Cellular and molecular mechanism for Kilham rat virus-induced autoimmune diabetes in DR-BB rats

Kilham rat virus (KRV) causes autoimmune diabetes in diabetes-resistant BioBreeding (DR-BB) rats; however, the mechanism by which KRV induces autoimmune diabetes without the direct infection of beta cells is not well understood. We first asked whether molecular mimicry, such as a common epitope between a KRV-specific peptide and a beta cell autoantigen, is involved in the initiation of KRV-induced autoimmune diabetes in DR-BB rats. We found that KRV peptide-specific T cells generated in DR-BB rats infected with recombinant vaccinia virus expressing KRV-specific structural and nonstructural proteins could not induce diabetes, indicating that molecular mimicry is not the mechanism by which KRV induces autoimmune diabetes. Alternatively, we asked whether KRV infection of DR-BB rats could disrupt the finely tuned immune balance and activate autoreactive T cells that are cytotoxic to beta cells, resulting in T cell-mediated autoimmune diabetes. We found that both Th1-like CD45RC+CD4+ and cytotoxic CD8+ T cells were up-regulated, whereas Th2-like CD45RC-CD4+ T cells were down-regulated, and that isolated and activated CD45RC+CD4+ and CD8+ T cells from KRV-infected DR-BB rats induced autoimmune diabetes in young diabetes-prone BioBreeding (DP-BB) rats. We conclude that KRV-induced autoimmune diabetes in DR-BB rats is not due to molecular mimicry, but is due to a breakdown of the finely tuned immune balance of Th1-like CD45RC+CD4+ and Th2-like CD45RC-CD4+ T cells, resulting in the selective activation of beta cell-cytotoxic effector T cells.     

Autoimmunity due to molecular mimicry as a cause of neurological disease

One hypothesis that couples infection with autoimmune disease is molecular mimicry. Molecular mimicry is characterized by an immune response to an environmental agent that cross-reacts with a host antigen, resulting in disease. This hypothesis has been implicated in the pathogenesis of diabetes, lupus and multiple sclerosis (MS). There is limited direct evidence linking causative agents with pathogenic immune reactions in these diseases. Our study establishes a clear link between viral infection, autoimmunity and neurological disease in humans. As a model for molecular mimicry, we studied patients with human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a disease that can be indistinguishable from MS (refs. 5,6,7). HAM/TSP patients develop antibodies to neurons. We hypothesized these antibodies would identify a central nervous system (CNS) autoantigen. Immunoglobulin G isolated from HAM/TSP patients identified heterogeneous nuclear ribonuclear protein-A1 (hnRNP-A1) as the autoantigen. Antibodies to hnRNP-A1 cross-reacted with HTLV-1-tax, the immune response to which is associated with HAM/TSP (refs. 5,9). Immunoglobulin G specifically stained human Betz cells, whose axons are preferentially damaged. Infusion of autoantibodies in brain sections inhibited neuronal firing, indicative of their pathogenic nature. These data demonstrate the importance of molecular mimicry between an infecting agent and hnRNP-A1 in autoimmune disease of the CNS.     

Epitope mimicry and its role in the development of autoimmune reactions

The role of molecular mimicry in the development of some autoimmune diseases, such as rheumatism, rheumatoid arthritis, the Julian-Barré syndrome, the antiphospholipid syndrome, multiple sclerosis, is reviewed. The data on the presence in bacteria and viruses antigenic determinants similar to those in human tissues are presented. The phenomenon of epitope mimicry is considered in the light of the latest research in the field of IgE autoreactivity, which may take part in the pathogenesis of allergic diseases.     

Molecular mimicry mediated by MHC class Ib molecules after infection with gram-negative pathogens

The development of many autoimmune diseases has been etiologically linked to exposure to infectious agents. For example, a subset of patients with a history of Salmonella infection develop reactive arthritis. The persistence of bacterial antigen in arthritic tissue and the isolation of Salmonella or Yersinia reactive CD8+ T cells from the joints of patients with reactive arthritis support the etiological link between Gram-negative bacterial infection and autoimmune disease. Models proposed to account for the link between infection and autoimmunity include inflammation-induced presentation of cryptic self-epitopes, antigen persistence and molecular mimicry. Several studies support molecular mimicry as a mechanism for the involvement of class II epitopes in infectious disease-induced self-reactivity. Here, we have identified an immunodominant epitope derived from the S. typhimurium GroEL molecule. This epitope is presented by the mouse H2-T23-encoded class Ib molecule Qa-1 and was recognized by CD8+ cytotoxic T lymphocytes induced after natural infection. S. typhimurium-stimulated cytotoxic T lymphocytes recognizing the GroEL epitope cross-reacted with a peptide derived from mouse heat shock protein 60 and recognized stressed macrophages. Our results indicate involvement of MHC class Ib molecules in infection-induced autoimmune recognition and indicate a mechanism for the etiological link between Gram-negative bacterial infection and autoimmunity.     

A mathematical design of vector vaccine against autoimmune disease

Viruses have been implicated in the initiation, progression, and exacerbation of several human autoimmune diseases. Evidence also exists that viruses can protect against autoimmune disease. Several proposed mechanisms explain the viral effects. One mechanism is “molecular mimicry” which represents a shared immunologic epitope with a microbe and the host. We consider, using a simple mathematical model, whether and how a viral infection with molecular mimicry can be beneficial or detrimental for autoimmune disease. Furthermore, we consider the possibility of development of a vector therapeutic vaccine that can relieve autoimmune disease symptoms. Our findings demonstrate that vaccine therapy success necessitates (i) appropriate immune response function, (ii) appropriate affinities with self and non-self antigen, and (iii) a replicative vector vaccine. Moreover, the model shows that the viral infection can cause autoimmune relapses.     

DNA vaccination breaks tolerance for a neo-self antigen in liver: a transgenic murine model of autoimmune hepatitis

Understanding the pathogenesis of autoimmune hepatitis requires an animal model in which chronic progressive immune injury develops spontaneously or with minimal manipulations. The new transgenic mouse model proposed in this study is based on the hypothesis that infectious agents have the potential to initiate autoreactivity through molecular mimicry. A transgenic mouse expressing lymphocytic choriomeningitis virus nucleoprotein (NP) in a H-2(b) background developed liver injury when vaccinated with plasmids expressing NP as an intracellular or a secretory protein. Coinjection of plasmids coding for NP and IL-12 facilitated the induction of a Th1 phenotype as detected by a specific B lymphocyte response characterized by a predominance of IgG2 subclass anti-NP Abs. CTLs activated in peripheral lymphoid organs by DNA vaccination migrated to the periportal and lobular areas of the liver. Their presence was associated with a significant degree of cytolysis, as evidenced by elevated transaminases several weeks after immunization. As activated specific T lymphocytes proliferated in the periphery and caused cytolysis of target cells, this study suggests that autoimmune hepatitis can be triggered by molecular mimicry, and that local injury may not be essential to initiate autoreactivity in the liver.     

Butyrophilin, a milk protein, modulates the encephalitogenic T cell response to myelin oligodendrocyte glycoprotein in experimental autoimmune encephalomyelitis

Experimental autoimmune encephalomyelitis (EAE) induced by sensitization with myelin oligodendrocyte glycoprotein (MOG) is a T cell-dependent autoimmune disease that reproduces the inflammatory demyelinating pathology of multiple sclerosis. We report that an encephalitogenic T cell response to MOG can be either induced or alternatively suppressed as a consequence of immunological cross-reactivity, or "molecular mimicry" with the extracellular IgV-like domain of the milk protein butyrophilin (BTN). In the Dark Agouti rat, active immunization with native BTN triggers an inflammatory response in the CNS characterized by the formation of scattered meningeal and perivascular infiltrates of T cells and macrophages. We demonstrate that this pathology is mediated by a MHC class II-restricted T cell response that cross-reacts with the MOG peptide sequence 76-87, I GEG KVA LRIQ N (identities underlined). Conversely, molecular mimicry with BTN can be exploited to suppress disease activity in MOG-induced EAE. We demonstrate that not only is EAE mediated by the adoptive transfer of MOG74-90 T cell lines markedly ameliorated by i.v. treatment with the homologous BTN peptide, BTN74-90, but that this protective effect is also seen in actively induced disease following transmucosal (intranasal) administration of the peptide. These results identify a mechanism by which the consumption of milk products may modulate the pathogenic autoimmune response to MOG.     

Viral delivery of an epitope from Haemophilus influenzae induces central nervous system autoimmune disease by molecular mimicry

Multiple sclerosis (MS) is an autoimmune CNS demyelinating disease in which infection may be an important initiating factor. Pathogen-induced cross-activation of autoimmune T cells may occur by molecular mimicry. Infection with wild-type Theiler's murine encephalomyelitis virus induces a late-onset, progressive T cell-mediated demyelinating disease, similar to MS. To determine the potential of virus-induced autoimmunity by molecular mimicry, a nonpathogenic neurotropic Theiler's murine encephalomyelitis virus variant was engineered to encode a mimic peptide from protease IV of Haemophilus influenzae (HI), sharing 6 of 13 aa with the dominant encephalitogenic proteolipid protein (PLP) epitope PLP(139-151). Infection of SJL mice with the HI mimic-expressing virus induced a rapid-onset, nonprogressive paralytic disease characterized by potent activation of self-reactive PLP(139-151)-specific CD4(+) Th1 responses. In contrast, mice immunized with the HI mimic-peptide in CFA did not develop disease, associated with the failure to induce activation of PLP(139-151)-specific CD4(+) Th1 cells. However, preinfection with the mimic-expressing virus before mimic-peptide immunization led to severe disease. Therefore, infection with a mimic-expressing virus directly initiates organ-specific T cell-mediated autoimmunity, suggesting that pathogen-delivered innate immune signals may play a crucial role in triggering differentiation of pathogenic self-reactive responses. These results have important implications for explaining the pathogenesis of MS and other autoimmune diseases.     

Temperature-dependent phenotypic variation of <Emphasis Type="Italic">Campylobacter jejuni</Emphasis> lipooligosaccharides

Background  

Campylobacter jejuni is a major bacterial cause of food-borne enteritis, and its lipooligosaccharide (LOS) plays an initiating role in the development of the autoimmune neuropathy, Guillain-Barré syndrome, by induction of anti-neural cross-reactive antibodies through ganglioside molecular mimicry.     

Narcolepsy with hypocretin/orexin deficiency, infections and autoimmunity of the brain

The loss of hypothalamic hypocretin/orexin (hcrt) producing neurons causes narcolepsy with cataplexy. An autoimmune basis for the disease has long been suspected and recent results have greatly strengthened this hypothesis. Narcolepsy with hcrt deficiency is now known to be associated with a Human Leukocyte Antigen (HLA) and T-cell receptor (TCR) polymorphisms, suggesting that an autoimmune process targets a single peptide unique to hcrt-cells via specific HLA-peptide-TCR interactions. Recent data have shown a robust seasonality of disease onset in children and associations with Streptococcus Pyogenes, and influenza A H1N1-infection and H1N1-vaccination, pointing towards processes such as molecular mimicry or bystander activation as crucial for disease development. We speculate that upper airway infections may be common precipitants of a whole host of CNS autoimmune complications including narcolepsy.     

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

The etiology of multiple sclerosis (MS) is believed to involve environmental factors, but their identity and mode of action are unknown. In this study, we demonstrate that Ab specific for the extracellular Ig-like domain of myelin oligodendrocyte glycoprotein (MOG) cross-reacts with a homologous N-terminal domain of the bovine milk protein butyrophilin (BTN). Analysis of paired samples of MS sera and cerebrospinal fluid (CSF) identified a BTN-specific Ab response in the CNS that differed in its epitope specificity from that in the periphery. This effect was statistically significant for the Ab response to BTN(76-100) (p = 0.0026), which cosequestered in the CSF compartment with Ab to the homologous MOG peptide MOG(76-100) in 34% of MS patients (n = 35). These observations suggested that intratheccal synthesis of Ab recognizing BTN peptide epitopes in the CNS was sustained by molecular mimicry with MOG. Formal evidence of molecular mimicry between the two proteins was obtained by analyzing MOG-specific autoantibodies immunopurified from MS sera. The MOG-specific Ab repertoire cross-reacts with multiple BTN peptide epitopes including a MOG/BTN(76-100)-specific component that occurred at a higher frequency in MS patients than in seropositive healthy controls, as well as responses to epitopes within MOG/BTN(1-39) that occur at similar frequencies in both groups. The demonstration of molecular mimicry between MOG and BTN, along with sequestration of BTN-reactive Ab in CSF suggests that exposure to this common dietary Ag may influence the composition and function of the MOG-specific autoimmune repertoire during the course of MS.     

Molecular mimicry and autoantigens in connective tissue diseases

Conclusion Unless the basis of reactivity can be strictly elucidated the biological significance of molecular mimicry must be held in question and the attention given to fulfilling the criteria outlined in table 2 cannot be overstressed. Nevertheless, the evidence so far is intriguing in implicating some form of role for retroviruses or bacteria in certain autoimmune diseases. The reader would be well advised to keep an open mind and await with critical interest more stringent data from those laboratories with the resources, patience and dedication to pursue this line of research.     

Association of Helicobacter pylori and gastric autoimmunity: A population-based study

Abstract Based on clinical studies, a negative association between Helicobacter pylori and autoimmune corpus gastritis is described. In the present investigation of an unselected population of 1461 adults we can state, however, that there exists a relationship between H. pylori infection and the development of gastric corpus autoimmunity. As confirmation for the gastric autoantibody development through molecular mimicry, a high homology (72% in 25 amino acid overlap) between the beta subunit of H. pylori urease and that of H + K + ATPase, the gastric parietal cell autoantigen, was revealed.     

T cells of multiple sclerosis patients target a common environmental peptide that causes encephalitis in mice

Multiple sclerosis (MS) is a chronic autoimmune disease triggered by unknown environmental factors in genetically susceptible hosts. MS risk was linked to high rates of cow milk protein (CMP) consumption, reminiscent of a similar association in autoimmune diabetes. A recent rodent study showed that immune responses to the CMP, butyrophilin, can lead to encephalitis through antigenic mimicry with myelin oligodendrocyte glycoprotein. In this study, we show abnormal T cell immunity to several other CMPs in MS patients comparable to that in diabetics. Limited epitope mapping with the milk protein BSA identified one specific epitope, BSA(193), which was targeted by most MS but not diabetes patients. BSA(193) was encephalitogenic in SJL/J mice subjected to a standard protocol for the induction of experimental autoimmune encephalitis. These data extend the possible, immunological basis for the association of MS risk, CMP, and CNS autoimmunity. To pinpoint the same peptide, BSA(193), in encephalitis-prone humans and rodents may imply a common endogenous ligand, targeted through antigenic mimicry.     

Feature saltation and the evolution of mimicry

In Batesian mimicry, a harmless prey species imitates the warning coloration of an unpalatable model species. A traditional suggestion is that mimicry evolves in a two-step process, in which a large mutation first achieves approximate similarity to the model, after which smaller changes improve the likeness. However, it is not known which aspects of predator psychology cause the initial mutant to be perceived by predators as being similar to the model, leaving open the question of how the crucial first step of mimicry evolution occurs. Using theoretical evolutionary simulations and reconstruction of examples of mimicry evolution, we show that the evolution of Batesian mimicry can be initiated by a mutation that causes prey to acquire a trait that is used by predators as a feature to categorize potential prey as unsuitable. The theory that species gain entry to mimicry through feature saltation allows us to formulate scenarios of the sequence of events during mimicry evolution and to reconstruct an initial mimetic appearance for important examples of Batesian mimicry. Because feature-based categorization by predators entails a qualitative distinction between nonmimics and passable mimics, the theory can explain the occurrence of imperfect mimicry.     

A concept on the role of Helicobacter pylori infection in autoimmune pancreatitis

Autoimmune pancreatitis, an inflammatory process of the pancreas due to an autoimmune mechanism establishing etiology of chronic pancreatitis, is characterized by the presence of autoantibodies, hypergammaglobulinemia, pancreatic enlargement, pancreatic duct strictures, and pathologic features of fibrotic changes with intense, mainly lymphocytic infiltrations, which may contribute to tissue destruction probably by apoptosis. In almost 60% of the cases, this type of pancreatitis coexists with other autoimmune diseases such as Sjogren's syndrome, sclerosing extrahepatic cholangitis, primary biliary cirrhosis, autoimmune hepatitis, or other extrapancreatic disorders, and recently with gastric peptic ulceration. The diversity of extrapancreatic lesions with similar histopathologic findings suggests general involvement of the digestive system in this disease, although the presence of such involvement has not been fully elucidated. Similarly, Helicobacter pylori (H. pylori) infection, a well known cause of gastric ulcer, has been associated, via molecular mimicry of host structures by its constituents with the same autoimmune conditions, also characterized by fibrotic changes and/or lymphoplasmacytic inflammations, accompanied by aberrations of T cell apoptosis that contribute to hepatobiliary- or extrahepatic-tissue destruction. Considering that H. pylori is involved in the pathogenesis and pathophysiology of these autoimmune disorders, we propose that this organism might trigger autoimmune pancreatitis through induction of autoimmunity and apoptosis.     

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

Pediatric autoimmune liver disease is mainly represented by two similar liver disorders: autoimmune hepatitis (AIH) and autoimmune sclerosing cholangitis (ASC), both characterized by hypergammalobulinemia, interface hepatitis and the presence of a wide range of circulating autoantibodies. Although similar features are seen in AIH and inflammatory bowel disease, histological biliary changes are more common in ASC. In addition to their role as diagnostic markers, autoantibodies, such as anti-extractable nuclear antigen (ENA) antibodies and liver kidney microsomal antibody type 1 (LKM1) may be involved directly in inducing aggressive liver diseases. Although the cellular immune response in pediatric autoimmune liver disease has been less intensively investigated than humoral immunity, the importance of antigen specific T cells has been explored. Both alphabeta and gammadelta T cells derived from either peripheral blood and liver biopsies have highly heterogeneous TCR gene usage and cytolytic activity has been demonstrated. There have been attempts to seek triggers of liver autoimmunity and several sequences shared in common between autoantigens and hepatotropic viruses, namely hepatitis B, C and cytomegalovirus have been identified. The presence of cross-reactivity between homologous sequences, especially between HCV and cytochromes, supports the possibility that molecular mimicry plays a role in the induction of autoantibodies and autoreactive cytotoxic T cells.     

Molecular mimicry--hypothesis or reality?

A number of observations support molecular mimicry as a possible pathogenetic mechanism in diseases such as acute rheumatic fever, reactive arthritis after enteric infection or associated with Reiter''s syndrome, myasthenia gravis, or even in rheumatoid arthritis. Molecular mimicry can be defined as a sharing of epitopes in linear or 3-dimensional presentation on disparate proteins from entirely different sources--for instance, group A streptococcal membranes and human cardiac myosin. How exposure to or infection with organisms sharing molecular similarity with antigens of the human host can evade tolerance and actually induce a self-reacting humoral or cellular immune response is still not clear; however, a large body of evidence has now been accumulated that documents apparent molecular mimicry mechanisms in these disorders. In some diseases, the molecular mimicry appears to involve human target organs and specific components of the infectious organism, whereas in others the host HLA cell surface molecules appear to share antigens with presumed bacterial or viral initiators of disease.     

Functional activation of myelin-specific T cells by virus-induced molecular mimicry

Molecular mimicry is the process by which T cells activated in response to determinants on an infecting microorganism cross-react with self epitopes, leading to an autoimmune disease. Normally, infection of SJL/J mice with the BeAn strain of Theiler's murine encephalomyelitis virus (TMEV) results in a persistent CNS infection, leading to a chronic progressive, CD4(+) T cell-mediated demyelinating disease. Myelin damage is initiated by T cell responses to virus persisting in CNS APCs, and progressive demyelinating disease (50 days postinfection) is perpetuated by myelin epitope-specific CD4(+) T cells activated by epitope spreading. We developed an infectious model of molecular mimicry by inserting a sequence encompassing the immunodominant myelin epitope, proteolipid protein (PLP) 139-151, into the coding region of a nonpathogenic TMEV variant. PLP139-TMEV-infected mice developed a rapid onset paralytic inflammatory, demyelinating disease paralleled by the activation of PLP139-151-specific CD4(+) Th1 responses within 10-14 days postinfection. The current studies demonstrate that the early onset demyelinating disease induced by PLP139-TMEV is the direct result of autoreactive PLP139-151-specific CD4(+) T cell responses. PLP139-151-specific CD4(+) T cells from PLP139-TMEV-infected mice transferred demyelinating disease to naive recipients and PLP139-151-specific tolerance before infection prevented clinical disease. Finally, infection with the mimic virus at sites peripheral to the CNS induced early demyelinating disease, suggesting that the PLP139-151-specific CD4(+) T cells could be activated in the periphery and traffic to the CNS. Collectively, infection with PLP139-151 mimic encoding TMEV serves as an excellent model for molecular mimicry by inducing pathologic myelin-specific CD4(+) T cells via a natural virus infection.     

Microbial view of central nervous system autoimmunity

Not much is known about the initial events leading to the development of the central nervous system (CNS)-specific autoimmune disorder Multiple Sclerosis (MS). Environmental factors are suspected to trigger the pathogenic events in people with genetic disease susceptibility. Historically, many infectious microbes were linked to MS, but no infection has ever been demonstrated to be the cause of the disease. Recent emerging evidence from animal models of MS suggests a causal link with resident commensal bacteria. Microbial organisms may trigger the activation of CNS-specific, auto-aggressive lymphocytes either through molecular mimicry or via bystander activation. In addition, several gut microbial metabolites and bacterial products may interact with the immune system to modulate CNS autoimmunity.