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PubMed2002

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.

Amino Acid Sequence↗

PubMed2004

The Guillain-Barré syndrome: a true case of molecular mimicry.

Molecular mimicry between microbial antigens and host tissue forms an attractive hypothetical mechanism for the triggering of autoimmune disease by preceding infections. Recent crucial reviews state that molecular mimicry, as the causative mechanism, remains unproven for any human autoimmune disease. However, the peripheral neuropathy Guillain-Barré syndrome (GBS) is largely overseen in this debate. Based on recent evidence, we argue that GBS should be considered as an excellent paradigm and an attractive model for elucidation of both host and microbial aspects of molecular mimicry.

Animals↗

PubMed2004

Innate and adaptive immune requirements for induction of autoimmune demyelinating disease by molecular mimicry.

Molecular mimicry is the main postulated mechanism by which infectious agents induce autoimmune disease. A number of animal models have been utilized to establish a link between molecular mimicry and autoimmunity. However, a model of infectious disease whereby a natural pathogen expressing a known mimic epitope can induce autoimmunity to a known self-antigen leading to clinical autoimmune disease is still lacking. We have engineered a recombinant Theiler's murine encephalomyelitis virus (TMEV) to express an encephalitogenic myelin proteolipid protein PLP139-151 epitope (PLP-TMEV) and a PLP139-151 mimic peptide naturally expressed by Haemophilus influenzae (HI-TMEV). Infection of mice with either PLP-TMEV or HI-TMEV induces early-onset disease that is associated with the activation of cross-reactive PLP139-151-specific immunopathologic CD4+ Th1 cells. Based on results from this model, we hypothesize, due to the considerable degeneracy in the T cell repertoire, that induction of full-blown autoimmune disease via molecular mimicry is a tightly regulated process requiring multiple factors related to the pathogen expressing the potential mimic epitope. In this review, we will discuss how various factors related to the infectious environment control whether or not autoimmune disease is initiated. Contributing factors include the nature of the innate immune response to the pathogen which determines the immunopathologic potential of the induced cross-reactive T cells, the capacity of the mimic epitope to be processed and presented from its natural flanking sequences in the pathogen-encoded protein, the site(s) of the primary infection in the host and the ability of the pathogen to persist, and the potential requirement for multiple infections with the same or different pathogens.

Animals↗

PubMed1995

Similar antigenic surfaces, rather than sequence homology, dictate T-cell epitope molecular mimicry.

Molecular mimicry, normally defined by the level of primary-sequence similarities between self and foreign antigens, has been considered a key element in the pathogenesis of autoimmunity. Here we describe an example of molecular mimicry between two overlapping peptides within a single self-antigen, both of which are recognized by the same human self-reactive T-cell clone. Two intervening peptides did not stimulate the T-cell clone, even though they share nine amino acids with the stimulatory peptides. Molecular modeling of major histocompatibility complex class II-peptide complexes suggests that both of the recognized peptides generate similar antigenic surfaces, although these are composed of different sets of amino acids. The molecular modeling of a peptide shifted one residue from the stimulatory peptide, which was recognized in the context of the same HLA molecule by another T-cell clone, generated a completely different antigenic surface. Functional studies using truncated peptides confirmed that the anchor residues of the two "mimicking" epitopes in the HLA groove differ. Our results show, for two natural epitopes, how molecular mimicry can occur and suggest that studies of potential antigenic surfaces, rather than sequence similarity, are necessary for analyzing suspected peptide mimicry.

Amino Acid Sequence↗

PubMed2005

Induction of endothelial cell damage by hCMV molecular mimicry.

Molecular mimicry between infectious agents and normal human host cell components is one of the mechanisms responsible for autoimmunity. Among infectious agents, some viruses represent ideal candidates for their ability to infect human cells, where they are harbored for the duration of the life of the host in a latent state. Human cytomegalovirus (hCMV) infection has been implicated in the pathogenesis of vascular damage in systemic sclerosis (SSc) and atherosclerosis. Based on recent data describing a cause and effect relationship between hCMV and endothelial cell damage in SSc and atherosclerosis, we propose that the immune response to particular hCMV proteins might result in autoaggression through a mechanism of molecular mimicry of normally expressed endothelial cell surface molecules.

Arteriosclerosis↗

PubMed1991

HIV-1: seven facets of functional molecular mimicry.

Molecular mimicry, where structural properties borne by a pathogen "imitate" or "simulate" molecules of the host, is shown to take make different forms in the molecular biology of the human immunodeficiency virus type 1 (HIV-1). There is considerable evidence that a number of important immunopathologic processes are incited by HIV-1 infection, due to molecular mimicry. Accordingly, a systematic review of this evidence is intended to define the fundamental immunopathogenic properties of this virus in terms relevant to the science of acquired immunodeficiency syndrome (AIDS) susceptibility, prevention, and treatment.

Adaptation, Biological↗

PubMed2005

Molecular mimicry or structural mimicry?

"Molecular mimicry" should be changed to "structural mimicry". The immune system recognizes shapes--three-dimensional shapes--not sequences. For two sequences to act biologically similar they must possess similar three-dimensional structures.

Amino Acid Sequence↗

PubMed2004

Disease mimicry--a pathogenetic concept for T cell-mediated autoimmune disorders triggered by molecular mimicry?

Molecular mimicry is considered as a mechanism by which infectious pathogens may break immunological tolerance and cause autoimmune disease. It implicates that peptides shared between pathogen and host may induce cross-reactive immune reactions. According to this hypothesis, the resulting autoimmune response actually represents a secondary immune response. It is mediated by cross-reactive T cells that have been educated in a primary immune response against a particular pathogen. Using psoriasis vulgaris as a model, this article discusses the potential functional consequences molecular mimicry should have for the resulting autoimmune disease. It proposes that due to the functional memory of T cells, which is an integral feature of adaptive immunity, the phenotype of an autoimmune disease induced by molecular mimicry should reflect the immune mechanisms raised in the primary immune response. This process might be called 'disease mimicry'.

Autoimmune Diseases↗

PubMed1994

Sequence homology of the diabetes-associated autoantigen glutamate decarboxylase with coxsackie B4-2C protein and heat shock protein 60 mediates no molecular mimicry of autoantibodies.

Molecular mimicry between viral antigens and host proteins was often suggested to be involved in induction of autoimmune diseases. In type 1 diabetes where pancreatic beta cells are destroyed by autoimmune phenomena, a linear sequence homology between a major autoantigen, glutamate decarboxylase (GAD), and the 2C protein of coxsackie B4 was identified. In addition, a sequence homology between GAD and the mycobacterial heat shock protein 60 was described and the suggestions were made that molecular mimicry between GAD, coxsackievirus B4-2C protein, and/or heat shock protein 60 (hsp60) may be actively involved in an autoimmune reaction towards the pancreatic beta-cells. Our group was the first to isolate human monoclonal autoantibodies to GAD (MICA 1-6) from a patient with newly diagnosed type 1 diabetes. The MICA allowed a detailed characterization of the diabetes associated self-epitopes in GAD and represent a set of GAD autoantibodies present in sera from patients with type 1 diabetes. Using deletion mutants of GAD we demonstrated that the regions of GAD covering the homology sequences to coxsackievirus B4 and to the hsp60 were absolutely required for binding of the MICA to GAD. We now designed an antibody-based analysis to ask whether molecular mimicry between GAD and coxsackie B4-2C or hsp60 is relevant in type 1 diabetes. Since part of the MICA recognize conformational epitopes, they allow to test for conformational molecular mimicry in viruses that have been incriminated in the development of type 1 diabetes. Our data reveal no crossreactivity between the diabetes associated GAD epitopes defined by the MICA and hsp60, rubellavirus, cytomegalovirus, and coxsackie B1-B6 virus antigens. Neither coxsackie B4-specific antibodies in sera from normal individuals nor GAD-positive sera from patients with type 1 diabetes indicated a crossreactivity between coxsackie B4-2C and GAD. Although the regions in GAD homologous to coxsackie B4-2C and hsp60 represented parts of GAD indispensible for binding of diabetes associated autoantibodies they did not mediate a crossreactivity of autoantibodies between GAD and these two proteins. No evidence for molecular mimicry between GAD and a whole panel of foreign antigens was detected by autoantibodies in type 1 diabetes.

Amino Acid Sequence↗

PubMed2005

A structural basis for CD8+ T cell-dependent recognition of non-homologous peptide ligands: implications for molecular mimicry in autoreactivity.

Molecular mimicry of self-epitopes by viral antigens is one possible pathogenic mechanism underlying induction of autoimmunity. A self-epitope, mDBM, derived from mouse dopamine beta-mono-oxygenase (KALYDYAPI) sharing 44% sequence identity with the lymphocytic choriomeningitis virus-derived immunodominant epitope gp33 (KAVYNFATC/M), has previously been identified as a cross-reactive self-ligand, presentation of which results in autoimmunity. A rat peptide homologue, rDBM (KALYNYAPI, 56% identity to gp33), which displayed similar properties to mDBM, has also been identified. We herein report the crystal structure of H-2Db.rDBM and a comparison with the crystal structures of the cross-reactive H-2Db.gp33 and non-cross-reactive H-2Db.gp33 (V3L) escape variant (KALYNFATM, 88% identity to gp33). Despite the large sequence disparity, rDBM and gp33 peptides are presented in nearly identical manners by H-2Db, with a striking juxtaposition of the central sections of both peptides from residues p3 to p7. The structural similarity provides H-2Db in complex with either a virus-derived or a dopamine beta-mono-oxygenase-derived peptide with a shared antigenic identity that conserves the positioning of the heavy chain and peptide residues that interact with the T cell receptor (TCR). This stands in contrast to the structure of H-2Db.gp33 (V3L), in which a single conserved mutation, also present in rDBM, induces large movements of both the peptide backbone and the side chains that interact with the TCR. The TCR-interacting surfaces of the H-2Db.rDBM and H-2Db.gp33 major histocompatibility complexes are very similar with regard to shape, topology, and charge distribution, providing a structural basis for CD8 T cell activation by molecular mimicry and potential subsequent development of autoreactivity.

Animals↗

PubMed2006

Molecular mimicry in mercury toxicology.

Molecular mimicry occurs when one molecular entity is "mistaken" for another by cellular or other biological processes, and is thought to arise from structural similarities between the two molecules in question. It has been postulated by others to be important in the mechanism of uptake of toxic metal species into living tissues. A widely accepted example is the transport of methylmercury-cysteine species, which are thought to mimic the amino acid methionine. We have used mass spectrometry and mercury L(III)-edge X-ray absorption spectroscopy to understand the solution structure of complexes between methylmercury and cysteine. With a view to understanding the basis of the suggested molecular mimicry mechanisms, we have used computational chemistry to compare the structure of methionine with that of the dominant solution species L-cysteinato(methyl)mercury(II), and the structure of cystine with that of mercury(II) bis-L-cysteineate. We conclude that the structural similarities between metal compounds and natural products are insufficient to support a mechanism based on molecular mimicry, but instead, mechanisms involving a less-specific mimicry based on similarity with the L(alpha) region of the amino acid part of the molecule.

Amino Acids↗

PubMed2002

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.

Antibodies, Monoclonal↗

PubMed2001

A virus-induced molecular mimicry model of multiple sclerosis.

Molecular mimicry is the process by which virus infection activates T cells that are cross-reactive with self antigens. Infection of SJL/J mice with the neurotropic picornavirus Theiler's murine encephalomyelitis virus (TMEV) leads to a progressive CD4(+) T cell-mediated demyelinating disease similar to multiple sclerosis. To study the potential of virus-induced molecular mimicry to initiate autoimmune demyelination, a nonpathogenic TMEV variant was engineered to encode a 30-mer peptide encompassing the immunodominant encephalitogenic myelin proteolipid protein (PLP139-151) epitope. Infection with the PLP139-151-encoding TMEV led within 10-14 days to a rapid-onset paralytic demyelinating disease characterized by PLP139-151-specific CD4(+) Th1 responses; insertion of a non-self ovalbumin sequence led to restoration of the normal late-onset disease. Early-onset disease was also observed in mice infected with a TMEV encoding PLP139-151 with an amino acid substitution at the secondary T cell receptor (TCR) contact residue (H147A), but not in mice infected with TMEV encoding a PLP139-151 substitution at the primary TCR contact (W144A). Most significantly, mice infected with TMEV encoding a Haemophilus influenzae mimic peptide, sharing only 6 of 13 amino acids with PLP139-151, displayed rapid-onset disease and developed cross-reactive PLP139-151-specific CD4(+) Th1 responses. To our knowledge, this is the first study showing that a naturally infectious virus encoding a myelin epitope mimic can directly initiate organ-specific T cell-mediated autoimmunity.

Amino Acid Sequence↗

PubMed1994

Molecular mimicry between Fc receptors and viral antigens.

Molecular mimicry has been characterized as the presence of common epitopes, either linear or conformational, shared by host and microbial determinants. Such cross-reactivity may lead to an autoimmune disease. On the other hand molecular mimicry between certain viral proteins and host determinant may protect invading virus to be eliminated by immune system and may promote persistence. In this mini-review I discuss the molecular mimicry of S peplomer protein of mouse hepatitis virus, strain JHM (MHV-JHM) to the host Fc gamma receptor (Fc gamma R). MHV-JHM induces in rodents acute encephalomyelitis and surviving animals develop demyelinating disease with concomitant persistent infection. We have demonstrated that rabbit IgG, but not is F(ab')2 fragments, monoclonal rat and mouse IgG and the rat 2.4G2 anti-Fc gamma R mab immunoprecipitated natural and recombinant S peplomer protein of several strains of MHV. Furthermore, MHV-JHM infected cells formed rosettes with anti-sheep red blood cell (SRBC) - antibody coated SRBC. The 2.4G2 anti-Fc gamma R mab are able to neutralize several strains of MHV, presumably by binding to S peplomer protein. Therefore, the Fc binding site of S is present on the surface of MHV-infected cells. This molecular mimicry between S peplomer protein of MHV-JHM and Fc gamma R has been extended to other members of Coronaviridae, namely bovine coronavirus and transmissible gastroenteritis virus but not to infectious bronchitis virus. The molecular mimicry of viral antigens to Fc receptors has been described also for members of Herpesviridae, namely Herpes simplex, cytomegalovirus and Varicella zoster.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1997

[Molecular mimicry and mechanisms of autoantibody production].

Molecular mimicry is defined as similar structures shared by products of dissimilar genes. This review article discusses a possible role of molecular mimicry in the production of autoantibodies. Antibodies reactive with products of bacterial and viral genes sometime cross-react with normal cellular proteins. Sera from patients with systemic autoimmune diseases show crossreactivity with some bacterial and/or viral gene products at a significant frequency. Identification of the structures of antigenic epitopes recognized by disease-associated autoantibodies by expression cloning of autoantigen molecules and gene fragment expression revealed the amino acid residues that are shared by autoantibody-defined epitopes and microbial proteins. The presence of amino acid sequences shared between microbial proteins and autoantigens and the detection of antibodies in patients' sera that bind to the crossreactive epitopes suggest that immune responses to bacterial and viral infections may initiate the production of autoantibodies. Receptor-mediated phagocytosis of autoantigen molecules by crossreactive B cells and subsequent antigen presentation to helper T cells may facilitate the production of autoantibodies reactive with separate epitopes, if the autoantigen complex contains multiple B-cell epitopes and a shared T helper cell epitope. Analyses of the fine specificity of T helper cell epitopes on Friend murine leukemia virus env gene products revealed unexpected heterogeneity and redundancy of T cell responses even to a single epitope. This heterogeneity in T cell responses might play a role in the activation of self-reactive T helper cells through molecular mimicry.

Animals↗

PubMed2001

Exploiting molecular mimicry: defining rules of the game.

Molecular mimicry has been touted as a mean to develop new generation of vaccines to target carbohydrate antigens on pathogens and on tumor cells. Structural and immunological rules governing molecular mimicry require definition for its successful exploitation. Of interest are the kinds of structures that peptides adopt as carbohydrate mimics, the extent to which topological or sequence similarities among peptide mimeotopes define serum cross-reactivity to carbohydrate antigens and the extent to which peptide mimeotopes affect T-cell responses. Rational design concepts can be applied to define how a peptide may mimic carbohydrate antigens, similarities in binding affinities of antibodies for carbohydrate and for peptides, how peptides can mimic core structures on otherwise dissimilar carbohydrate antigens, and how peptide mimeotopes can be used to manipulate cellular responses not achievable by carbohydrate antigens.

Amino Acid Sequence↗

PubMed1998

Molecular mimicry and immune-mediated diseases.

Molecular mimicry has been proposed as a pathogenetic mechanism for autoimmune disease, as well as a probe useful in uncovering its etiologic agents. The hypothesis is based in part on the abundant epidemiological, clinical, and experimental evidence of an association of infectious agents with autoimmune disease and observed cross-reactivity of immune reagents with host 'self' antigens and microbial determinants. For our purpose, molecular mimicry is defined as similar structures shared by molecules from dissimilar genes or by their protein products. Either the molecules' linear amino acid sequences or their conformational fits may be shared, even though their origins are as separate as, for example, a virus and a normal host self determinant. An immune response against the determinant shared by the host and virus can evoke a tissue-specific immune response that is presumably capable of eliciting cell and tissue destruction. The probable mechanism is generation of cytotoxic cross-reactive effector lymphocytes or antibodies that recognize specific determinants on target cells. The induction of cross-reactivity does not require a replicating agent, and immune-mediated injury can occur after the immunogen has been removed a hit-and-run event. Hence, the viral or microbial infection that initiates the autoimmune phenomenon may not be present by the time overt disease develops. By a complementary mechanism, the microbe can induce cellular injury and release self antigens, which generate immune responses that cross-react with additional but genetically distinct self antigens. In both scenarios, analysis of the T cells or antibodies specifically engaged in the autoimmune response and disease provides a fingerprint for uncovering the initiating infectious agent.

Animals↗

PubMed2003

Molecular mimicry in the decoding of translational stop signals.

Molecular mimicry was a concept that was revived as we understood more about the ligands that bound to the active center of the ribosome, and the characteristics of the active center itself. It has been particularly useful for the termination phase of protein synthesis, because for many years this major process seemed not only to be out of step) with the initiation and elongation phases but also there were no common features of the process between eubacteria and eukaryotes. As the facts that supported molecular mimicry emerged, it was seen that the protein factors that facilitated polypeptide chain release when the decoding of an mRNA was complete had common features with the ligands involved in the other phases. Moreover, now common features and mechanisms began to emerge between the eubacterial and eukaryotic RFs and suddenly there seemed to be remarkable synergy between the external ligands and commonality in at least some features of the mechanistic prnciples. Almost 10 years after molecular mimicry took hold as a framework concept, we can now see that this idea is probably too simple. For example, structural mimicry can be apparent if there are extensive conformational changes either in the ribosome active center or in the ligand itself or, most likely, both. Early indications are that the bacterial RF may indeed undergo extensive conformational changes from its solution structure to achieve this accommodation. Thus, as important if not more important than structural and functional mimicry among the ligands, might be their accomodation of a common single active center made up of at least three parts to carry out a complex series of reactions. One part of the ribosomal active center is committed to decoding, a second is committed to the chemistry of putting the protein together and releasing it, and a third part, perhaps residing in the subdomains, is committed to binding ligands so that they can perform their respective single or multiple functions. It might be more accurate to regard the decoding RF as the cuckoo taking over the nest that was crafted and honed through evolution by another, the tRNA. A somewhat ungainly RF, perhaps bigger in dimensions than the tRNA, is able, nevertheless, like the cuckoo, to maneuvre into the nest. Perhaps it pushes the nest a little out of shape, but is still able to use the site for its own functions of stop signal decoding and for facilitating the release of the polypeptide. The term molecular mimicry has been dominant in the literature for a period of important advances in the understanding of protein synthesis. When the first structures of the ribosome appeared, the concept survived and was seen to be valid still. Now, we are at the stage of understanding the more detailed molecular interactions between ligands and the rRNA in particular, and how subtle changes in localized spatial orientations of atoms occur within these interactions. The simplicity of the original concept of mimicry will inevitably be blurred by this more detailed analysis. Nevertheless, it has provided a significant set of principles that allowed development of experimental programs to enhance our understanding of the dynamic events at this remarkable active site at the interface between the two subunits of this fascinating cell organelle, the ribosome.

Amino Acid Sequence↗