Evidence For Molecular Mimicry Research Articles

Evidence for Molecular Mimicry between SARS-CoV-2 and Human Antigens: Implications for Autoimmunity in COVID-19.

As for other viral diseases, the mechanisms behind the apparent relationship between COVID-19 and autoimmunity are yet to be clearly defined. Molecular mimicry, the existence of sequence and/or conformational homology between viral and human antigens, could be an important contributing factor. Here, we review the accumulated evidence supporting the occurrence of mimicry between SARS-CoV-2 and human proteins. Both bioinformatic approaches and antibody cross-reactions have yielded a significant magnitude of mimicry events, far more common than expected to happen by chance. The clinical implication of this phenomenon is ample since many of the identified antigens may participate in COVID-19 pathophysiology or are targets of autoimmune diseases. Thus, autoimmunity related to COVID-19 may be partially explained by molecular mimicry and further research designed specifically to address this possibility is needed.

Editors' Note: Guillain-Barré Syndrome in the Placebo and Active Arms of a COVID-19 Vaccine Clinical Trial

In “Guillain-Barré Syndrome in the Placebo and Active Arms of a COVID-19 Vaccine Clinical Trial,” Márquez Loza et al. presented a patient who developed the Guillain-Barré syndrome (GBS) after being vaccinated in a COVID-19 vaccine clinical trial and highlighted the fact that this should not be considered a postvaccination complication, given that, by chance alone, 900–2,200 people can be expected to develop GBS within 6 weeks of a 1-dose vaccine and 1,500–3,700 people can be expected to develop GBS within 10 weeks of a 2-dose vaccine. Willer comments that although vaccines can increase the risk of GBS because of antibody production, they can also decrease the risk of GBS because of infection prevention. On behalf of the authors, Amato agrees that vaccines can reduce the risk of postinfection GBS in general but notes that a large epidemiologic cohort study found no causal relationship between COVID-19 and GBS and no evidence of molecular mimicry between any SARS-CoV-2 proteins and axonal or myelin proteins in human nerves. Amato recommends performance of large-scale epidemiologic studies and meta-analyses to better understand the relationship between COVID-19 vaccination and GBS. In “Guillain-Barré Syndrome in the Placebo and Active Arms of a COVID-19 Vaccine Clinical Trial,” Márquez Loza et al. presented a patient who developed the Guillain-Barré syndrome (GBS) after being vaccinated in a COVID-19 vaccine clinical trial and highlighted the fact that this should not be considered a postvaccination complication, given that, by chance alone, 900–2,200 people can be expected to develop GBS within 6 weeks of a 1-dose vaccine and 1,500–3,700 people can be expected to develop GBS within 10 weeks of a 2-dose vaccine. Willer comments that although vaccines can increase the risk of GBS because of antibody production, they can also decrease the risk of GBS because of infection prevention. On behalf of the authors, Amato agrees that vaccines can reduce the risk of postinfection GBS in general but notes that a large epidemiologic cohort study found no causal relationship between COVID-19 and GBS and no evidence of molecular mimicry between any SARS-CoV-2 proteins and axonal or myelin proteins in human nerves. Amato recommends performance of large-scale epidemiologic studies and meta-analyses to better understand the relationship between COVID-19 vaccination and GBS.

Evidence for Molecular Mimicry between Human T Cell Epitopes in Rotavirus and Pancreatic Islet Autoantigens

In type 1 diabetes, insulin-producing beta cells in the islets of the pancreas are destroyed by autoreactive T cells. Rotavirus (RV) has been implicated in the pathogenesis of type 1 diabetes. Peptides in VP7, a major immunogenic protein of RV, have high sequence similarity to T cell epitope peptides in the islet autoantigens tyrosine phosphatase-like insulinoma Ag 2 (IA2) and glutamic acid decarboxylase 65 (GAD65). We aimed to educe evidence for the hypothesis that molecular mimicry with RV promotes autoimmunity to islet autoantigens. Peptides in RV and their sequence-similar counterparts in IA2 and GAD65 were assayed for binding to HLA molecules associated with type 1 diabetes and for the ability to elicit T cell proliferative responses in HLA-typed individuals. T cells expanded or cloned to epitopes in IA2 or RV were then tested for cross-reactivity with these epitopes. Peptides in RV-VP7, similar to T cell epitopes in IA2 and GAD65, bound strongly to HLA-DRB1*04 molecules that confer susceptibility to type 1 diabetes and were also T cell epitopes in humans at risk for type 1 diabetes. The proliferative responses of T cells to the similar peptides in RV and islet autoantigens were significantly correlated. T cells expanded to the IA2 epitope could be restimulated to express IFN-gamma by the similar peptide in RV-VP7, and T cell clones generated to this RV-VP7 peptide cross-reacted with the IA2 epitope. Our findings are consistent with the hypothesis that molecular mimicry with RV could promote autoimmunity to islet Ags.

Campylobacter coli enteritis and Guillain–Barré syndrome: No evidence of molecular mimicry and serological relationship

Campylobacter coli was isolated from two Guillain–Barré syndrome (GBS) patients who had anti-GM1 and anti-GD1 IgG antibodies. Although both this bacteria and Campylobacter jejuni are common causes of diarrheal illness, previous studies have focused only on C. jejuni as the causal agent of GBS. To determine whether C. coli also is a causative agent, we examined the hypothesis that production of anti-ganglioside antibodies is induced by ganglioside-mimics on that bacterial lipo-oligosaccharide (LOS), as in C. jejuni-associated GBS. LOSs of both C. coli isolates had very weak reactivities with anti-GM1 and anti-GD1a IgG monoclonal antibodies, whereas those of some GBS-related C. jejuni isolates had strong reactivities. Anti-GM1 and anti-GD1a IgG antibodies from the two patients were not absorbed as much by the LOSs of their isolates as were those of GBS-related C. jejuni strains. These findings do not support the hypothesis of ganglioside mimicry on C. coli isolates' LOSs. We next made a serological assay of recent C. coli infection in 74 patients with GBS, 26 with Fisher syndrome (FS), 49 with other neurological diseases (OND), and 37 normal controls (NC) using the bacterial outer membrane protein as antigen. Eight (11%) GBS and two (8%) FS patients had two or three classes of IgG, IgM, and IgA anti- C. coli antibodies. Anti- C. jejuni IgG and IgA antibody titers were significantly higher than those of anti- C. coli (respectively, p = 0.03 and 0.01). This suggests that anti- C. coli antibodies cross-react with C. jejuni protein. We concluded that a C. coli infection was not the cause of GBS in our patients. Both isolation of a microorganism from, and the positive infectious serology of, GBS patients do not always indicate the causal agent.

Anti-Gal-C antibodies in GBS subsequent to mycoplasma infection: evidence of molecular mimicry.

The authors previously reported the presence of antibody against galactocerebroside (Gal-C) in sera from patients with Guillain-Barré syndrome subsequent to Mycoplasma pneumoniae infection. Anti-Gal-C antibody activities in these sera were inhibited specifically by the M. pneumoniae reagent. A rabbit anti-Gal-C antibody recognized several glycolipids in M. pneumoniae. These data show that a Gal-C-like structure is present in M. pneumoniae, indicative of molecular mimicry between a major myelin glycolipid, Gal-C, and M. pneumoniae.

Measles vaccination and inflammatory bowel disease: controversy laid to rest?

The increasing incidence of Crohn's disease has lead to speculation about changes in exposures to environmental or infectious agents. Considerable attention has focused on the role of measles infection and/or vaccination in the pathogenesis of Crohn's disease and ulcerative colitis. Current evidence regarding the association between measles vaccination and inflammatory bowel disease (IBD) comprises analytic epidemiological studies, a case-series report and ecological studies. The first of these, a 1995 cohort study, found an association between measles vaccination and Crohn's disease and ulcerative colitis, but was widely questioned on methodological grounds. This was followed by a 1997 case-control study showing no association between measles vaccination and IBD. In 1998, public concern was rekindled by a report of 12 children with nonspecific colitis, ileal-lymphoid-nodular hyperplasia, and developmental disorders largely attributed to measles-mumps-rubella vaccine, but the nature of the report limited its scientific conclusions. Two additional studies, one case-control and one cohort, then followed and neither found an association with measles vaccination. Of the several ecological studies of measles vaccine coverage or measles schedule changes, none found an association with rates of IBD. The role of measles infection in IBD has been examined more extensively with studies of in utero measles exposure, measles infection early in life, and laboratory based investigations. An initial report of high rates of Crohn's disease among pregnancies affected by measles infection was followed by negative studies. Numerous case-control and ecological studies of children with measles infections early in life have also had discordant findings. Of three recent cohort studies, two showed no relationship between infection with early measles exposure and risk for IBD, while one found an approximate 3-fold elevation in risk. Laboratory investigations into persistent measles infection and IBD have been contentious. While some investigators have claimed to find persistent measles infection among patients with IBD, others, using highly sensitive polymerase chain reaction techniques, have not been able to replicate the findings. Recent controversy has centred on whether there is any evidence for molecular mimicry in the pathogenesis of IBD. In summary, available evidence does not support an association between measles-containing vaccines and risk of IBD, nor between measles infection and IBD. While further research is necessary into the causal factors underlying Crohn's disease and ulcerative colitis, continued public education efforts are needed to reassure the public about vaccine safety and to prevent declines in vaccine coverage.

Rheumatoid Arthritis Sera React with a Phage-Displayed Peptide Selected by a Monoclonal Antibody to Type II Collagen that has Homology to EBNA-1

Antibodies to type II collagen, and to Epstein Barr virus nuclear antigen-1 (EBNA-1) have been associated with rheumatoid arthritis (RA). In studies involving probing of phage-displayed random peptide libraries with an antibody to type II collagen, CII-Cl, we observed that among 17 phagotopes selected 5 expressed peptides with homology with the sequence of EBNA-1. The residues in common were RLPFG. Hence we tested sera from 50 patients with RA, of whom 26 had antibodies to native type II collagen, and 43 healthy controls, for reactivity by ELISA with a phagotope selected 4 times, which expressed the peptide RRLPFGSQM. Eight RA sera (16%) but no normal sera reacted with the phagotope (p = 0.025). This reactivity could not be correlated with reactivity of RA sera with EBNA-1 by semi-quantitative western blot, with which reactivity occurred in 78% of RA patients and 81% of controls. Evidence for molecular mimicry was not found insofar as the phagotope did not inhibit reactivity of RA sera with EBNA-1 and CII-Cl was not reactive with EBNA-1. We conclude that the reactivity of the RA sera with the phagotope is most likely due to the phagotope being a mimic of an epitope of type II collagen for a proportion of RA sera.

PATHOGENESIS OF PRIMARY BILIARY CIRRHOSIS, PRIMARY SCLEROSING CHOLANGITIS, AND AUTOIMMUNE CHOLANGIOPATHY

Autoimmune liver diseases have much in common with each other, and there are clear associations with genetic haplotypes. Elegant studies have shown autoimmune liver disease induced by viruses and drugs. Although there is evidence for nonimmunological events precipitating immune disease, especially in primary sclerosing cholangitis, the precise pathways, what is bystander and what is essential, have not been determined. This article reviews some of the mechanisms involved in pathogenesis.

Anti-GM1 IgG antibodies and Campylobacter bacteria in Guillain-Barré syndrome: evidence of molecular mimicry.

In Guillain-Barré syndrome antibodies to GM1 and the presence of an antecedent Campylobacter jejuni infection are correlated with a more severe course of the disease. From a group of 137 consecutive GBS patients, 11 sera had elevated titers of anti-GM1 IgG antibodies during the acute stage of disease. Each serum sample was preincubated with three different Penner serotypes of whole C. jejuni (PEN O:4/59, PEN O:41) and Campylobacter coli (PEN O:22) bacteria. The PEN O:4/59 serotype, isolated from the stools of a Guillain-Barré syndrome patient, inhibited 63 to 93% of the anti-GM1 activity in 6 of 11 patients. The PEN O:41 inhibited 63 to 100% of the anti-GM1 antibody activity in 9 of 11 patients. The PEN O:22 inhibited anti-GM1 antibody activity in only 2 of 11 patients (80 and 86%). Two Guillain-Barré syndrome patients did not show antibody absorption by any of the Campylobacter serotypes tested, although this does not exclude the involvement of other serotypes. An Escherichia coli control strain did not significantly absorb anti-GM1 antibodies. The results of this study indicate that anti-GM1 IgG antibodies in Guillain-Barré syndrome sera recognize surface epitopes on whole Campylobacter bacteria and that this recognition is strain-specific. This provides evidence for molecular mimicry in the pathogenesis of Guillain-Barré syndrome.

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

We established six T cell clones specific for pyruvate dehydrogenase complex (PDC)-E2 peptides from four different patients with primary biliary cirrhosis using 33 different peptides of 17-20 amino acid residues corresponding to human PDC-E2 as stimulating antigens. The minimal T cell epitopes of these six T cell clones were all mapped to the same region of the PDC-E2 peptide 163-176 (GDLLAEIETDKATI), which corresponds to the inner lipoyl domain of PDC-E2. The HLA restriction molecules for this epitope were all identified as HLA DRB4 0101. The common essential amino acids of this epitope for these T cell clones were E, D, and K at positions 170, 172, and 173, respectively; other crucial amino acids for this epitope differed in each T cell clone. In addition, the alanine-substituted peptides at positions 170 and 173, but not 172, inhibited the proliferation of all T cell clones induced by the original peptide of human PDC-E2 163-176, indicating that amino acid D at position 172 is a critical MHC-binding site for all T cell clones tested. Interestingly, all T cell clones reacted to PDC-E2 peptide 36-49 (GDLIAEVETDKATV), which corresponds to the outer lipoyl domain of human PDC-E2. Furthermore, one T cell clone cross-reacted with exogenous antigens such as Escherichia coli PDC-E2 peptide 31-44/134-147/235-248 (EQSLITVEGDKASM), which has an EXDK sequence. This is a definite demonstration of the presence of molecular mimicry at the T cell clonal level in human autoimmune diseases. It is also considered possible to design peptide-specific immunotherapy based on the findings of T cell autoepitopes in primary biliary cirrhosis.

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.

Would the real mccoy please stand up?

HepatologyVolume 19, Issue 3 p. 793-794 Hepatology ElsewhereFree Access Would the real mccoy please stand up? First published: March 1994 https://doi.org/10.1002/hep.1840190338AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Abstract Sera from patients with primary biliary cirrhosis (PBC) react with enzymes of the 2-oxo dehydrogenase pathways, particularly PDC-E2. These enzymes are present in all nucleated cells, yet autoimmune damage is confined to biliary epithelial cells. Using a panel of eight mouse monoclonal antibodies and a human combinatorial antibody specific for PDC-E2, we examined by indirect immunofluorescence and confocal microscopy sections of liver from patients with PBC, progressive sclerosing cholangitis, and hepatocarcinoma. The monoclonal antibodies gave typical mitochondrial immunofluorescence on biliary epithelium and on hepatocytes from patients with either PBC, progressive sclerosing cholangitis, or hepatocarcinoma. However, one of eight mouse monoclonal antibodies (C355.1) and the human combinatorial antibody reacted with great intensity and specificity with the luminal region of biliary epithelial cells from patients with PBC. Simultaneous examination of these sections with an antiisotype reagent for human IgA revealed high IgA staining in the luminal region of biliary epithelial cells in patients with PBC. IgG and IgA antibodies to PDC-E2 were detected in the bile of patients with PBC but not normal controls. We believe that this data may be interpreted as indicating that a molecule cross-reactive with PDC-E2 is expressed at high levels in the luminal region of biliary epithelial cells in PBC. References 1 Walker JG, Doniach D, Roitt IM, et al. Serological tests in diagnosis of primary biliary cirrhosis. Lancet 1965; 1: 827. 2 Gershwin ME, Mackay IR. Primary biliary cirrhosis: paradigm or paradox for autoimmunity. Gastroenterology 1991; 100: 822. 3 Yeaman SJ, Fussey SPM, Danner DJ, et al. Primary biliary cirrhosis: identification of two major M 2 mitochondrial autoantigens. Lancet 1988; 1: 1067– 1069. 4 van de Water J, Turchany J, Leung PSC, Lake J, Munoz S, Surh CD, Coppel R, et al. Molecular mimicry in primary biliary cirrhosis: evidence for biliary epithelial expression of a molecule cross-reactive with pyruvate dehydrogenase complex, E2. J Clin Invest 1993; 91: 2653– 2664. 5 Joplin R, Lindsay JG, Johnson GD, Strain A, Neuberger JM. Membrane dihydrolipoamide acetyltransferase (E2) on human biliary epithelial cells in primary biliary cirrhosis. Lancet 1992; 339: 93– 94. 6 van de Water J, Ansari AA, Surh CD, Coppel R, Roche T, Bonkovsky H, Kaplan M, et al. Evidence for the targeting by 2-oxo-dehydrogenase enzymes in the T cell response on primary biliary cirrhosis. J Immunol 1991; 146: 89– 94. 7 Hopf U, Möller B, Stemerowitz R, et al. Relation between Escherichia coli R (rough) forms in gut, lipid A in liver, and primary biliary cirrhosis. Lancet 1988; 2: 1419. 8 Burroughs AK, Rosenstein IJ, Epstein O, et al. Bacteriuria and primary biliary cirrhosis. Gut 1984; 25: 133. 9 Nickowitz RE, Worman HJ. Autoantibodies against nuclear pore membrane protein GP 210: Evidence for molecular mimicry. Hepatology 1993; 18: 109A. 10 Manns MP, Griffin KJ, Sullvan KF, Johnson EF. LKM autoantibodies recognize a short linear sequence in P 450 IID6, a cytochrome P-4450 monooxygenase. J Clin Invest 1991; 88: 1370– 1378. 11 Manns MP and Krüger M. Immunogenetics in chronic liver diseases. Gastroenterology. In press. 12 Ballardini G, Mirakian R, Bianchi FB. Aberrant expression of HLA-DR antigens on bile duct epithelium in PBC: relevance to pathogenesis. Lancet 1984; 2: 1009. Volume19, Issue3March 1994Pages 793-794 ReferencesRelatedInformation

Autoantibodies against nuclear pore membrane protein GP210: Evidence for molecular mimicry in primary biliary cirrhosis? . Department of Medicine and Brookdate Center for Molacular Biology, Mount Sinai School of Medicine, New York, NY

Autoantibodies against nuclear pore membrane protein GP210: Evidence for molecular mimicry in primary biliary cirrhosis? . Department of Medicine and Brookdate Center for Molacular Biology, Mount Sinai School of Medicine, New York, NY

A perspective on human autoimmune thyroid disease: is there an abnormality of the target cell which predisposes to the disorder?

It has been suggested recently that autoimmunity could be regarded as a physiological response of the normal immune system to autoantigens caught up in an inflammatory response to viral or bacterial antigen expressed in the target tissue. Other theories to explain autoimmunity include molecular mimicry whereby a viral or microbial hapten similar to an autoantigen initiates the production of autoantibodies that cross react with an autoantigen, with a subsequent immune response reacting with autologous cell structures which are homologous with the particular microorganism. There has also been a suggestion that there may be a genetic abnormality of the target cell which is necessary for the initiation of autoimmune thyroid disease. The present review examines these proposals and provides evidence against an antigen-driven origin for autoimmune thyroid disease (AITD). Currently, there is no valid evidence for viral involvement, and likewise the evidence for molecular mimicry as an initiating factor does not hold up to scrutiny. While a genetic abnormality of the thyrocyte may be important in certain animal models of AITD, in the human there is no evidence for such an abnormality. Evidence that AITD is derived from a disturbance of immunoregulatory mechanisms has been documented elsewhere and would appear to be the most appropriate explanation for these disorders. The immunoregulatory disturbance itself may be related to an abnormality of the mechanism of specific antigen (i.e. normal autoantigen) presentation to appropriately induce T lymphocytes and that theory will require further illumination.

Reaction of anti-HLA-B monoclonal antibodies with envelope proteins of Shigella species. Evidence for molecular mimicry in the spondyloarthropathies.

Immunologic cross-reactivity between enteric bacteria and the HLA-B27 protein may play a role in the etiology of Reiter's syndrome and reactive arthritis. The reactivity of two anti-B27 mAb (B27M1 and B27M2) with envelope proteins of Shigella flexneri isolated from Reiter's syndrome patients was studied by Western blot analysis. Proteins with an apparent Mr of approximately 36 and 23 kDa reacted with both mAb in ascites. mAb against related HLA class I Ag B7 and B40 did not react with the 23 kDa protein. Relatively high concentrations of antibody were required for reactivity, suggesting a low affinity interaction. Additional evidence for cross-reactive epitopes was obtained by ELISA against whole envelope and by using unsolubilized envelope to inhibit binding of M1 and M2 to B27-positive cell lines, as measured by quantitative flow microfluorimetry. The presence of cross-reactive proteins was not related to the presence of the intact virulence-associated plasmid or the invasive phenotype. Two Shigella sonnei isolates not implicated as causative agents of Reiter's syndrome or reactive arthritis showed a similar pattern of cross-reactivity. These results indicate that cross-reactive epitopes may be present on "arthritogenic" bacteria, but their presence is not a unique feature of such strains and is not the sole factor in induction of arthritis in B27-positive individuals.

Mycobacteria and autoimmunity

Autoimmune disease appears to be influenced by multiple factors, including the genetic, hormonal and immunological status of the individual. However, environmental agents have also been implicated in the initiation of these diseases, and mycobacteria have for a long time been listed among these agents. In this article, Yehuda Shoenfeld and David Isenberg summarize the current evidence linking mycobacterial infection with autoimmune disease. Based on considerable evidence of molecular mimicry between mycobacteria and host antigens, they postulate possible ways in which mycobacteria may precipitate autoimmune disease.