, monitoring of the microbial/host immunity is as important as the isolation of potentially harmful bacterial products, since the host/ microbe immunological interaction is the likely cause of the selfdestruction in the case of non-cytopathic viruses and microbes.

Although the infectome and microbiome are distinct entities, they may be used symbiotically to provide a micropathological profile (or profiles) of a particular disease. As well, the microbiome is essential to define what "normal" actually is. Recent microbiome studies have been able to provide an idea of what "normal" may be in the gut by performing metagenomic screens of bacterial populations in these regions [288] [289] [290] [291] 294] . For example, in the case of PBC it may be pertinent to understand the normal microbiome of the urinary bladder and vagina, as infections in these sites have been associated with PBC [155] [156] [157] [158] 296, 297] . Other body sites may also need investigation, as inhalation or consumption of potentially pathogenic organisms has also been implicated [275, 298] . All associated organisms located in all potential body-sites, would comprise the infectome. The establishment of what is normal as well as infectious may contribute to the understanding of the network of events or exposures which lead to disease development. It is possible that a series of exposures leads to increased susceptibility to further exposures, which could be defined by the infectomal model.

Unlike GWAS and the microbiome, it is unlikely that population screening of infectomal components could be performed due to the lack of integrated analysis platforms. It may be more reasonable to screen particular groups of individuals who are at risk of developing autoimmune disease, like family members or individuals with an HLA profile conferring risk for a given disease. Further monitoring may reveal whether additional infections play a role in the progression of the disease to a symptomatic stage. Additionally, particular exposome/infectome profiles may be found among patients with rapidly progressive diseases (as in a subset of PBC patients), or in relapse remittance states in MS, and flares in SLE. This approach may delineate which infectious agents are responsible for disease development and/or progression, as well as identifying those that are associated with rapid versus slow progression, remittance, and flares.

The establishment of the infectome would have to rely on the detection of microbiological materials in patients, favourably in ease-to-sample material like blood, urine or saliva. There are several methods by which this may be done, and some of those have already been used for research purposes. Serological detection of IgM, IgA and IgG antibody responses to microbes, viruses, and fungi is likely to be the most common, fastest, and most cost effective method and independent of the actual presence of a respective infectious agent. Monitoring for seroconversion of antibody responses and isotype class switching from IgM to IgG is imperative for the identification of newly acquired infectious triggers over time. To this end, the part of the immunome which relates to infections is an integral part of the infectome and its primary goal to identify microbial triggers of autoimmunity. Immunoassays for the determination of antibodies against most of them, e.g. ELISA, are broadly available, have a high degree of robustness and standardisation and are comparably cheap. Furthermore in some diagnostic scenarios, multi-parametric immunoassays, e.g. lineblots for the detection of antibodies against tick-borne diseases exist that facilitate the determination of antibodies against several or even multiple entities at the same time with a limited amount of sample. The highest complexity up-to-date can be reached by using protein microarrays that allow for the screening of several thousand antibody entities at the same time [299, 300] . However, such platforms have so far only been used to screen for immune profiles of individuals, and small numbers of similar infectious agents and commercial solutions with a similar degree of standardisation as those containing human proteins are not available. A major breakthrough might result from the development of high-density peptidome libraries of relevant microbes and viruses similar to the concepts of peptidome libraries covering human proteins, e.g. T7-Pep library for the human peptidome [301] .

A large German study used a PCR approach to detect a variety of organisms in archived liver tissues of PBC patients [302] . This approach has also been adopted in several other studies examining the role of mycobacteria in PBC [303] [304] [305] , as well as in another group which used this method to detect beta-retroviral material in the liver and lymph node tissue from PBC patients [276, 277] . Similar studies have been conducted in other autoimmune diseases. Multi-parametric detection of viral and bacterial genetic material in tissues may be another promising approach. In recent years, DNA sequencing technology has undergone an outstanding upgrade, and the so-called 'high-throughput DNA sequencers' can determine hundreds of megabases of DNA sequences per run, enabling the analysis of a broad range of infectious agents [306] [307] [308] [309] . Massive, parallel sequencing might be the next step of this approach for that it is the most sensitive procedure available and allows for the detection of a multitude of infectious agents at the same time [310] . However, the considerable costs of this testing limit its wide use. Immunohistochemistry detecting several microbial agents in tissue samples can be applied [311] , though it is likely that tissue based methods are not ideal in the establishment of the infectome, as they are time consuming, and tissue of the affected organ may not be readily available from all patients. The analysis of blood, faecal material, urine, or saliva is more plausible, and can be used for screening, reflecting the 'top-down' approach suggested by other researchers [35] . As mentioned, multiplex PCR is a useful tool for evaluating the presence of microorganisms from a variety of sample types. Microbiome studies have also highlighted the use of 16S/18S rRNA gene sequencing, which allows for the mass-analysis of samples [290, 292] . However, one drawback of this approach in comparison to immune profiles is the risk of missing the right time or site of sampling.

11. Where to screen?

The question also remains as to which body sites should be sampled. In addition to the affected organ, general or systemic infections should be an indication for sampling. This may include urine and stool samples in urinary and gastrointestinal tract infections respectively, or blood cultures in febrile patients. In addition to clinically overt infections, many patients with autoimmunity may have latent infections such as Lyme disease or Mycoplasma. Examples of this include hidden chronic low grade infection associated with dental treatments. In fact, the oral cavity is not commonly examined for infection in patients with autoimmune disease, and it would most likely be useful to examine and sample the oral cavity for such overt infections [312] [313] [314] . Accumulating evidence indicates that oral hygiene practices may induce alterations in the flora of the oral mucosa, which leads to a dysbiosis in the gut microbiome, and thereby contributes to the pathogenesis of IBD [312] . On the other hand, the increased frequency of dental problems in IBD patients may be due to alterations in oral flora. Complementing these findings, a study by the group of Helenius [314] indicates that patients with rheumatic conditions had various alterations in salivary flow and composition, and oral health. It remains to be seen whether the increased incidence of bacterial infections is common among all autoimmune diseases, and if so, which oral microorganisms are common among those conditions.

The proposed model of screening is not only useful in characterising the components which lead to autoimmune disease development/ progression, but may also provide further evidence as to preventative measures. For example, if it is demonstrated that progression of an autoimmune disease is dependent upon infectious triggers, the proper use of antibiotic or even antiviral therapy may be initiated early on in the management of these patients. Antibiotic treatment for infectious agents associated with autoimmune disease may slow the progression of the disease in some individuals, and possibly prevent the development of the disease in individuals found to be at risk. If exposure to a particular microbe is proven to be critical in a particular autoimmune disease development, measures may be taken to reduce the exposure to this microbe, regardless of whether it is exogenous or endogenous. Such treatments can only be incorporated in the routine management of these diseases through consensus statements and authoritative position papers/guidelines; otherwise are potentially dangerous for the wellbeing of the patient [272, 276, 277, 315] .

Genetic and environmental components are involved in the pathogenesis of most diseases. The GWAS have contributed greatly to the understanding of the genetic basis of disease. The theory of the exposome complementing GWAS is now evolving. The complexity of the exposome may require that it be broken down to several subcomponents such as the infectome, which reflects the characterisation and measurement of all infectious organisms that we are exposed to. The relationship of the exposome/infectome to the development of a disease, in individuals with particular genetic characteristics, may also help us characterise disease initiation and progression.

Given the growing knowledge of the genetic basis of disease, it may one day be possible to screen newborns for HLA and genetic characteristics which infer susceptibility to autoimmune disease, which may be done as routinely as the current newborn screening. Infants with a particular susceptibility profile can then be monitored closely for exposure to environmental triggers that may contribute to the development of a particular autoimmune disease. It is therefore essential that we establish not only the genetic basis of the disease (via GWAS), but also the environmental component of the disease, which must be established through an exposomal model. The covalent binding of xenobiotics to genomic DNA has been extensively explored and should be re-visited in this context in the light of more recent findings. As there is a clear delineation between organic and inorganic materials, the establishment of the infectome will represent the infectious component, comprised of all potential infections that initiate the disease, or alter the disease course. It is important that the subgroups of the exposome are considered together alongside the detailed investigation of each component part. It is likely that the methods used to establish and analyse the infectome will be simple modifications of technology already in use. It remains to be seen how this approach may be applied to other potential subgroups of the exposome, such as xenobiotics.

• The infectious/host immunological interactions in autoimmunity are poorly understood. • A direct link between infection and autoimmunity is difficult to obtain. • Infectome refers to the collection of an individual's exposures to infectious agents. • Infectome can be characterised with approaches employed for the "immunome" and "microbiome" projects. • The study of the infectome can help us to delineate the triggers of autoimmunity.

Mechanisms of disease: environmental factors in the pathogenesis of rheumatic disease

Autoimmune diseases: insights from genome-wide association studies

Environment and disease risks

Infections and autoimmunityfriends or foes?

Epidemiology and estimated population burden of selected autoimmune diseases in the United States

Autoimmunity: from the mosaic to the kaleidoscope

The mosaic of autoimmunity

The mosaic of autoimmunity. A classical case of inhalation of a polyclonal activating factor in a genetically and hormonally susceptible patient leading to multiple autoimmune diseases

Prediction and prevention of autoimmune diseases: additional aspects of the mosaic of autoimmunity

The mosaic of autoimmunity: prediction, autoantibodies, and therapy in autoimmune diseases-2008

The mosaic of autoimmunity: genetic factors involved in autoimmune diseases-2008

Multiple autoimmune diseases in a young woman: tuberculosis and splenectomy as possible triggering factors? Another example of the "mosaic" of autoimmunity

The mosaic of autoimmunity: the role of environmental factors

Genes, epigenetic regulation and environmental factors: which is the most relevant in developing autoimmune diseases

p38 mitogen-activated protein kinase (p38 MAPK)-mediated autoimmunity: lessons to learn from ANCA vasculitis and pemphigus vulgaris

Environmental and gene-environment interactions and risk of rheumatoid arthritis

The circulatory systemic environment as a modulator of neurogenesis and brain aging

Combined effects of smoking, anti-EBNA antibodies, and HLA-DRB1*1501 on multiple sclerosis risk

Emerging and critical issues in the pathogenesis of lupus

Mechanisms of environmental influence on human autoimmunity: a national institute of environmental health sciences expert panel workshop

A study of molecular mimicry and immunological cross-reactivity between hepatitis B surface antigen and myelin mimics

Smoking as a risk factor for autoimmune liver disease: what we can learn from primary biliary cirrhosis

Adjuvants and autoimmunity

Chronic fatigue syndrome with autoantibodies-the result of an augmented adjuvant effect of hepatitis-B vaccine and silicone implant

Vaccination in patients with chronic or autoimmune rheumatic diseases: the ego, the id and the superego

The common immunogenic etiology of chronic fatigue syndrome: from infections to vaccines via adjuvants to the ASIA syndrome

ASIA' -autoimmune/inflammatory syndrome induced by adjuvants

The spectrum of ASIA: 'Autoimmune (Auto-inflammatory) Syndrome induced by Adjuvants

Adjuvant immunization induces high levels of pathogenic antiphospholipid antibodies in genetically prone mice: another facet of the ASIA syndrome

Autoimmune syndrome induced by adjuvants (ASIA) in the Middle East: morphea following silicone implantation

Autoimmunity following hepatitis B vaccine as part of the spectrum of 'Autoimmune (Auto-inflammatory) Syndrome induced by Adjuvants' (ASIA): analysis of 93 cases

When APS (Hughes syndrome) met the autoimmune/inflammatory syndrome induced by adjuvants (ASIA)

EMS-sponsored workshop on biomarkers of exposure and oxidative DNA damage & 7th GUM-32P-postlabelling workshop

Observing the human exposome as reflected in breath biomarkers: heat map data interpretation for environmental and intelligence research

Implications of the exposome for exposure science

Complementing the genome with an "exposome": the outstanding challenge of environmental exposure measurement in molecular epidemiology

Environmental exposure measurement in cancer epidemiology

Benzene, the exposome and future investigations of leukemia etiology

IgG glycan hydrolysis by a bacterial enzyme as a therapy against autoimmune conditions

Human IgG/Fc gamma R interactions are modulated by streptococcal IgG glycan hydrolysis

Glycosylation of IgG during potentially arthritogenic lentiviral infections

Discovering mercury protein modifications in whole proteomes using natural isotope distributions observed in liquid chromatography-tandem mass spectrometry

The detection of DNA adducts (risk factors for DNA damage). A method for genomic DNA, the results and some effects of nutritional intervention

An Environment-Wide Association Study (EWAS) on type 2 diabetes mellitus

Immunological aspects of nutritional diabetes prevention in NOD mice: a pilot study for the cow's milk-based IDDM prevention trial

Antibody cross-reactivity between myelin oligodendrocyte glycoprotein and the milk protein butyrophilin in multiple sclerosis

Infection, vaccines and other environmental triggers of autoimmunity

Infections and autoimmunity: a panorama

Infections, rheumatism and autoimmunity: the conflicting relationship between humans and their environment

Infections and autoimmune thyroid diseases: parallel detection of antibodies against pathogens with proteomic technology

Role of secretory IgA in infection and maintenance of homeostasis

Silica, apoptosis, and autoimmunity

Dysregulation of autoimmunity caused by silica exposure and alteration of Fas-mediated apoptosis in T lymphocytes derived from silicosis patients

Occupational and environmental exposures and risk of systemic lupus erythematosus: silica, sunlight, solvents

Occupational silica and solvent exposures and risk of systemic lupus erythematosus in urban women

Occupational exposures and risk of systemic lupus erythematosus: a review of the evidence and exposure assessment methods in population-and clinic-based studies

CD4(+) T-cell activation and induction of autoimmune hepatitis following trichloroethylene treatment in MRL+/+ mice

Trichloroetheneinduced autoimmune response in female MRL +/+ mice

Environmental factors and thyroid autoimmunity

Insecticide use and risk of rheumatoid arthritis and systemic lupus erythematosus in the Women's Health Initiative Observational Study

Are residential insecticides exposure the missing link?

Environmental triggers of autoimmune thyroiditis

Systemic autoimmune disease mortality and occupational exposures

Acceleration of autoimmunity by organochlorine pesticides in (NZB × NZW)F1 mice

Epidemiologic studies of environmental agents and systemic autoimmune diseases

Influence of UV radiation on immunological system and occurrence of autoimmune diseases

UV radiation, vitamin D, and multiple sclerosis

The geoepidemiology of autoimmune muscle disease

Photosensitivity in lupus erythematosus

Immune haemolytic anaemia induced by allopurinol after liver transplantation

Autoimmune thrombocytopenia in three patients treated with captopril

Characteristics of human immunodeficiency virus and chlorpromazine induced antiphospholipid antibodies: effect of beta 2 glycoprotein I on binding to phospholipid

Chlorpromazine-induced anticardiolipin antibodies and lupus anticoagulant: absence of thrombosis

Hemolytic anemia associated with chlorpromazine therapy

Letter: Coombs-positive haemolytic anaemia provoked by chlorpromazine

Chlorpromazine-induced antinuclear factors

Immune-mediated drug-induced liver disease

Drug-induced lupus

Drug-induced autoimmune-like hepatitis

The role of environmental estrogens and autoimmunity

Serum markers of infections in patients with primary biliary cirrhosis: evidence of infection burden

Defining and analyzing geoepidemiology and human autoimmunity

Autoantibodies in nonautoimmune individuals during infections

Gut pharmacomicrobiomics: the tip of an iceberg of complex interactions between drugs and gut-associated microbes

Functions of intestinal microflora in children

Zinc competition among the intestinal microbiota

Silicone and scleroderma revisited

Protective autoantibodies: role in homeostasis, clinical importance, and therapeutic potential

Predictive and protective autoimmunity in cardiovascular diseases: is vaccination therapy a reality?

The putative protective role of hepatitis B virus (HBV) infection from autoimmune disorders

Predictive, protective, orphan autoantibodies: the example of anti-phospholipid antibodies

Infections may have a protective role in the etiopathogenesis of celiac disease

T-cell reactivity against streptococcal antigens in the periphery mirrors reactivity of heart-infiltrating T lymphocytes in rheumatic heart disease patients

Molecular mimicry between Helicobacter pylori antigens and H+, K+-adenosine triphosphatase in human gastric autoimmunity

Autoimmunity in Chagas' disease. Identification of cardiac myosin-B13 Trypanosoma cruzi protein crossreactive T cell clones in heart lesions of a chronic Chagas' cardiomyopathy patient

Mycoplasmal lipid-associated membrane proteins and Mycoplasma arthritidis mitogen recognition by serum antibodies from patients with rheumatoid arthritis

Are autoimmune diseases predictable

Pathogenesis of primary biliary cirrhosis

Primary biliary cirrhosis

Development of autoantibodies before the clinical onset of systemic lupus erythematosus

The curiously suspicious: a role for Epstein-Barr virus in lupus

Epstein-Barr virus infection induces lupus autoimmunity

Studies of Filipino patients with systemic lupus erythematosus: autoantibody profile of first-degree relatives

Exposure to Epstein-Barr virus infection is associated with mild systemic lupus erythematosus disease

Epstein-Barr virus and cytomegalovirus in autoimmune diseases: are they truly notorious? A preliminary report

No serological indications that systemic lupus erythematosus is linked with exposure to human parvovirus B19

Acute parvovirus B19 infection in connection with a flare of systemic lupus erythematodes in a female patient

Human cytomegalovirus in patients with systemic lupus erythematosus

Systemic lupus erythematosus in adults is associated with previous Epstein-Barr virus exposure

Two-year follow-up study after human parvovirus B19 infection

Association of Epstein-Barr virus with systemic lupus erythematosus: effect modification by race, age, and cytotoxic T lymphocyte-associated antigen 4 genotype

EBV latent membrane protein 2A induces autoreactive B cell activation and TLR hypersensitivity

Human cytomegalovirus pp 65 lower matrix protein: a humoral immunogen for systemic lupus erythematosus patients and autoantibody accelerator for NZB/W F1 mice

Infectious causes of multiple sclerosis

Environmental triggers of multiple sclerosis

The age-range of risk of developing multiple sclerosis: evidence from a migrant population in Australia

Multiple sclerosis in North African migrants to France

Multiple sclerosis in the Faroe Islands: I. Clinical and epidemiological features

Multiple sclerosis

Multiple sclerosis-the plaque and its pathogenesis

Infectious causes of multiple sclerosis

Multiple sclerosis: the environment and causation

A genetic basis for familial aggregation in multiple sclerosis. Canadian Collaborative Study Group

Evidence for genetic basis of multiple sclerosis. The Canadian Collaborative Study Group

Heterogeneity at the HLA-DRB1 locus and risk for multiple sclerosis

Risk alleles for multiple sclerosis identified by a genomewide study

The type I diabetes association of the IL2RA locus

Vitamin D and autoimmunity: new aetiological and therapeutic considerations

Anti-vitamin D, vitamin D in SLE: preliminary results

The effect of melanism and vitamin D synthesis on the incidence of autoimmune disease

Mycobacterium tuberculosis, autoimmunity, and vitamin D

Serum concentrations of 25-OH vitamin D in patients with systemic lupus erythematosus (SLE) are inversely related to disease activity: is it time to routinely supplement patients with SLE with vitamin D?

The role of vitamin D in regulating immune responses

Vitamin D and musculoskeletal health, cardiovascular disease, autoimmunity and cancer: recommendations for clinical practice

Vitamin D: an instrumental factor in the anti-phospholipid syndrome by inhibition of tissue factor expression

Vitamin D insufficiency in a sunny environment: a demographic and seasonal analysis

Vitamin D and autoimmune thyroid diseases

The clinical significance of 25OH-Vitamin D status in celiac disease

Vitamin D insufficiency in a large MCTD population

Vitamin D endocrine system involvement in autoimmune rheumatic diseases

Sun exposure and vitamin D are independent risk factors for CNS demyelination

Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis

Smoking and multiple sclerosis: an updated meta-analysis

Smoking and two human leukocyte antigen genes interact to increase the risk for multiple sclerosis

Diagnosis and treatment of metal-induced side-effects

Helminths and multiple sclerosis: will old friends give us new treatments for MS?

Can infections protect against autoimmunity?

The effect of human herpesvirus-6 (HHV-6) on cultured human neural cells: oligodendrocytes and microglia

Detection of human herpesviruses 6 and 7 genomic sequences in brain tumours

Detection of human herpesvirus 6 variant A in peripheral blood mononuclear cells from multiple sclerosis patients

Early and late HHV-6 gene transcripts in multiple sclerosis lesions and normal appearing white matter

Absence of human herpesvirus 6 and 7 from spinal fluid and serum of multiple sclerosis patients

Recognition of conserved amino acid motifs of common viruses and its role in autoimmunity

What is new in primary biliary cirrhosis

Demographic, lifestyle, medical and familial factors associated with primary biliary cirrhosis

Risk factors and comorbidities in primary biliary cirrhosis: a controlled interview-based study of 1032 patients

Risk factors for primary biliary cirrhosis in a cohort of patients from the united states

Case-control studies of risk factors for primary biliary cirrhosis in two United Kingdom populations

Update on primary biliary cirrhosis

Genetics and geoepidemiology of primary biliary cirrhosis: following the footprints to disease etiology

Genes and (auto)immunity in primary biliary cirrhosis

Primary biliary cirrhosis: family stories

Twin studies in autoimmune disease: genetics, gender and environment

The causes of primary biliary cirrhosis: convenient and inconvenient truths

Primary biliary cirrhosis: lymphocyte subsets and function in a time frame

Complement profile in primary biliary cirrhosis

Primary biliary cirrhosis and autoimmune rheumatic diseases: prediction and prevention

Primary biliary cirrhosis is a multisystem disorder

Primary biliary cirrhosis: increasing problem, approaching solution

The complement system and primary biliary cirrhosis

Primary biliary cirrhosis-association or overlap with other autoimmune diseases

Is it possible to predict and prevent primary biliary cirrhosis?

IL-2 receptor alpha deficiency and features of primary biliary cirrhosis

Serum inflammatory cytokines, complement components, and soluble interleukin 2 receptor in primary biliary cirrhosis

Antimitochondrial and other autoantibodies

The role of E. coli infection in the pathogenesis of primary biliary cirrhosis

Origin of cross-reactive autoimmunity in primary biliary cirrhosis

Bacteria and primary biliary cirrhosis

Primary biliary cirrhosis: paradigm or paradox for autoimmunity

The peculiar autoimmunity of primary biliary cirrhosis

HLA DRB4 0101-restricted immunodominant T cell autoepitope of pyruvate dehydrogenase complex in primary biliary cirrhosis: evidence of molecular mimicry in human autoimmune diseases

Mimicry peptides of human PDC-E2 163-176 peptide, the immunodominant T-cell epitope of primary biliary cirrhosis

Identification and precursor frequency analysis of a common T cell epitope motif in mitochondrial autoantigens in primary biliary cirrhosis

Positive markers in AMA-negative PBC

Primary biliary cirrhosis

Primary biliary cirrhosis

Autoimmune liver serology: current diagnostic and clinical challenges

Disease-specific autoantibodies in primary biliary cirrhosis

New ELISA for detecting primary biliary cirrhosis-specific antimitochondrial antibodies

PBC screen: an IgG/IgA dual isotype ELISA detecting multiple mitochondrial and nuclear autoantibodies specific for primary biliary cirrhosis

Key residues of a major cytochrome P4502D6 epitope are located on the surface of the molecule

Antimitochondrial antibodies of immunoglobulin G3 subclass are associated with a more severe disease course in primary biliary cirrhosis

Pediatric autoimmune liver diseases: the molecular basis of humoral and cellular immunity

Interpreting serological tests in diagnosing autoimmune liver diseases

Anti-mitochondrial antibody immunofluorescent titres correlate with the number and intensity of immunoblot-detected mitochondrial bands in patients with primary biliary cirrhosis

Antimitochondrial (pyruvate dehydrogenase) antibodies in leprosy

Antinuclear autoantibodies in chronic liver diseases

Common lupus anti-DNA antibody idiotypes in chronic liver diseases

Anti-Rnp antibodies in chronic liver diseases

Absence of anti-idiotypic antibodies in IVIG preparations to autoantibodies of rare autoimmune diseases

Natural (antiphospholipid-PDH,-DNA) autoantibodies and their physiologic serum inhibitors

Isotypic distribution of anti-pyruvate dehydrogenase antibodies in patients with primary biliary cirrhosis and their family members

Natural autoantibodies in sera of patients with Gaucher's disease

Anti-pyruvate dehydrogenase autoantibodies in primary biliary cirrhosis

Antimitochondrial (pyruvate dehydrogenase) autoantibodies in autoimmune rheumatic diseases

Pyruvate dehydrogenase as an antigen to detect antimitochondrial antibodies

Detection of antimitochondrial antibodies: characterization by enzyme immunoassay and immunoblotting

Primary Sjogren's syndrome and primary biliary cirrhosis: differences and similarities in the autoantibody profile

Carbohydrate-deficient transferrin and false-positive results for alcohol abuse in primary biliary cirrhosis: differential diagnosis by detection of mitochondrial autoantibodies

A comprehensive evaluation of serum autoantibodies in primary biliary cirrhosis

Natural history of early primary biliary cirrhosis

Autoepitope mapping and reactivity of autoantibodies to the dihydrolipoamide dehydrogenase-binding protein (E3BP) and the glycine cleavage proteins in primary biliary cirrhosis

Antimitochondrial antibodies in primary biliary cirrhosis

Characterization of the autoantibody responses to recombinant E3 binding protein (protein X) of pyruvate dehydrogenase in primary biliary cirrhosis

Autoantibodies of primary biliary cirrhosis recognize dihydrolipoamide acetyltransferase and inhibit enzyme function

Anti-gp210 antibody mirrors disease severity in primary biliary cirrhosis

Autoantibodies against nuclear pore complexes are associated with more active and severe liver disease in primary biliary cirrhosis

Profile and clinical significance of anti-nuclear envelope antibodies found in patients with primary biliary cirrhosis: a multicenter study

Anti-gp210 and anti-centromere antibodies are different risk factors for the progression of primary biliary cirrhosis

Prevalence and clinical significance of isotype specific antinuclear antibodies in primary biliary cirrhosis

Autoantibodies against a 210 kDa glycoprotein of the nuclear pore complex as a prognostic marker in patients with primary biliary cirrhosis

Autoantibodies to 200 kD polypeptide(s) of the nuclear envelope: a new serologic marker of primary biliary cirrhosis

Characterization and clinical impact of antinuclear antibodies in primary biliary cirrhosis

Correlation of initial autoantibody profile and clinical outcome in primary biliary cirrhosis

Do antinuclear antibodies in primary biliary cirrhosis patients identify increased risk for liver failure?

Primary biliary cirrhosis and the nuclear pore complex

IgM predominance in autoimmune disease: genetics and gender

Familial primary biliary cirrhosis

Prevalence of familial disease in primary biliary cirrhosis in Italy

Familial primary biliary cirrhosis in Hiroshima

Increased prevalence of antimitochondrial antibodies in first-degree relatives of patients with primary biliary cirrhosis

Are increased individual susceptibility and environmental factors both necessary for the development of primary biliary cirrhosis?

Primary biliary cirrhosis in mother and daughter

Immunological studies in familial primary biliary cirrhosis

Primary biliary cirrhosis: a 2010 update

Primary biliary cirrhosis: incidence and predictive factors of cirrhosis development in ursodiol-treated patients

Potential roles for infectious agents in the pathophysiology of primary biliary cirrhosis: what's new?

Animal models of primary biliary cirrhosis

Progress in the genetics of primary biliary cirrhosis

Etiopathogenesis of primary biliary cirrhosis

The unfinished business of primary biliary cirrhosis

Innate immunity and primary biliary cirrhosis: activated invariant natural killer T cells exacerbate murine autoimmune cholangitis and fibrosis

Primary biliary cirrhosis: one disease with many faces

Human leukocyte antigen in primary biliary cirrhosis: an old story now reviving

Shared familial aggregation of susceptibility to autoimmune diseases

Variants at IRF5-TNPO3, 17q12-21 and MMEL1 are associated with primary biliary cirrhosis

Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants

Genome-wide meta-analyses identify three loci associated with primary biliary cirrhosis

Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis

Replicated association of 17q12-21 with susceptibility of primary biliary cirrhosis in a Japanese cohort

Genetic association of Fc receptor-like 3 polymorphisms with susceptibility to primary biliary cirrhosis: ethnic comparative study in Japanese and Italian patients

Frequency of monosomy X in women with primary biliary cirrhosis

Female predominance and X chromosome defects in autoimmune diseases

Preferential X chromosome loss but random inactivation characterize primary biliary cirrhosis

Human leukocyte antigen polymorphisms in Italian primary biliary cirrhosis: a multicenter study of 664 patients and 1992 healthy controls

Association between the primary biliary cirrhosis specific anti-sp100 antibodies and recurrent urinary tract infection

Microbial mimics are major targets of crossreactivity with human pyruvate dehydrogenase in primary biliary cirrhosis

Primary biliary cirrhosis specific antinuclear antibodies in patients from Spain

Primary biliary cirrhosis is characterized by IgG3 antibodies cross-reactive with the major mitochondrial autoepitope and its Lactobacillus mimic

Antibodies against homologous microbial caseinolytic proteases P characterise primary biliary cirrhosis

Autoantibodies in primary biliary cirrhosis: analysis of reactivity against eukaryotic and prokaryotic 2-oxo acid dehydrogenase complexes

Anti-Helicobacter pylori antibody responses specific for VacA do not trigger primary biliary cirrhosis-specific antimitochondrial antibodies

Primary biliary cirrhosis: an infectious disease caused by Chlamydia pneumoniae?

Molecular mimicry in liver disease

Bacteriuria and primary biliary cirrhosis

Detection of M2 antibodies in patients with recurrent urinary tract infection using an ELISA and purified PBC specific antigens. Evidence for a molecular mimicry mechanism in the pathogenesis of primary biliary cirrhosis?

Natural history of bacteriuria in women with primary biliary cirrhosis and the effect of antimicrobial therapy in symptomatic and asymptomatic groups

M2 mitochondrial antibodies and urinary rough mutant bacteria in patients with primary biliary cirrhosis and in patients with recurrent bacteriuria

Genetics of liver disease: immunogenetics and disease pathogenesis

No specific association between primary biliary cirrhosis and bacteriuria?

Is there a relation between Chlamydia infection and primary biliary cirrhosis?

Patients with primary biliary cirrhosis make anti-viral and anti-mitochondrial antibodies to mouse mammary tumor virus

Are transient environmental agents involved in the cause of primary biliary cirrhosis? Evidence from space-time clustering analysis

Patients with primary biliary cirrhosis react against a ubiquitous xenobiotic-metabolizing bacterium

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

Cloning the human betaretrovirus proviral genome from patients with primary biliary cirrhosis

Does a betaretrovirus infection trigger primary biliary cirrhosis?

Infectious agents and xenobiotics in the etiology of primary biliary cirrhosis

Primary biliary cirrhosis following Lactobacillus vaccination for recurrent vaginitis

Molecular mimicry and autoimmune disease

Molecular mimicry and autoimmune liver disease: virtuous intentions, malign consequences

Unusual suspects in primary biliary cirrhosis

Epstein-Barr virus as a trigger of autoimmune liver diseases

Pathogenesis of autoimmune hepatitis

Autoimmune hepatitis

Oral microbiome profiles: 16S rRNA pyrosequencing and microarray assay comparison

Enterotypes of the human gut microbiome

Metagenomic analysis of the human distal gut microbiome

Comparative metagenomics revealed commonly enriched gene sets in human gut microbiomes

Human distal gut microbiome

A human gut microbial gene catalogue established by metagenomic sequencing

Gastrointestinal microbiome signatures of pediatric patients with irritable bowel syndrome

The human gut microbiome: are we our enterotypes?

A core gut microbiome in obese and lean twins

High diversity of the saliva microbiome in Batwa pygmies

Urinary tract infection as a risk factor for autoimmune liver disease: from bench to bedside

An increased risk of urinary tract infection precedes development of primary biliary cirrhosis

Autoimmunity and environment: am I at risk?

Protein microarrays and biomarkers of infectious disease

Functional immunomics: microarray analysis of IgG autoantibody repertoires predicts the future response of mice to induced diabetes

Autoantigen discovery with a synthetic human peptidome

Hepatic granulomas: histological and molecular pathological approach to differential diagnosis-a study of 442 cases

Mycobacterial DNA not detected in liver sections from patients with primary biliary cirrhosis

Are infectious agents involved in primary biliary cirrhosis? A PCR approach

Mycobacteria-related to the aetiopathogenesis of primary biliary cirrhosis?

Using a pan-viral microarray assay (Virochip) to screen clinical samples for viral pathogens

Pan-viral screening of respiratory tract infections in adults with and without asthma reveals unexpected human coronavirus and human rhinovirus diversity

Metagenomic analysis of bacterial infections by means of high-throughput DNA sequencing

Metagenomics for the discovery of novel human viruses

The sensitivity of massively parallel sequencing for detecting candidate infectious agents associated with human tissue

Induced expression of heat-shock protein on biliary epithelium in patients with primary sclerosing cholangitis and primary biliary cirrhosis

The role of oral hygiene in inflammatory bowel disease

Role of gut commensal microflora in the development of experimental autoimmune encephalomyelitis

Oral and salivary parameters in patients with rheumatic diseases

Detection of retroviral antibodies in primary biliary cirrhosis and other idiopathic biliary disorders

Alfa and beta estrogen receptors and the biliary tree

Estrogen receptors in immunity and autoimmunity

Effect of the anti-estrogen, Nafoxidine, on NZB/W autoimmune disease

Estrogen exaggerates lupus but suppresses T-cell-dependent autoimmune disease

Estrogen and autoimmune disease

Autoantibodies against CYP2D6 and other drug-metabolizing enzymes in autoimmune hepatitis type 2

Autoimmune hepatitis

Drug-induced immune hemolytic anemia

Autoimmune hepatitis and thyroiditis associated with rifampin and pyrazinamide prophylaxis: an unusual reaction

Rifampin-induced hypothyroidism in patients with Hashimoto's thyroiditis

Belated diagnosis in three patients with rifampicin-induced immune haemolytic anaemia

Drug-induced autoimmune-like hepatitis: a case of chronic course after drug withdrawal

Drug-induced autoimmune hepatitis: clinical characteristics and prognosis

Minocycline-induced dermatomyositis

Minocycline induced lupus and autoimmune hepatitis

Minocycline-induced lupus and autoimmune hepatitis: family autoimmune disorders as possible risk factors

Minocycline-induced hepatitis with autoimmune features and neutropenia

Minocycline-induced autoimmune hepatitis with subsequent cirrhosis

Minocycline induced lupus and autoimmune hepatitis

Minocycline induced autoimmune hepatitis and systemic lupus erythematosus-like syndrome

Minocycline-induced autoimmune hepatitis

Autoimmune hepatitis type 2 following anti-papillomavirus vaccination in a 11-year-old girl

Autoimmunity and hepatitis A vaccine in children

Neuromuscular disorders associated with hepatitis B vaccination

Hepatitis B-related autoimmune manifestations

Vaccination and systemic lupus erythematosus: the bidirectional dilemmas

Vaccines, viruses, and voodoo

Epidemiology of autoimmune reactions induced by vaccination

Vaccine-induced autoimmunity

Multiple sclerosis and hepatitis B vaccination

Autoimmunity, environmental exposure and vaccination: is there a link?

Vaccination as an additional player in the mosaic of autoimmunity

Vaccination and autoimmunity-'vaccinosis': a dangerous liaison?

Bcg and autoimmunity: another two-edged sword

Genes, epigenetic regulation and environmental factors: which is the most relevant in developing autoimmune diseases?

Effects of tobacco smoke on immunity, inflammation and autoimmunity

New insights into the immunology of chronic obstructive pulmonary disease

What can epidemiology tell us about systemic lupus erythematosus?

Cigarette smoking and autoimmune disease: what can we learn from epidemiology?

Effect of cigarette smoke on autoimmunity in murine and human systemic lupus erythematosus

An unusually complicated case of primary Sjogren's syndrome: development of transient "lupus-type" autoantibodies following silicone implant rejection

Silicone gel breast implants and connective tissue disease-a comprehensive review

Multiple autoantibodies in patients with silicone breast implants

Where there's smoke there's fire: the silicone breast implant controversy continues to flicker: a new disease that needs to be defined

Rupture of silicone gel breast implants and symptoms of pain and fatigue

A comparison of autoantibody production in asymptomatic and symptomatic women with silicone breast implants

Silicone and autoimmunity

Epstein-Barr virus in pediatric multiple sclerosis

Epstein-Barr virus and multiple sclerosis: evidence of association from a prospective study with long-term follow-up

The causal cascade to multiple sclerosis: a model for MS pathogenesis

Primary infection with the Epstein-Barr virus and risk of multiple sclerosis

Temporal relationship between elevation of Epstein-Barr virus antibody titers and initial onset of neurological symptoms in multiple sclerosis

Epidemiological investigation of the association between infectious mononucleosis and multiple sclerosis

Increased frequency and broadened specificity of latent EBV nuclear antigen-1-specific T cells in multiple sclerosis

Broadened and elevated humoral immune response to EBNA1 in pediatric multiple sclerosis

EBNA1-specific T cells from patients with multiple sclerosis cross react with myelin antigens and co-produce IFN-gamma and IL-2

A case-control study of multiple sclerosis

Epstein Barr virus is not a characteristic feature in the central nervous system in established multiple sclerosis

Absence of Epstein-Barr virus in the brain and CSF of patients with multiple sclerosis

Dysregulated Epstein-Barr virus infection in the multiple sclerosis brain

Epstein-Barr virus: exploiting the immune system

Multiple sclerosis and Epstein-Barr virus

Epstein-Barr virus infection is not a characteristic feature of multiple sclerosis brain

Chlamydia pneumoniae infection of the central nervous system in multiple sclerosis

Plaque-associated expression of human herpesvirus 6 in multiple sclerosis

Human herpesvirus 6

Lyme borreliosis and multiple sclerosis: any connection? A seroepidemic study

Increased prevalence of varicella zoster virus DNA in cerebrospinal fluid from patients with multiple sclerosis

Brief presence of varicella-zoster viral DNA in mononuclear cells during relapses of multiple sclerosis

Varicella-zoster virus in cerebrospinal fluid at relapses of multiple sclerosis

Spinal fluid lymphocytes from a subgroup of multiple sclerosis patients respond to mycobacterial antigens

Cytomegalovirus isolation from a chimpanzee with acute demyelinating disease after inoculation of multiple sclerosis brain cells

Molecular identification of a novel retrovirus repeatedly isolated from patients with multiple sclerosis. The Collaborative Research Group on Multiple Sclerosis

Expression of endogenous retroviruses in blood mononuclear cells and brain tissue from multiple sclerosis patients

Detection of coronavirus RNA and antigen in multiple sclerosis brain

Human coronavirus gene expression in the brains of multiple sclerosis patients

Detection of JC virus DNA in cerebrospinal fluid from multiple sclerosis patients

Characterization of JC virus DNA amplified from urine of chronic progressive multiple sclerosis patients

Viral antibodies in cerebrospinal fluid of multiple sclerosis and control patients: comparison between radioimmunoassay and conventional techniques

Fusion of cultured multiple-sclerosis brain cells with indicator cells: presence of nucleocapsids and virions and isolation of parainfluenza-type virus

Measles virus nucleotide sequences: detection by hybridization in situ

Impaired measles virus-specific cytotoxic T cell responses in multiple sclerosis

Viral antibody titers, immunogenetic markers, and their interrelations in multiple sclerosis patients and controls

Infectious agents in the pathogenesis of primary biliary cirrhosis

Fine specificity of T cells reactive to human PDC-E2 163-176 peptide, the immunodominant autoantigen in primary biliary cirrhosis: implications for molecular mimicry and cross-recognition among mitochondrial autoantigens

Correlation of Chlamydia pneumoniae infection with primary biliary cirrhosis

Disease-specific cross-reactivity between mimicking peptides of heat shock protein of Mycobacterium gordonae and dominant epitope of E2 subunit of pyruvate dehydrogenase is common in Spanish but not British patients with primary biliary cirrhosis

Antibodies to mycobacterial 65-kD heat shock protein cross-react with the main mitochondrial antigens in patients with primary biliary cirrhosis

Cross-reactivity of anti-Mycobacterium gordonae antibodies with the major mitochondrial autoantigens in primary biliary cirrhosis

Analysis of TCR antagonism and molecular mimicry of an HLA-A0201-restricted CTL epitope in primary biliary cirrhosis

Detection and characterization of antibodies to bacterial heat-shock protein 60 in sera of patients with primary biliary cirrhosis

Autoantibodies from patients with primary biliary cirrhosis recognize a restricted region within the cytoplasmic tail of nuclear pore membrane glycoprotein Gp210

Are antimitochondrial antibodies in primary biliary cirrhosis induced by R(rough)-mutants of Enterobacteriaceae?

A possible role of histone-like DNA-binding protein of Streptococcus intermedius in the pathogenesis of bile duct damage in primary biliary cirrhosis

Possible cross-reactivity of human anti-mitochondrial antibodies with membrane vesicles of Paracoccus denitrificans

Borrelia burgdorferi: a new self-mimicking trigger in primary biliary cirrhosis

Molecular identification of bacterial 16S ribosomal RNA gene in liver tissue of primary biliary cirrhosis: is Propionibacterium acnes involved in granuloma formation?

Mycoplasma antigens as a possible trigger for the induction of antimitochondrial antibodies in primary biliary cirrhosis

Biochemical and antigenic characterisation of Mycoplasma gallisepticum membrane proteins P52 and P67 (pMGA)

PBC: animal models of cholangiopathies and possible endogenous viral infections

Mouse mammary tumor virus in anti-mitochondrial antibody producing mouse models

Increased expression of Epstein-Barr virus in primary biliary cirrhosis patients

Correlation of oligomycin-sensitive ATPase activity in trypanosomes with their content of an antigen to primary biliary cirrhosis

The occurrence and localization in trypanosomes and other endo-parasites of an antigen cross-reacting with mitochondrial antibodies of primary biliary cirrhosis

Anti-Saccharomyces cerevisiae antibodies in primary biliary cirrhosis

We are indebted to Diego Vergani, Harold Baum, Lars Komorowski, and Andrew K. Burroughs for helpful comments and fruitful discussions leading to the initiation of the concept of infectome. We thank Timoklia Orfanidou and Maria G. Mytilinaiou for editing assistance.