Reaction of Amyloid-β Peptide Antibody with Different Infectious Agents Involved in Alzheimer’s Disease - IOS Press

As early as the 1980s, molecular virologist Ruth Itzhaki began to
investigate if there was a causal connection between infections and
neurodegenerative disorder. Although the theory has yet to be
universally embraced, in 2016 Itzhaki and 33 other scientists from all
over the world published a review
article in this very journal presenting evidence for the causal role of
pathogens in Alzheimer’s disease (AD). Exactly how and in what way
pathogens affect the induction of AD has yet to be determined, but one
possible answer may involve the cross-reactivity of different pathogens
with amyloid-β (Aβ). Aβ autoantibodies have been detected in the serum
and cerebrospinal fluid of AD patients and in some healthy individuals.
In the present study our major goal was to investigate whether
antibodies made against Aβ would react both with other brain proteins as
well as pathogens associated with AD as a result of molecular mimicry
or the binding of bacterial toxins to Aβ42. Our study used a specific
monoclonal antibody made against Aβ42, which not only reacted strongly
with Aβ42, tau protein, and α-synuclein, but also had from weak to
strong reactions with 25 different pathogens or their molecules, some of
which have been associated with AD. The homology between peptide
stretches of microbial origin and proteins involved in AD could be a
mechanism by which antibodies to homologous peptides mount attacks
against autoantigens in AD. We concluded that bacterial molecules bind
to Aβ protein, forming small oligomers, then encasing pathogens and
their molecules to form amyloid plaques, the tell-tale markers of AD.
Conversely, these same Aβ peptides induce the production of antibodies
to both Aβ42 and bacterial molecules, which may inhibit bacterial
pathogenesis, but in the process may promote amyloid plaque formation.

Commensal Microbes May Initiate and Drive Immune Responses in Lupus | Taconic Biosciences

At the end of March, researchers at Yale University published a paper entitled "Commensal orthologs of the human autoantigen Ro60 as triggers of autoimmunity in lupus"
in the journal Science Translational Medicine in which the authors
demonstrated that Ro60 orthologs exist in commensal bacteria commonly
found in or on the human body.


Greiling et al. demonstrated in human and mouse studies that
these bacterial orthologs of Ro may generate autoimmune responses that
drive lupus. The authors revealed that a high level of homology exists
between the major T and B cell epitopes within human Ro60 (hRo60) and
commensal Ro60 orthologs. Antibodies from anti-Ro60 positive lupus
patients, but not negative control patients preferentially
coimmunoprecipitated Ro60 ribonucleoproteins (RNPs) from a Ro60
ortholog-containing commensal organism. Further demonstrating the
cross-reactivity of orthologous Ro60, hRo60-reactive T cell clones, and
freshly isolated anti-Ro60-positive memory T cells responded to epitopes
derived from commensal Ro60 in vitro.

Mycoplasma pneumoniae triggering the Guillain-Barré syndrome: A case-control study - Meyer Sauteur - 2016 - Annals of Neurology

Guillain-Barré syndrome (GBS) is an acute postinfectious immune-mediated polyneuropathy. Although preceding respiratory tract infections with Mycoplasma pneumoniae have been reported in some cases, the role of M. pneumoniae in the pathogenesis of GBS remains unclear. We here cultured, for the first time, M. pneumoniae from a GBS patient with antibodies against galactocerebroside (GalC), which cross-reacted with the isolate. This case prompted us to unravel the role of M. pneumoniae in GBS in a case-control study.
Methods
We included 189 adults and 24 children with GBS and compared them to control cohorts for analysis of serum antibodies against M. pneumoniae (n = 479) and GalC (n = 198).
Results
Anti–M. pneumoniae immunoglobulin (Ig) M antibodies were detected in GBS patients and healthy controls in 3% and 0% of adults (p = 0.16) and 21% and 7% of children (p = 0.03), respectively. Anti-GalC antibodies (IgM and/or IgG) were found in 4% of adults and 25% of children with GBS (p = 0.001). Anti-GalC-positive patients showed more-frequent preceding respiratory symptoms, cranial nerve involvement, and a better outcome. Anti-GalC antibodies correlated with anti–M. pneumoniae antibodies (p < 0.001) and cross-reacted with different M. pneumoniae strains. Anti-GalC IgM antibodies were not only found in GBS patients with M. pneumoniae infection, but also in patients without neurological disease (8% vs 9%; p = 0.87), whereas anti-GalC IgG was exclusively found in patients with GBS (9% vs 0%; p = 0.006).
Interpretation
M. pneumoniae infection is associated with GBS, more frequently in children than adults, and elicits anti-GalC antibodies, of which specifically anti-GalC IgG may contribute to the pathogenesis of GBS. Ann Neurol 2016;80:566–580"





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Epstein-Barr virus and Mycobacterium avium subsp. paratuberculosis peptides are cross recognized by anti-myelin basic protein antibodies in multiple sclerosis patients.

Epstein-Barr virus and Mycobacterium avium subsp. paratuberculosis (MAP)
have been associated to multiple sclerosis (MS). We searched for
antibodies against the homologous peptides Epstein-Barr virus nuclear
antigen 1 (EBNA1)_400-413, MAP_0106c protein (MAP)_121-132, and myelin basic protein (MBP)_85-98
on a MS Sardinian cohort, showing that these antibodies are highly
prevalent among MS patients compared to healthy controls. Competitive
assay demonstrated that antibodies recognizing EBNA1_400-413 and MAP_121-132 cross-react with MBP_85-98,
possibly through a molecular mimicry mechanism. Indeed, the fact that
peptides from different pathogens can be cross-recognized by antibodies
targeting self-epitopes supports the hypothesis that EBV and MAP might
trigger autoimmunity through a common target.

H1N1-Flu triggered narcolepsy may stem from 'molecular mimicry'

In genetically susceptible people, narcolepsy can sometimes be triggered by a similarity between a region of a protein called hypocretin and a portion of a protein from the pandemic H1N1 virus, according to a new study by researchers at the Stanford University School of Medicine.

Epitopes of microbial and human heat shock protein 60 and their recognition in myalgic encephalomyelitis.

Myalgic encephalomyelitis (ME, also called Chronic Fatigue Syndrome), a common disease with chronic fatigability, cognitive dysfunction and myalgia of unknown etiology, often starts with an infection. The chaperonin human heat shock protein 60 (HSP60) occurs in mitochondria and in bacteria, is highly conserved, antigenic and a major autoantigen. The anti-HSP60 humoral (IgG and IgM) immune response was studied in 69 ME patients and 76 blood donors (BD) (the Training set) with recombinant human and E coli HSP60, and 136 30-mer overlapping and targeted peptides from HSP60 of humans, Chlamydia, Mycoplasma and 26 other species in a multiplex suspension array. Peptides from HSP60 helix I had a chaperonin-like activity, but these and other HSP60 peptides also bound IgG and IgM with an ME preference, theoretically indicating a competition between HSP60 function and antibody binding. A HSP60-based panel of 25 antigens was selected. When evaluated with 61 other ME and 399 non-ME samples (331 BD, 20 Multiple Sclerosis and 48 Systemic Lupus Erythematosus patients), a peptide from Chlamydia pneumoniae HSP60 detected IgM in 15 of 61 (24%) of ME, and in 1 of 399 non-ME at a high cutoff (p<0.0001). IgM to specific cross-reactive epitopes of human and microbial HSP60 occurs in a subset of ME, compatible with infection-induced autoimmunity.

Peptide matching between Epstein-Barr virus and human proteins

Epstein-Barr virus proteins were examined for amino acid sequence matching to human proteins at the decapeptide level. We report that numerous EBV peptides of different length (from 10- to 13-mer) are present in 28 human proteins. The viral versus human peptide overlap mainly involves the glycine-rich region allocated in the NH2-terminus of Epstein-Barr nuclear antigen 1 protein and host cellular components that play crucial roles in basic biochemical pathways, such as chromatin remodelling, RNA splicing, transmission across chemical/electrical synapses, neurogenesis, and that, when altered, may characterize various pathologies such as immunodeficiency, systemic lupus erythematosus, myelination, and speech disorders. The present results might contribute to understand and define the (physio)pathological relationships and interactions occurring between EBV and the human host.

Humans Have Antibodies against a Plant Virus: Evidence from Tobacco Mosaic Virus.

Tobacco mosaic virus (TMV), a widespread plant pathogen, is found in tobacco (including cigarettes and smokeless tobacco) as well as in many other plants. Plant viruses do not replicate or cause infection in humans or other mammals. This study was done to determine whether exposure to tobacco products induces an immune response to TMV in humans. Using a sandwich ELISA assay, we detected serum anti-TMV antibodies (IgG, IgG1, IgG3, IgG4, IgA, and IgM) in all subjects enrolled in the study (20 healthy smokers, 20 smokeless-tobacco users, and 20 non-smokers). Smokers had a higher level of serum anti-TMV IgG antibodies than non-smokers, while the serum level of anti-TMV IgA from smokeless tobacco users was lower than smokers and non-smokers. Using bioinformatics, we also found that the human protein TOMM40L (an outer mitochondrial membrane 40 homolog - like translocase) contains a strong homology of six contiguous amino acids to the TMV coat protein, and TOMM40L peptide exhibited cross-reactivity with anti-TMV antibodies. People who smoke cigarettes or other tobacco products experience a lower risk of developing Parkinson's disease, but the mechanism by which this occurs is unclear. Our results showing molecular mimicry between TMV and human TOMM40L raise the question as to whether TMV has a potential role in smokers against Parkinson's disease development. The potential mechanisms of molecular mimicry between plant viruses and human disease should be further explored.

Structural and Dynamical Insights on HLA-DR2 Complexes That Confer Susceptibility to Multiple Sclerosis in Sardinia: A Molecular Dynamics Simulation Study.

Sardinia is a major Island in the Mediterranean with a high incidence of multiple sclerosis, a chronic autoimmune inflammatory disease of the central nervous system. Disease susceptibility in Sardinian population has been associated with five alleles of major histocompatibility complex (MHC) class II DRB1 gene. We performed 120 ns of molecular dynamics simulation on one predisposing and one protective alleles, unbound and in complex with the two relevant peptides: Myelin Basic Protein and Epstein Barr Virus derived peptide. In particular we focused on the MHC peptide binding groove dynamics. The predisposing allele was found to form a stable complex with both the peptides, while the protective allele displayed stability only when bound with myelin peptide. The local flexibility of the MHC was probed dividing the binding groove into four compartments covering the well known peptide anchoring pockets. The predisposing allele in the first half cleft exhibits a narrower and more rigid groove conformation in the presence of myelin peptide. The protective allele shows a similar behavior, while in the second half cleft it displays a narrower and more flexible groove conformation in the presence of viral peptide. We further characterized these dynamical differences by evaluating H-bonds, hydrophobic and stacking interaction networks, finding striking similarities with super-type patterns emerging in other autoimmune diseases. The protective allele shows a defined preferential binding to myelin peptide, as confirmed by binding free energy calculations. All together, we believe the presented molecular analysis could help to design experimental assays, supports the molecular mimicry hypothesis and suggests that propensity to multiple sclerosis in Sardinia could be partly linked to distinct peptide-MHC interaction and binding characteristics of the antigen presentation mechanism.

Potential T cell epitopes of Mycobacterium tuberculosis that can instigate molecular mimicry against host: implications in autoimmune pathogenesis.

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

RESULTS:

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

CONCLUSIONS:

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