The X and why of xenobiotics in primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is a chronic autoimmune liver disease characterized by inflammation and destruction of intrahepatic biliary epithelial cells, ultimately leading to liver failure. The serological hallmark of PBC is the presence of high-titer antimitochondrial antibodies (AMA) against the inner lipoyl domain of E2 subunits of 2-oxo-acid dehydrogenase complexes, in particular the E2 component of the pyruvate dehydrogenase complex (PDC-E2). The initiating events triggering the autoimmune response are not yet identified but the hypothesis of molecular mimicry is a widely proposed mechanism for the development of autoimmunity in PBC. Several candidates, including bacteria and viruses, have been suggested as causative agents, but also environmental factors, such as chemical xenobiotics, have been implicated in the pathogenesis of primary biliary cirrhosis. In this review, we will discuss our current knowledge of the immunoreactivity of xenobiotically modified PDC peptide antigens. In addition, we will provide a working hypothesis how xenobiotic modification of antigens might occur that ultimately leads to the breaking of self-tolerance and the induction of PBC.     

Infection as a risk factor in the pathogenesis of primary biliary cirrhosis: pros and cons

Primary biliary cirrhosis (PBC) is a chronic and slowly progressive cholestatic liver disease of autoimmune etiology, characterized by injury of the intrahepatic bile ducts that may eventually lead to cirrhosis and liver failure. Evidence suggests cardinal roles for both environmental factors and genetic susceptibility. Nevertheless, the absolute etiology of PBC is unclear, despite recent well-designed case-control studies that reported environmental risk factors, including infectious agents, for PBC. Of the reported infectious agents, some of them are not reproducible and remain controversial. However, infection is no doubt one of the major risks among the environmental factors. This is supported by the fact that infectious agents in autoimmune diseases express antigens resulting in molecular mimicry and xenobiotics that play a role in breaking tolerance. Taken together, recent findings from genome wide assays as well as novel animal models may enable us to better understand the mechanism of pathogenesis responsible for this disease.     

Molecular mimicry as a mechanism of autoimmune disease

A variety of mechanisms have been suggested as the means by which infections can initiate and/or exacerbate autoimmune diseases. One mechanism is molecular mimicry, where a foreign antigen shares sequence or structural similarities with self-antigens. Molecular mimicry has typically been characterized on an antibody or T cell level. However, structural relatedness between pathogen and self does not account for T cell activation in a number of autoimmune diseases. A proposed mechanism that could have been misinterpreted for molecular mimicry is the expression of dual T cell receptors (TCR) on a single T cell. These T cells have dual reactivity to both foreign and self-antigens leaving the host vulnerable to foreign insults capable of triggering an autoimmune response. In this review, we briefly discuss what is known about molecular mimicry followed by a discussion of the current understanding of dual TCRs. Finally, we discuss three mechanisms, including molecular mimicry, dual TCRs, and chimeric TCRs, by which dual reactivity of the T cell may play a role in autoimmune diseases.     

Promiscuous T cells selected by Escherichia coli: OGDC-E2 in primary biliary cirrhosis

The etiology of primary biliary cirrhosis (PBC) remains enigmatic. One theory that has attracted attention proposes that PBC is induced via molecular mimicry with Escherichia coli. If molecular mimicry is responsible for the immunogenic response in PBC, then T cell clones specific for E. coli antigens should stimulate and be cross-reactive with peptides specific for the human immunodominant autoepitopes. To address this issue, we developed T cell clones specific for E. coli OGDC-E2 peptide. Importantly, we demonstrate the presence of T cell clones specific for E. coli OGDC-E2 that react promiscuously with the human mitochondrial equivalents. Indeed, there was a significant increase in the liver derived T cell precursor frequency of such reactivity and such liver clones were only found in patients with PBC. In conclusion, these data suggest that PBC is a multi-hit disease involving a genetic predisposition, a mucosal response, and activation of promiscuous T cells; such activation may occur either directly from bacterial antigens, or indirectly through chemically-modified bacterial antigens. Dissection of the mechanisms involved will lead not only to understanding the immunogenetic basis of PBC, but likely its pathogenic etiology.     

Multiple cross-reactive self-ligands for Borrelia burgdorferi-specific HLA-DR4-restricted T cells

T cell recognition of self antigens is a key event in the pathogenesis of autoimmune diseases. To date, the initial events that trigger autoreactive T cells are unknown. The "molecular mimicry" hypothesis predicts that during an infection T cells that recognize both a microbial antigen and a related self peptide become activated and cause autoimmune disease. We have systematically examined the recognition of self antigens by HLA-DR4-restricted T cells specific for peptides of the outer surface protein A (OspA) of Borrelia burgdorferi, the etiological agent of Lyme disease. We used the peptide spot synthesis technique for complete peptide substitution analyses of two immunodominant OspA epitopes. Each amino acid residue of the epitopes was substituted with all 20 naturally occurring amino acids and the altered peptides were tested for recognition by a panel of OspA-specific T cells. The binding motifs (supertopes) revealed by these analyses were used to screen public databases for matching human or murine peptides. Several hundred peptides were identified by this search and synthesized. Of these, 28 were recognized by OspA-specific T cells. Thus, T cell cross-reactivity is a common phenomenon and the existence of cross-reactive epitopes alone does not imply molecular mimicry-mediated pathology and autoimmunity.     

Cervical cancer cell lines expressing NKG2D-ligands are able to down-modulate the NKG2D receptor on NKL cells with functional implications

Background

Molecular mimicry between microbial antigens and host-proteins is one of the etiological enigmas for the occurrence of autoimmune diseases. T cells that recognize cross-reactive epitopes may trigger autoimmune reactions. Intriguingly, autoimmune diseases have been reported to be prevalent in tuberculosis endemic populations. Further, association of Mycobacterium tuberculosis (M. tuberculosis) has been implicated in different autoimmune diseases, including rheumatoid arthritis and multiple sclerosis. Although, in silico analyses have identified a number of M. tuberculosis specific vaccine candidates, the analysis on prospective cross-reactive epitopes, that may elicit autoimmune response, has not been yet attempted. Here, we have employed bioinformatics tools to determine T cell epitopes of homologous antigenic regions between M. tuberculosis and human proteomes.

Results

Employing bioinformatics tools, we have identified potentially cross-reactive T cell epitopes restricted to predominant class I and II alleles of human leukocyte antigens (HLA). These are similar to peptides of mycobacterial proteins and considerable numbers of them are promiscuous. Some of the identified antigens corroborated with established autoimmune diseases linked with mycobacterial infection.

Conclusions

The present study reveals many target proteins and their putative T cell epitopes that might have significant application in understanding the molecular basis of possible T cell autoimmune reactions during M. tuberculosis infections.     

The immunopathology of primary biliary cirrhosis: thoughts for the millennium

Primary biliary cirrhosis is an organ specific autoimmune disease that produces progressive cholestatic liver failure. It is predominantly a disease of women characterized by chronic progressive destruction of small intrahepatic bile ducts with portal inflammation and ultimately fibrosis. The serologic hallmark of primary biliary cirrhosis (PBC) is the presence of antibodies to mitochondria. The mechanisms by which and if which such antibodies produce liver tissue injury is unknown. However, the presence of these antibodies have allowed detailed immunological definition of the antigenic epitopes, the nature of reacting autoantibodies and the characterization of T cell responses. Several mechanisms may now be proposed regarding the immune mediated bile duct damage in PBC, including the possible role of T cell-mediated cytotoxicity and intracellular interaction between the IgA class of antimitochondrial antibodies (AMA) and mitochondrial autoantigens. The advent of molecular biology, the ability to clone and define epitopes, and the use of in situ nucleic acid hybridization, have all led to advances in understanding the natural history of immunopathology in PBC. There are major questions which remain unanswered, including, of course, etiology, but also including the questions of why there is female predominance, the absence of PBC in children, the relative ineffectiveness of immunosuppressive drugs, and the specific role of mitochondrial antigens. In this review, we focus on these issues and particularly on the immunobiology of patients with this disease.     

Solving the primary biliary cirrhosis puzzle: The emerging image of immunopathology in primary biliary cirrhosis

The role of adaptive as well as innate immune responses in the pathology of primary biliary cirrhosis (PBC) has been a major subject of investigation. Primary biliary cirrhosis is an autoimmune liver disease involving the destruction of small bile ducts, which eventually leads to liver cirrhosis. Adaptive immune responses involving autoantibody production by B cells and autoreactive T cells have been labeled as the most probable mediators of tissue destruction. Autoantibody production against mitochondrial antigens is used as a key diagnostic marker in PBC, being present in 90-95% of patient sera. Besides blood, these antimitochondrial antibodies are found in liver, bile, saliva, and urine of patients and target mitochondrial autoantigens that are well conserved between species. One possible mechanism of antibody-mediated tissue destruction is via the transcytosis of immunoglobulin A antimitochondrial antibodies through biliary epithelium. Another mechanism may involve the recognition by antimitochondrial antibodies of the mitochondrial autoantigens abnormally expressed on patient biliary epithelium. The second component of the adaptive immune response in PBC involves T cells, which comprise a large fraction of infiltrating leukocytes in diseased livers. Autoreactive CD4⁺ and CD8⁺ T cells recognizing mitochondrial antigens targeted by antimitochondrial antibodies have been isolated with specificity for epitopes that overlap with those of B cells. Cytokines production of such infiltrates indicates the involvement of both T_H1 and T_H2 responses in the diseased tissue. Besides adaptive responses, innate immunity effector mechanisms involving eosinophils, macrophages, and B cells hyperresponsive to bacterial DNA CpG motifs has been implicated in the pathology of PBC. Despite research efforts, the etiology of PBC still remains elusive, although theories involving the participation of genetic factors, molecular mimicry due to microorganisms, and a role for modification of native autoantigens by xenobiotics have been proposed.     

HLA, molecular mimicry and multiple sclerosis

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system in which an autoimmune response most probably contributes to pathogenesis. To date, the best characterized susceptibility-associated gene has been mapped to the HLA complex. The HLA-DRB1*1501 - DRB5*0101 - DQA1*0102 - DQB1*0602 haplotype is both associated and linked to MS in different ethnic groups. The locus within the HLA class II region encoding the MS-susceptibility gene is under intensive investigation. Epidemiological studies, however, have suggested that environmental antigens also play a critical role in MS pathogenesis. One of the ways a pathogen could trigger autoimmune disease is via immunological cross-reactivity or molecular mimicry. This concept argues that a microbial peptide with certain degree of homology to a self peptide can stimulate pathogenic self-reactive specific T cells to cause an autoimmune disease. Many microbial agents have regions of sequences that may serve as binding motifs for HLA-DR2. HLA genetics and molecular mimicry may therefore be intimately interlinked in the disease process. In the present review, we focus on the HLA association with MS and the role of microbial antigens in MS, with special reference to the molecular mimicry hypothesis.     

Postinfectious immunodeficiency and autoimmunity: pathogenic and clinical values and implications

Autoimmunity is still a mystery of clinical immunology and medicine as a whole. The etiology and pathogenesis of autoimmune disorders remain unclear and, thus, are assessed as a balance between hereditary predisposition, triggering factors and the appearance of autoantibodies and/or self-reactive T cells. Among the immunological armamentarium, molecular mimicry, based on self-reactive T- and B-cell activation by cross-reactive epitopes of infectious agents, is of special value. Hypotheses regarding the possible involvement of molecular mimicry in the development of postinfectious autoimmunity are currently very intriguing. They provide new approaches for identifying etiological agents that are associated with postinfectious autoimmunity, paired microbial- and tissue-linked epitopes targeted for autoimmune reaction determination, postinfectious autoimmunity pathogenesis recognition and specific prevention, and therapy for autoimmune disorder development.     

Infectious agents in the pathogenesis of primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is a chronic progressive cholestatic liver disease which is characterized by the breakdown of self-tolerance to the highly conserved pyruvate dehydrogenase complex, specially the pyruvate dehydrogenase E2 complex (PDC-E2). The breakdown of the tolerance to such antigens leads to an autoimmune process characterized by portal inflammation and immune-mediated destruction of the intrahepatic bile ducts. Epidemiological studies have suggested that infections agents can trigger or even exacerbate the disease. Among other gram negative bacteria, Escherichia Coli, and Nosphingobium aromaticivorans are the most associated agents reported hitherto. Epidemiological and molecular evidence points towards molecular mimicry between some components of these microorganisms and specific amino-acid sequences that are present in proteins on normal cells of the biliary tract. In this review, we revisit all reports suggesting that infectious agents might be associated with the autoimmune pathogenesis of PBC. We also retrieve the immune molecular mimicry mechanisms that are likely involved with the autoimmune process in PBC.     

Primary biliary cirrhosis and the nuclear pore complex

Experimental models of autoimmune diseases have led to the conclusion that an immune response to nuclear antigens is a sentinel marker for loss of tolerance and potential tissue damage. Various proteins are targets of antinuclear antibodies in a variety of autoimmune diseases, ranging from systemic rheumatologic disorders to diseases affecting specific organs such as the liver. Autoantibodies against specific nuclear constituents have also been used as probes to understand the structure and the function of the targeted components and their relevance to disease pathogenesis. Approximately a quarter of patients with primary biliary cirrhosis (PBC) have antibodies targeting proteins of the nuclear pore complex (NPC), a multi-protein structure that mediates molecular transport across the nuclear envelope. Autoantibodies against the integral membrane glycoprotein gp210 and nucleoporin p62 appear to be highly specific for PBC, an autoimmune disease characterized by progressive destruction of intrahepatic biliary epithelial cells. This review discusses the diagnostic and clinical relevance of anti-NPC antibodies in PBC and the possibility that this autoimmune response may arise as a result of molecular mimicry.     

Autoimmunity in coxsackievirus B3 induced myocarditis

Virus infections are implicated in several autoimmune diseases. Multiple mechanisms of autoimmunity induction have been proposed including antigenic mimicry, production of cryptic epitopes and infection acting as both adjuvant for self-antigens and the mechanism of releasing these cell antigens. Evidence for these mechanisms in coxsackievirus B3 induced myocarditis is discussed.     

Human herpesvirus 6 and multiple sclerosis: a study of T cell cross-reactivity to viral and myelin basic protein antigens

Several reports have suggested an association of human herpesvirus 6 (HHV-6) with multiple sclerosis. Autoreactive T lymphocytes directed against myelin components seem to contribute to the pathogenesis of the disease. It has been suggested that molecular mimicry between viral and self-antigens might be one of the mechanisms that determine the onset of several autoimmune diseases. Following this hypothesis, the purpose of the present study was to evaluate if HHV-6 could play a role in activating T cells capable of cross-reaction with an important myelin component, the myelin basic protein. T cell lines were established from 22 multiple sclerosis patients and from 16 healthy controls, and their capability to react to both virus and myelin basic protein antigens was compared. The analysis of T cell cross-reactivity in patients and controls did not show significant differences in the HHV-6 ability to activate myelin basic protein-reactive T cells. Similarly, the evaluation of the humoral immune response to HHV-6 in patients and controls did not mirror any abnormality in the HHV-6 status in multiple sclerosis patients. Therefore, although the findings of activity in vitro of T cell lines with dual specificity are consistent with the hypothesis of molecular mimicry, the lack of differences in cross-reactivity between patients and controls do not support molecular mimicry as an important mechanism in the physiopathology of this disease.     

Experimental evidence on the immunopathogenesis of primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease for which an autoimmune pathogenesis is supported by clinical and experimental data, including the presence of autoantibodies and autoreactive T cells. The etiology remains to be determined, yet data suggest that both a susceptible genetic background and unknown environmental factors determine disease onset. Multiple infectious and chemical candidates have been proposed to trigger the disease in a genetically susceptible host, mostly by molecular mimicry. Most recently, several murine models have been reported, including genetically determined models as well as models induced by immunization with xenobiotics and bacteria.     

Induction of arthritis and uveitis in Lewis rats by antigenic mimicry of peptides from HLA-B27 and cytokeratin.

Ankylosing spondylitis (AS) is highly associated with HLA-B27. We have previously shown that peripheral blood lymphocytes from AS patients respond to stimulation with a peptide from the sequence of HLA-B27. Here we report on molecular mimicry of peptides from HLA-B27 and cytokeratin, the latter being specifically expressed in synovial membranes and eyes, the main targets of the autoaggressive immune response in AS patients. Immunization of rats with these peptides induced an inflammatory response in joints, spine and eyes, resembling the symptoms in AS. Furthermore, both HLA-B27- and cytokeratin-derived peptides, are effective oral tolerogens: feeding these peptides ameliorated arthritis and uveitis induced with the cytokeratin peptide. Our model might elucidate the role of peptides from the sequence of HLA-B27 as an antigen of the immune response in AS, introducing a new aspect of antigenic mimicry between HLA-B27 and tissue-specific antigens. We propose this as a mechanism directing a systemic autoimmune response to specific target organs by antigenic mimicry of T cell epitopes.     

Heart infiltrating T cell clones from a rheumatic heart disease patient display a common TCR usage and a degenerate antigen recognition pattern

CD4+ T cells are most likely the ultimate effectors of chronic heart lesions in rheumatic heart disease (RHD). We have demonstrated that infiltrating CD4+ T cell clones were able to recognize several heart tissue and streptococcal antigens by molecular mimicry. Clonality analysis of the mitral valve and myocardium infiltrating T cell lines showed several oligoclonal expansions, some of which were found in both sites of the lesions. The results presented in this study showed a degenerate pattern of reactivity of intralesional T cell clones from one RHD patient. Four mitral valve and one papillar muscle-derived T cell clones, presenting the same TCR-BV13 BJ2S7 with same sequences of the CDR3 region recognized different antigens. They expressed two alpha chains at the RNA level and the AV AJ segments were the same for mitral valve T cell clones, but not for the papillar muscle-derived T cell clone. Two other intralesional T cell clones using the same TCR-BV3 JB2S1 segments with identical CDR3 sequences also recognized different antigens. These results indicate that intralesional T cell clones with common TCR usage can recognize several epitopes that probably amplify the deleterious immune reaction. These data, allow us to hypothesize that degenerate T cell recognition may lead to intramolecular degenerate reactivity against epitopes with low homology. This can be a novel mechanism of epitope spreading, of relevance in the increase of epitopes targets that can activate cross-reactive autoimmune T cells.     

Virus-induced autoimmunity: potential role of viruses in initiation, perpetuation, and progression of T-cell-mediated autoimmune disease

Virus infections have been implicated in the initiation of multiple human autoimmune diseases. This article focuses on reviewing the role of viruses in initiation, progression, and perpetuation of autoimmune diseases. Various mechanisms by which virus infections can induce autoimmune responses including molecular mimicry, epitope spreading, direct bystander activation, and release of cryptic epitopes are discussed. Evidence implicating virus infections in the pathogenesis of various human autoimmune diseases is reviewed. Last, the characteristics of animal models that have been developed for the study of the potential role of viruses in the initiation and progression of autoimmune disease are reviewed.     

Activation of myelin reactive T cells in multiple sclerosis: A possible role for T cell degeneracy?

While it is widely accepted that myelin reactive T cells are key players in the immunopathogenesis of multiple sclerosis (MS), the initial triggers that turn on these self-reactive T-cells remain to be determined. One mechanism, which is already text book knowledge for a decade, is molecular mimicry by which viral or microbial antigens are able to cross-activate T cells specific for myelin epitopes, the major target in MS pathology. Although proof of concept for this principle was given in animal model studies, evidence for such a mechanism in MS is limited. In this issue, Zhang et al. demonstrate an increased frequency of T cells that cross-react with a wide variety of antigens, a phenomenon termed as T cell degeneracy. While the role of these degenerate T cells in MS remains to be determined the authors now provide new elegant tools to study this T cell population, thus providing a starting point to better understand their function in MS.     

Chagas' disease and the autoimmunity hypothesis

The notion that the pathology of Chagas' disease has an autoimmune component was initially based on the finding of circulating antibodies binding heart tissue antigens in patients and mice chronically infected with Trypanosoma cruzi. Later, T lymphocytes reactive with heart or nerve tissue antigens were found in chagasic mice and patients, extending the concept to include cell-mediated immunity. However, there is disagreement about whether the observed immunologic autoreactivities are triggered by T. cruzi epitopes and then affect host tissue antigens by virtue of molecular mimicry or are elicited by host antigens exposed to lymphocytes after tissue damage caused by the parasite. There is also disagreement about the relevance of immunologic autoreactivities to the pathogenesis of Chagas' disease because of the lack of reproducibility of some key reports supporting the autoimmunity hypothesis, conflicting data from independent laboratories, conclusions invalidated by advances in our understanding of the immunologic mechanisms underlying cell lysis, and, last but not least, a lack of direct, incontrovertible evidence that cross-reacting antibodies or autoreactive cells mediate the typical pathologic changes associated with human Chagas' disease. The data and views backing and questioning the autoimmunity hypothesis for Chagas' disease are summarized in this review.