Role Of Molecular Mimicry Research Articles

Potential role of molecular mimicry between human U1-70kDa and fungal proteins in the development of T-cell mediated anti-U1-70kDa autoimmunity

Context: Molecular mimicry between human and microbial antigens is a possible trigger of autoimmunity. The possible role of this mechanism in the onset of autoimmunity against the human autoantigen U1-70kDa, typical of mixed connective tissue disease, is not fully elucidated.Objective: We aimed to identify microbial proteins highly similar to U1-70kDa and potentially triggering anti-U1-70kDa autoimmunity.Materials and methods: We compared in silico the amino acid sequence of human U1-70kDa and those of all the sequenced fungal, viral and bacterial proteins.Results: Human U1-70kDa shares highly significant (E<10−20) amino acid sequence homology, spanning a segment containing T-cell epitopes, with 13 fungal (but no viral or bacterial) proteins, belonging to human pathogens. Nine of these proteins include the amino acid sequence VLVDVERGRTV, identical to the most frequent U1-70kDa T-cell epitope in anti-U1-70kDa positive patients, and sequences highly similar to the epitope DAFKTLFVARVN (identical residues or conservative residue substitutions in positions crucial for epitope binding).Discussion and conclusion: Cross-reactivity between human U1-70kDa and microbial proteins was demonstrated for B-cell epitopes, but never investigated before for T-cell epitopes. Our data identify some fungal proteins as possible triggers of anti-U1-70kDa autoimmunity via molecular mimicry. Research in this field could improve the understanding of the mechanisms leading to anti-U1-70kDa autoimmunity, with potential consequences on prevention.

The human Ku autoantigen shares amino acid sequence homology with fungal, but not bacterial and viral, proteins

Context: Molecular mimicry between autoantigens and microbial antigens is a possible triggering mechanism of autoimmunity. Human Ku is a DNA-associated autoantigen targeted by autoantibodies in patients with systemic lupus erythematosus and related disorders; available data are consistent with a role of molecular mimicry in the pathogenesis of Anti-Ku autoimmunity, but no research exist on this topic.Objective: We aimed to define the most probable microbial triggers of anti-Ku autoimmunity via molecular mimicry. Materials and methods. We performed a computer-assisted search for amino acid sequence homologies between the two subunits of human Ku and proteins of known human pathogens.Results: Some fungal, but no bacterial or viral, proteins have statistically significant amino acid sequence homology with the p70 or p80 subunit of Ku. Twenty-six fungal proteins contain long segments highly homologous to p70 (14 proteins) or p80 (12 proteins) and belong to human pathogens (Aspergillus clavatus, Aspergillus fumigatus, Aspergillus nidulans, Aspergillus niger, Aspergillus terreus, Chaetomium globosum, Cryptococcus neoformans, Coccidioides immitis, Malassezia globosa, Neosartorya fischeri, Penicillium chrysogenum Wisconsin, Penicillium marneffei, and Yarrowia lipolytica). Twelve p70-homologous and eleven p80-homologous segments span at least one T cell epitope-containing part of the respective human Ku subunit (in the other cases, overlap is almost complete).Discussion and Conclusion: We postulate that, in genetically predisposed persons, infection by the above fungi can be a trigger in the onset of anti-Ku autoimmunity via molecular mimicry between fungal proteins and the Ku autoantigen. Due to the low frequency of anti-Ku autoimmunity, multicentric collaboration is necessary to verify our hypothesis.

Breaking self-tolerance toward cytochrome P4502E1 (CYP2E1) in chronic hepatitis C: Possible role for molecular mimicry

Circulating auto-antibodies targeting conformational antigens on cytochrome P4502E1 (CYP2E1) are detectable in patients with chronic hepatitis C (CHC) and are associated with more severe necro-inflammation. This study investigated the antigen specificity and the possible origin of these auto-antibodies. CYP2E1 site-directed mutagenesis and molecular simulation were used to characterize the epitope specificity of CHC-associated anti-CYP2E1 auto-antibodies. Immunoprecipitation experiments using differently mutated human CYP2E1s revealed that conformational anti-CYP2E1 antibodies targeted two epitopes located on the molecule surface in an area between Lys(324)-Glu(346) at J-K'' helices overlapping. Such epitopes were not recognized by the sera targeting linear CYP2E1 antigens. The CYP2E1(324-346) peptide showed good homology with two sequences (NS5b(438-449) and NS5b(456-465)) within the NS5b protein of hepatitis C virus (HCV). Consistently, conformational anti-CYP2E1 IgG bind to GST-conjugated NS5b(438-449) and NS5b(456-465) more efficiently than those recognizing CYP2E1 linear antigens. Competition experiments confirmed the cross-reactivity of conformational anti-CYP2E1 IgG with both NS5b(438-449) and NS5b(456-465). Moreover, mice immunized with GST-conjugated NS5b(438-449) or NS5b(456-465) peptides developed antibodies recognizing human CYP2E1. In CHC patients cross-reactivity between CYP2E1 and specific sequences in HCV-NS5b protein can promote the development of auto-antibodies targeting conformational epitopes on the CYP2E1 surface that might contribute to hepatic injury.

W1938 Antibody to Cytolethal Distending Toxin of Campylobacter Jejuni Stains Small Bowel Myenteric Neuromuscular Elements in Control and C. Jejuni Exposed Rats: A Possible Role of Molecular Mimicry

W1938 Antibody to Cytolethal Distending Toxin of Campylobacter Jejuni Stains Small Bowel Myenteric Neuromuscular Elements in Control and C. Jejuni Exposed Rats: A Possible Role of Molecular Mimicry

Pentapeptide overlapping between human immunodeficiency viruses and Home sapiens proteomes is higher than 90%

We used sequence-to-sequence peptide matching to analyze the similarity level of the HIV-1, HIV-2 and HTLV polyprotein sequences to the human proteome. The following results were obtained: 1) pentapeptides from the viral polyproteins are widely, repeatedly and intensively represented in a large number of human proteins; 2) high level of similarity of viral versus human proteomes is still present even using esa- or eptapeptide motifs as probes for sequence identity scanning; 3) a relatively limited number of viral pentameric fragments (about 10% or less) are unique to the viruses with no similarity to the human host; 4) the distribution of the zero similarity pentapeptides is not random in the three main immunodeficiency virus strains, with a maximum clustering in the HIV-2 p160 aa 1007-1019 sequence. The data are important in relation to the role of molecular mimicry in the genesis and diagnosis of immunodeficiency diseases, and the use of low similarity amino acid sequences as a peptidome platform for anti-HIV vaccine constructs exempt from harmful collateral cross-reactions.

ORIGINAL ARTICLE: Murine Monoclonal Antibody 26 Raised Against Tetanus Toxoid Cross‐Reacts with β2‐Glycoprotein I: Its Characteristics and Role in Molecular Mimicry

Problem Studies on experimental antiphospholipid syndrome (APS) models proved that molecular mimicry between plasma protein β2‐glycoprotein I (β2GPI) and structure within micro‐organisms or their products, might be a cause for experimental APS. Considering the heterogeneity of polyclonal antiphospholipid antibodies (aPLs), it is important to define the precise characteristics of pathogenic aPLs. To avoid the influence of polyclonality and to further analyse the connection between molecular mimicry and APS, we produced monoclonal antibodies (MAbs) against tetanus toxoid (TTd) and tested their reactivity against β2GPI.Method of study In this report, we analysed the characteristics of MAb26 raised against TTd and cross‐reactive with β2GPI: its binding properties in various in vitro immunoassays, its specific interactions with surface epitopes expressed on apoptotic cells and its role in vivo.Results We have demonstrated that MAb26: (i) binds β2GPI being immobilized on an appropriate surface: irradiated polystyrene plates, non‐irradiated plates pre‐coated with anionic phospholipids and polyvinylidene fluoride membrane; (ii) binds specifically to apoptotic but not to viable cells and the binding is β2GPI‐dependent; and (iii) induces a pathologic pregnancy outcome when passively injected into BALB/c mice.Conclusion This study concluded that certain subpopulations of antibodies raised against TTd and cross‐reactive with β2GPI, because of the molecular mimicry mechanism, could have pathologic potential.

Bacteria and Primary Biliary Cirrhosis

Infectious agents have been postulated to play a pathogenic role in the loss of immunological tolerance and the induction of primary biliary cirrhosis, an immune-mediated cholestatic liver disease characterized by progressive destruction of the small intrahepatic bile ducts and subsequent cirrhosis and liver failure. This review discusses emerging issues implicating infectious agents such as Escherichia coli, mycobacteria, chlamydia, helicobacter species, lactobacilli, Novosphingobium aromaticivorans, and betaretroviruses in the pathogenesis of primary biliary cirrhosis. We also review the immunopathological mechanisms responsible for the induction of the disease with special emphasis on the role of molecular mimicry and microbial/self immunological cross-reactivity.

Possible role of molecular mimicry in pathogenesis of Ebola virus: implications for a rational vaccine design

Ebola Virus (EBOV) presents a challenge for vaccine development because immune correlates of protection in humans are not well known. In earlier studies we developed a concept of local similarity which refers to resemblance of structural patterns of unrelated proteins as a function of their amino acid composition. The search for local similarities between human and EBOV proteins was performed. The resemblance of NP protein of EBOV to vascular endothelial growth factor and its receptor, which play a key role in the regulation of vascular permeability, was identified. A high degree of local similarity of Ebola GP protein with the tactile protein of the T-cell surface was also revealed. The similarity of the Ebola VP24 protein fragment with complement receptor type 1 (CD35 antigen) appears to be correlated with early activation of complement in lethal Ebola fever. This finding supports our prior studies indicating that VP24 determines the difference between lethal and non-lethal strains of EBOV. Several other similarities of potential significance were identified that might play an important role in the aetiology of Ebola-induced disease. In conclusion, local similarities between EBOV and human host proteins may provide a key to rational design of safe and effective filovirus vaccines. Such a vaccine must be free from epitopes that could potentially trigger Ebola-like hemorrhagic fever due to an autoimmune reaction induced by vaccination and other unanticipated adversities.

Response to Hyland and Engman: Chagas disease – the solutions lie ahead

Response to Hyland and Engman: Chagas disease – the solutions lie ahead

Role of immunologic cross-reactivity in neurological diseases

Although the immune system evolved to protect the host from foreign infection, it can sometimes recognize and attack host tissues, a phenomenon known as autoimmunity. In addition to genetic factors, environmental elements such as viruses and bacteria are thought to play a role in the development of autoimmune diseases. The major hypothesized mechanism by which infection with these agents can lead to autoimmunity is termed molecular mimicry. Here, immune responses initiated against foreign antigens are cross-reactive with self-antigens. This is thought to occur especially if the foreign antigen is similar in structure or amino acid sequence to the self-antigen. In this review, we explore evidence for the role of molecular mimicry in neurological diseases.

Роль молекулярної мімікрії у тестуванні ВІЛ-інфекції

Роль молекулярної мімікрії у тестуванні ВІЛ-інфекції

Most nuclear systemic autoantigens are extremely disordered proteins: implications for the etiology of systemic autoimmunity

Patients with systemic autoimmune diseases usually produce high levels of antibodies to self-antigens (autoantigens). The repertoire of common autoantigens is remarkably limited, yet no readily understandable shared thread links these apparently diverse proteins. Using computer prediction algorithms, we have found that most nuclear systemic autoantigens are predicted to contain long regions of extreme structural disorder. Such disordered regions would generally make poor B cell epitopes and are predicted to be under-represented as potential T cell epitopes. Consideration of the potential role of protein disorder may give novel insights into the possible role of molecular mimicry in the pathogenesis of autoimmunity. The recognition of extreme autoantigen protein disorder has led us to an explicit model of epitope spreading that explains many of the paradoxical aspects of autoimmunity – in particular, the difficulty in identifying autoantigen-specific helper T cells that might collaborate with the B cells activated in systemic autoimmunity. The model also explains the experimentally observed breakdown of major histocompatibility complex (MHC) class specificity in peptides associated with the MHC II proteins of activated autoimmune B cells, and sheds light on the selection of particular T cell epitopes in autoimmunity. Finally, the model helps to rationalize the relative rarity of clinically significant autoimmunity despite the prevalence of low specificity/low avidity autoantibodies in normal individuals.

Generation of liver/kidney microsomal-1 antibody in HCV infection: The role of molecular mimicry

Generation of liver/kidney microsomal-1 antibody in HCV infection: The role of molecular mimicry

Molecular pathogenesis of multiple sclerosis

Multiple sclerosis (MS) is best understood as an inflammatory disease of the central nervous system (CNS) white matter characterized by demyelination, focal T cell and macrophage infiltrates, axonal injury and loss of neurological function. Our current understanding invokes proinflammatory cells and mediators that may be triggered by environmental factors to mediate disease in a genetically susceptible host. Five major themes which have been associated with the pathogenesis of MS lesions will be discussed: (1) The differential activation states of myelin-reactive T cells from MS patients vs. normal individuals, (2) the selective expression of chemokines, adhesion molecules and matrix metalloproteinases, (3) the proposed roles of the B7 costimulatory pathway, (4) the proinflammatory cytokines and (5) the role of molecular mimicry.

Quantitative determination of TCR cross-reactivity using peptide libraries and protein databases.

A single T cell clone can be activated by many different peptides in the context of a particular HLA molecule. To quantify the number of peptides that can be recognized by a CD4(+) T cell clone, we screened a one-bead-one-peptide synthetic peptide library and a protein database for peptides that stimulate an HLA-DR3-restricted, human glutamic acid decarboxylase (GAD65)-reactive CD4(+) T cell clone. Both the library screening and the database analysis indicated that this T cell clone is able to recognize approximately 10(6) 11-mer peptides at low nanomolar concentration. Furthermore, we determined that the frequency of cross-reactivity increased only 1.5-3 times when the peptide concentration increased 10 times, in the range of 0.01 - 1 microM. These data imply that there is a considerable potential for T cell cross-reactivity and are useful for studies on the role of molecular mimicry in the etiology of T cell-mediated disease.

A humoral response to oligodendrocyte-specific protein in MS: a potential molecular mimic.

To determine the antibody response to oligodendrocyte-specific protein (OSP) in patients with MS. OSP is a recently identified CNS-specific myelin protein that is abundant and therefore a candidate autoantigen in MS. The presence of anti-OSP antibodies was determined using Western blot analysis, peptide blots, and ELISA in patients with MS and in other neurologic and normal control subjects. Using Western blot analysis, seven patients with relapsing-remitting MS (RRMS) were found to contain anti-OSP antibodies in their CSF that were not present in control subjects. Peptide mapping determined that the antibody response was directed to a seven aa peptide (OSP 114-120), which has 71% homology with several common pathogenic proteins. Using OSP 114-120 as antigen, ELISAs were performed on CSF from 85 MS and 51 control patients. Eighty percent of the samples from RRMS patients followed at the University of California at Los Angeles had an ELISA reading above 0.55 optical density units, whereas all 20 control CSF samples had values less than 0.55 U. Similar results were found in specimens from an outside research bank. ELISAs performed on CSF using homologous viral peptides as antigen showed a close correlation with anti-OSP 114-120 ELISA readings, and in some, the readings were higher than those using OSP peptides. There is a specific humoral response directed against a region of OSP in RRMS patients that cross-reacts with several common viral peptides. This suggests a possible role for molecular mimicry in the development of MS.

A humoral response to OSP in multiple sclerosis: A molecular mimic?

Oligodendrocyte-specifie protein (OSP) is a recently isolated novel protein found only in CNS laminar myelin and therefor is a good candidate as an autoantigen in patients with MS. In order to determine the humoral response in patients with MS. Westren blot analysis was performed on CSF from 6 patients with clinically stable relapsing MS (rMS) and 2 normal controls. All 6 of the CSF samples from rMS patients contained anti-OSP antibodies and none were detected in controls. Peptide mapping determined that the antigenic response was directed at a 7 amino acid peptide (OSP 114-120) which was 71% homologous with several common viral and bacterial proteins and 100% identical to the human OSP protein. ELISAs were performed using OSP 114-20 as antigen on a total 32 MS patints followed at UCLA, 53 MS patients from the National Neurological Rescarch Specimen Bank (NNRSB), and on 51 neurological control samples. Eighty % of UCLA rMS patients had an OSP ELISA reading above 0.55 OD units (median ± SD, 0.94 ± .35) while 0 of 14 CSF samples from HTLV-1 patients and normal controls had values above 0.55 units (0.28 ± .12; p&lt;.01). Similar results were found in specimens from the NNRSB. No differences in anti-OSP titers were found in serum of MS and control patients. ELISAs performed on CSF samples using homologus viral peptieds as antigen (e.g. EBV, HSV HIV) showed a close correlation with anti-OSP 114-120 titers, and in some, the anti-viral titers far exceeded them. These data demonstrate a specific humoral response directed against a region of OSP in rMS patinets which cross reacts with several common viral peptides and suggests a possible role of molecular mimicry in the development of MS.

Immunogenetics in the analysis of resistance to intracellular pathogens

Recent studies have identified genes involved in resistance to intracellular pathogens. Such genes include the murine MHC class I gene, L d (toxoplasmosis), HLA-BW53, HLA DRB1 ∗ 1302-DQ B10s01 and TNF2 (malaria), murine Nramp (toxoplasmosis, leishmaniasis and tuberculosis), gene(s) modulating the T-helper type 1 and type 2 dichotomy (leishmaniasis, leprosy and HIV infection) and the natural killer cell complex (cytomegalovirus infection). There also been other advances in immunogenetics that have led to a better understanding of resistance to intracellular pathogens. These include effector mechanisms of immune response genes and factors modulating genetic susceptibility. Identification of genes that determine resistance/susceptibility (and their effector mechanisms) has impacted on vaccine development. Immunogenetics has been important in characterizing roles of TCR genes, superantigens, and host genes that play a role in molecular mimicry in disease pathogenesis. In addition, recent work with gene knockout, recombinant inbred or congenic, mutant, consomic, and transgenic mice, positional cloning, mouse/human gene homologies to identify candidate human resistance genes, and the rapid expansion of the gene transcription maps of the human genome, have been important in analysis of resistance to intracellular pathogens.