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Gut-derived T cells are observed in extraintestinal organs, contributing to certain human and mouse autoimmune diseases. The gut microbiota can modulate the egress of intestinal T cells. Aberrant expression of gut-derived T cell homing ligands in extraintestinal organs enables the infiltration of these cells in certain tissues, where they can induce damage. Modulating the ligand–receptor interactions of gut-derived T cells may be a promising approach to treating certain extraintestinal autoimmune diseases. Molecular mimicry from intestinal microbiota-derived antigens along with gut education can confer pathogenicity to gut-derived T cells. Further investigation is needed to understand how the migration and function of gut-derived T cells are regulated in certain extraintestinal autoimmune diseases. Intestinal T cells and microbiota interact to collectively maintain gut homeostasis, the disruption of which is implicated in disease pathogenesis, including autoimmune disorders. Pathogenic T cells can egress from a dysregulated gut microenvironment to contribute to autoimmunity in extraintestinal organs. The gut microbiota can modulate the migration of intestinal T cells and enable their pathogenicity, partially through molecular mimicry. A deeper understanding of the mechanisms regulating the migration and function of gut-derived T cells might inspire novel, safe, and effective therapeutic approaches to treat autoimmune diseases. The mammalian intestine harbors abundant T cells with high motility, where these cells can affect both intestinal and extraintestinal disorders. Growing evidence shows that gut-derived T cells migrate to extraintestinal organs, contributing to the pathogenesis of certain autoimmune diseases, including type 1 diabetes (T1D) and multiple sclerosis (MS). However, three key questions require further elucidation. First, how do intestinal T cells egress from the intestine? Second, how do gut-derived T cells enter organs outside the gut? Third, what is the pathogenicity of gut-derived T cells and their correlation with the gut microenvironment? In this Opinion, we propose answers to these questions. Understanding the migration and functional regulation of gut-derived T cells might inform precise targeting for achieving safe and effective approaches to treat certain extraintestinal autoimmune diseases. [ABSTRACT FROM AUTHOR]

Understanding the etiopathogenesis of schizophrenia has always been an unsolved puzzle for modern medicine. This seems to be due to both disease complexity and lack of sufficient knowledge regarding the biological and non-biological anomalies that exhibit schizophrenia subjects. However, dysregulated immunity is a commonly identified feature in affected individuals. Thus, recently, a hallmark study showed causality relationship between anti-NCAM antibodies and schizophrenia-related behaviors in mice. NCAM plays crucial role in neurodevelopment during early life and neuroplasticity against different stressors during adulthood, and its dysfunction in schizophrenia is increasingly proven. The present review provides the main evidence that support the contribution of autoimmunity and NCAM abnormalities in the development of schizophrenia. Furthermore, it introduces five hypotheses that may explain the mechanism by which anti-NCAM antibodies are produced in the context of schizophrenia: (i) molecular mimicry, (ii) gut dysbiosis, (iii) viral infection, (iv) exposure to environmental pollutants, (v) and NCAM production anomalies. [ABSTRACT FROM AUTHOR]

The pathogenesis of human leukocyte antigen (HLA)-B27-associated diseases such as acute anterior uveitis (AAU) and ankylosing spondylitis (AS) remains poorly understood, though Gram-negative bacteria and subclinical bowel inflammation are strongly implicated. Accumulating evidence from animal models and clinical studies supports several hypotheses, including HLA-B27-dependent dysbiosis, altered intestinal permeability, and molecular mimicry. However, the existing literature is hampered by inadequate studies designed to establish causation or uncover the role of viruses and fungi. Moreover, the unique disease model afforded by AAU to study the gut microbiota has been neglected. This review critically evaluates the current literature and prevailing hypotheses on the link between the gut microbiota and HLA-B27-associated disease. We propose a new potential role for HLA-B27-driven altered antibody responses to gut microbiota in disease pathogenesis and outline recommendations for future well-controlled human studies, focusing on AAU. Emerging human and animal studies of human leukocyte antigen (HLA)-B27-associated diseases have led to the development of several hypotheses for how HLA-B27 can influence the composition and function of the gut microbiota to mediate its disease associations. Shared metabolic dysregulations, despite the heterogenous taxa signatures observed, may underpin how the microbiome contributes to HLA-B27-associated disease, but it remains unclear if dysbiosis is directly driving disease. HLA-B27 transgenic rats that develop a spontaneous spondyloarthropathy-like illness do not develop disease when raised in a germ-free environment, but mono-association with Phocaeicola vulgatus is sufficient to induce disease. Progress in the field has been relatively slow due to the lack of integration between human studies and available animal models of disease, and increased attention should be paid to the microbiome in HLA-B27-associated acute anterior uveitis. [ABSTRACT FROM AUTHOR]

• Epigenetic traits are deregulated by Cd in the bioaccumulators kidney and plants. • Comparison of Cd-affected epigenetics in mammalian kidneys and plants. • Specific, not global, DNA methylation patterns and histone acetylation by Cd stress. • Impact of non-coding RNA alterations on target genes remains elusive. • Cd similarly affects DNA methylation and histone acetylation in kidney and plants. Faced with unpredictable changes in global weather patterns, release and redistribution of metals through land erosion and water movements add to the increasing use of metals in industrial activities causing high levels of environmental pollution and concern to the health of all living organisms. Cadmium is released into the environment by smelting and mining, entering the food chain via contaminated soils, water, and phosphate fertilizers. Bioaccumulation of cadmium in plants represents the first major step into the human food chain and contributes to toxicity of several organs, especially the kidneys, where biomagnification of cadmium occurs over decades of exposure. Even in small amounts, cadmium brings about alterations at the molecular and cellular levels in eukaryotes through mutagenicity, molecular mimicry at metal binding sites and oxidative stress. The epigenome dictates expression of a gene's output through a number of regulatory steps involving chromatin remodeling, nucleosome unwinding, DNA accessibility, or nucleic acid modifications that ultimately impact the transcriptional and translational machinery. Several epigenetic enzymes exhibit zinc-dependence as zinc metalloenzymes and zinc finger proteins thus making them susceptible to deregulation through displacement by cadmium. In this review, we summarize the literature on cadmium-induced epigenetic mechanisms in mammalian kidneys and plants, compare similarities in the epigenetic defense between these bioaccumulators, and explore how future studies could advance our understanding of the cadmium-induced stress response and disruption to biological health. [ABSTRACT FROM AUTHOR]

Autoimmune diseases constitute a broad, heterogenous group with many diverse and often overlapping symptoms. Even so, they are traditionally classified as either systemic, rheumatic diseases or organ-directed diseases. Several theories exist about autoimmune diseases, including defective self-recognition, altered self, molecular mimicry, bystander activation and epitope spreading. While there is no consensus about these theories, it is generally accepted that genetic, pre-disposing factors in combination with environmental factors can result in autoimmune disease. The relative contribution of genetic and environmental factors varies between diseases, as does the significance of individual contributing factors within related diseases. Among the genetic factors, molecules involved in antigen (Ag) recognition, processing, and presentation stand out (e.g., MHC I and II) together with molecules involved in immune signaling and regulation of cellular interactions (i.e., immuno-phenotypes). Also, various immuno-deficiencies have been linked to development of autoimmune diseases. Among the environmental factors, infections (e.g., viruses) have attracted most attention, but factors modulating the immune system have also been the subject of much research (e.g., sunlight and vitamin D). Multiple sclerosis currently stands out due to a very strong and proven association with Epstein-Barr virus infection, notably in cases of late infection and in cases of EBV-associated mononucleosis. Thus, a common picture is emerging that both systemic and organ-directed autoimmune diseases may appropriately be described as auto-immuno-deficiency syndromes (AIdeSs), a concept that emphasizes and integrates existing knowledge on the role of immuno-deficiencies and chronic infections with development of overlapping disease syndromes with variable frequencies of autoantibodies and/or autoreactive T cells. This review integrates and exemplifies current knowledge on the interplay of genetically determined immuno-phenotypes and chronic infections in the development of AIdeSs. [Display omitted] • Autoimmune diseases show considerable genetic overlaps. • Autoimmune diseases have environmental factors in common. • Autoimmune diseases dispose to infections. • Immunodeficiencies are linked to autoimmune diseases. • Autoimmune diseases may appropriately be labelled as autoimmunodeficiency syndromes. [ABSTRACT FROM AUTHOR]

Immune thrombocytopenia (ITP) is a complex autoimmune disorder characterized by thrombocytopenia and an increased bleeding risk, arising from autoantibody-mediated platelet destruction and impaired megakaryocyte function. The pathogenesis of ITP involves a multifaceted interplay of genetic predispositions, immune dysregulation, and environmental triggers, though the precise mechanisms remain uncertain. Several infectious agents, mostly viruses, have been implicated in both acute and chronic ITP through mechanisms such as molecular mimicry, direct bone marrow suppression, and immune dysregulation. Vaccinations, particularly those containing adjuvants like aluminum and those capable of inducing molecular mimicry, have also been associated with ITP, either as a new onset or as a relapse in preexisting cases. The role of drugs, particularly quinine, quinidine and certain antibiotics, in inducing ITP through various immunological pathways further illustrates the diverse etiologies of this condition. The multiple triggers of the disease raise the question of whether ITP may be classified as an autoimmune/inflammatory syndrome induced by adjuvants (ASIA). This condition encompasses a range of autoimmune and inflammatory symptoms triggered by adjuvants, such as silicones, polypropylene meshes, metal implants, and mineral oils present in various medical materials and medications. Similar to that observed in some cases of ITP, adjuvants can trigger autoimmune or autoinflammatory responses via molecular mimicry, epitope spreading, and polyclonal activation. This narrative review explores the underlying environmental factors related to ITP and examines ITP triggers that could potentially support an association between ITP and ASIA syndrome. • Immune thrombocytopenia (ITP) may be triggered by environmental factors, including infections, vaccines, and medications. • ITP and ASIA syndrome share mechanisms like molecular mimicry and polyclonal activation, linking them to environmental triggers. • Similar to ASIA syndrome, addressing specific triggers in ITP may lead to improved treatment outcomes and symptom resolution [ABSTRACT FROM AUTHOR]

• Largest case series of new onset myasthenia gravis following SARS-CoV-2 vaccination including the first paediatric case. • Overview of autoimmune complications following SARS-CoV-2 vaccination and infection. • Discussion on potential pathogenic mechanisms for myasthenia gravis following vaccination. Myasthenia gravis (MG) is an antibody-mediated immune disorder of the neuromuscular junction. SARS-CoV-2 is now recognised as a trigger factor for autoimmune diseases and to cause immune-mediated dysregulation, likely due to molecular mimicry induced by viral antigens. SARS-CoV-2 vaccination, similarly, results in exposure to viral antigen. Here we report 7 cases of new-onset myasthenia gravis in timely association with SARS-CoV-2 vaccination, including the first paediatric case identified to date. We also reviewed the literature for other new-onset MG cases reported within 4 weeks of SARS-CoV-2 vaccination and discuss our findings in the context of altered (auto)immunity following SARS-CoV-2 vaccination and/or infection. [ABSTRACT FROM AUTHOR]

• SARS-CoV-2 possesses similar sequences to MYH6 and collagens. • Some potential molecular mimicry peptides have high affinity to HLAs. • The viral peptide EKMVSLL mimicking MYH6 is associated with MIS-C pathogenesis. [ABSTRACT FROM AUTHOR]

Dedicated loader proteins play essential roles in bacterial DNA replication by opening ring-shaped DnaB-family helicases and chaperoning single-stranded (ss)DNA into a central motor chamber as a prelude to DNA unwinding. Although unrelated in sequence, the Escherichia coli DnaC and bacteriophage λ P loaders feature a similar overall architecture: a globular domain linked to an extended lasso/grappling hook element, located at their N and C termini, respectively. Both loaders remodel a closed DnaB ring into nearly identical right-handed open conformations. The sole element shared by the loaders is a single alpha helix, which binds to the same site on the helicase. Physical features of the loaders establish that DnaC and λ P evolved independently to converge, through molecular mimicry, on a common helicase-opening mechanism. The initiation of DNA replication is a tightly regulated process in all cellular domains of life and involves regulated recruitment and assembly of essential factors, including the replicative hexameric helicase complex, to replication origins. A crucial step during the replication initiation phase of DNA replication is loading of hexameric, ring-shaped replicative helicases onto DNA. In bacteria, the DnaB family of replicative helicases comprise six identical subunits, which collectively create a central chamber to bind one of the ssDNA strands of double-stranded DNA; the translocation of DnaB on ssDNA ahead of DNA polymerase in the replisome separates the two strands to provide substrates for DNA synthesis. Recent structure determinations of two bacterial helicase loaders bound to the same DnaB helicase offer an opportunity to extract fundamental principles associated with DnaB opening and loading onto ssDNA. Escherichia coli DnaC and bacteriophage λ P evolved independently to converge, through molecular mimicry, on a common helicase-opening mechanism. [ABSTRACT FROM AUTHOR]

• Complex aetiology and systemic impact on various organs made RA challenging. • Dysbiosis emphasized the significance of microbial homeostasis. • The mutual relationship between RA and Gut microbiota was investigated. • Probiotics emerged as a hopeful avenue for RA management. Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation and joint damage. Existing treatment options primarily focus on managing symptoms and slowing disease progression, often with side effects and limitations. The gut microbiome, a vast community of microorganisms present in the gastrointestinal tract, plays a crucial role in health and disease. Recent research suggests a bidirectional relationship between the gut microbiome and RA, highlighting its potential as a therapeutic option. This review focuses on the interaction between the gut microbiome and RA development, by discussing how dysbiosis, an imbalance in gut bacteria, can contribute to RA through multiple mechanisms such as molecular mimicry, leaky gut, and metabolic dysregulation. Probiotics, live microorganisms with health benefits, are emerging as promising tools for managing RA. They can prevent the negative effects of dysbiosis by displacing harmful bacteria, producing anti-inflammatory metabolites like short-chain fatty acids (SCFA), Directly influencing immune cells, and modifying host metabolism. animal and clinical studies demonstrate the potential of probiotics in improving RA symptoms and disease outcomes. However, further research is needed to optimize probiotic strains, dosages, and treatment protocols for personalized and effective management of RA. This review summarizes the current understanding of the gut microbiome and its role in RA and discusses future research directions. In addition to the established role of gut dysbiosis in RA, emerging strategies like fecal microbiota transplantation, prebiotics, and postbiotics offer exciting possibilities. However, individual variations in gut composition necessitate personalized treatment plans. Long-term effects and clear regulations need to be established. Future research focusing on metagenomic analysis, combination therapies, and mechanistic understanding will unlock the full potential of gut microbiome modulation for effective RA management. [ABSTRACT FROM AUTHOR]

NT1 is a rare, chronic and disabling neurological disease causing excessive daytime sleepiness and cataplexy. NT1 is characterized pathologically by an almost complete loss of neurons producing the hypocretin (HCRT)/orexin neuropeptides in the lateral hypothalamus. While the exact etiology of NT1 is still unknown, numerous studies have provided compelling evidence supporting its autoimmune origin. The prevailing hypothetical view on the pathogenesis of NT1 involves an immune-mediated loss of HCRT neurons that can be triggered by Pandemrix® vaccination and/or by infection in genetically susceptible patients, specifically carriers of the HLA-DQB1*06:02 MHC class II allele. The molecular mechanisms by which infection/vaccination can induce autoimmunity in the case of NT1 remain to be elucidated. In this review, evidence regarding the involvement of vaccination and infection and the potential mechanisms by which it could be linked to the pathogenesis of NT1 will be discussed in light of the existing findings in other autoimmune diseases. • Narcolepsy type 1 (NT1) is a neurological disease characterized by a loss of HCRT-producing neurons. • Strong evidence suggests an autoimmune origin of NT1. • NT1 has been associated with Pandemrix® vaccination and H1N1 infection. • Activation of potential autoreactive T cells could be mediated by various mechanisms including molecular mimicry, bystander effect or epitope spreading. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is an autoimmune disease caused by genetic and environmental factors such as viral infections. Genomic and serologic tests were applied to detect significant blood-borne viruses in SLE patients to determine whether there was a possible association between viral infections and SLE. Antibodies (Abs) against HHV-8, HCMV, EBV, HIV, HBV, and HCV in SLE patients suffering from SLE were assessed by ELISA. In addition, HHV-8 DNA and HIV-1 RNA were quantified by real-time PCR, and the HCV and HBV genomes were detected using nested PCR. Compared to those in the control group, a high prevalence of anti-HHV-8 (p < 0.0001), anti-HCMV (p = 0.014), and anti-EBV (p = 0.017) Abs was detected in SLE patients. HHV-8, HIV, HCV, and HBV genomic tests were negative in both groups, while only 1.1 %, 2.2 %, and 1.1 % of SLE patients were positive for anti-HIV, anti-HCV Abs, and HBsAg, respectively. The most frequent major complaint in patients was arthralgia (76.7 %). The increased prevalence of anti-HHV-8 Abs may not be related to the natural history of infection but to molecular mimicry. Increased anti-HCMV and anti-EBV Abs may also be associated with the development of SLE and may play direct or indirect roles in such infections or molecular mimicry. Since arthralgia is the most common symptom in SLE patients, the presence of these symptoms in any patient is a suggestive clue for the diagnosis of SLE. Defining the typical pattern of SLE in divergent nations with distinct environmental and geographical factors can be beneficial for obtaining a prompt diagnosis. [ABSTRACT FROM AUTHOR]

A non-pathogenic Mycoplasma pneumoniae -based chassis is leading the development of live biotherapeutic products (LBPs) for respiratory diseases. However, reports connecting Guillain-Barré syndrome (GBS) cases to prior M. pneumoniae infections represent a concern for exploiting such a chassis. Galactolipids, especially galactocerebroside (GalCer), are considered the most likely M. pneumoniae antigens triggering autoimmune responses associated with GBS development. In this work, we generated different strains lacking genes involved in galactolipids biosynthesis. Glycolipid profiling of the strains demonstrated that some mutants show a complete lack of galactolipids. Cross-reactivity assays with sera from GBS patients with prior M. pneumoniae infection showed that certain engineered strains exhibit reduced antibody recognition. However, correlation analyses of these results with the glycolipid profile of the engineered strains suggest that other factors different from GalCer contribute to sera recognition, including total ceramide levels, dihexosylceramide (DHCer), and diglycosyldiacylglycerol (DGDAG). Finally, we discuss the best candidate strains as potential GBS-free Mycoplasma chassis. [ABSTRACT FROM AUTHOR]

Guillain-Barré syndrome (GBS) is a rapidly progressive, monophasic, and potentially devastating immune-mediated neuropathy in humans. Preceding infections trigger the production of cross-reactive antibodies against gangliosides concentrated in human peripheral nerves. GBS is elicited by at least five distinct common bacterial and viral pathogens, speaking to the notion of polymicrobial disease causation. This opinion emphasizes that GBS is the best-supported example of true molecular mimicry at the B cell level. Moreover, we argue that mechanistically, single and multiplexed microbial carbohydrate epitopes induce IgM, IgA, and IgG subclasses in ways that challenge the classic concept of thymus-dependent (TD) versus thymus-independent (TI) antibody responses in GBS. Finally, we discuss how GBS can be exemplary for driving innovation in diagnostics and immunotherapy for other antibody-driven neurological diseases. Guillain-Barré syndrome (GBS) after Campylobacter jejuni infection is a true case of molecular mimicry–driven disease. The immunopathogenesis of GBS sheds new light on the multimolecular identities of self-antigens. The glycan nature of mimicry epitopes that drives antibody class switching to IgG subclasses challenges rigid concepts of thymus-dependent and -independent B cell responses because antiglycolipid antibodies are mainly IgG1 and IgG3, albeit short-lasting. Combinatorial chemoenzymatic technologies and arrays allow the development of novel diagnostic and research tools to identify antibodies against mono- and multimeric carbohydrate epitopes. A certain degree of dissimilarity may be required for the occurrence of molecular mimicry in Campylobacter jejuni –associated GBS. [ABSTRACT FROM AUTHOR]

While adaptive immunity recognizes a nearly infinite range of antigenic determinants, immune tolerance renders adaptive immunity vulnerable to microbes decorated in self-like antigens. Recent studies suggest that sugar-binding proteins galectin-4 and galectin-8 bind microbes expressing blood group antigens. However, the binding profile and potential antimicrobial activity of other galectins, particularly galectin-9 (Gal-9), has remained incompletely defined. Here, we demonstrate that while Gal-9 possesses strong binding preference for ABO(H) blood group antigens, each domain exhibits distinct binding patterns, with the C-terminal domain (Gal-9C) exhibiting higher binding to blood group B than the N-terminal domain (Gal-9N). Despite this binding preference, Gal-9 readily killed blood group B-positive Escherichia coli, whereas Gal-9N displayed higher killing activity against this microbe than Gal-9C. Utilization of microarrays populated with blood group O antigens from a diverse array of microbes revealed that Gal-9 can bind various microbial glycans, whereas Gal-9N and Gal-9C displayed distinct and overlapping binding preferences. Flow cytometric examination of intact microbes corroborated the microbial glycan microarray findings, demonstrating that Gal-9, Gal-9N, and Gal-9C also possess the capacity to recognize distinct strains of Providencia alcalifaciens and Klebsiella pneumoniae that express mammalian blood group-like antigens while failing to bind related strains that do not express mammalian-like glycans. In each case of microbial binding, Gal-9, Gal-9N, and Gal-9C induced microbial death. In contrast, while Gal-9, Gal-9N, and Gal-9C engaged red blood cells, each failed to induce hemolysis. These data suggest that Gal-9 recognition of distinct microbial strains may provide antimicrobial activity against molecular mimicry. [ABSTRACT FROM AUTHOR]

• SARS-COV-2 is often hypothesised as a trigger for autoimmunity via molecular mimicry. • We report 28 human proteins with peptides homologous to SARS-COV-2 B cell epitopes. • These proteins have a widespread tissue distribution in the human body. • Autoantibodies against them have been detected in typical autoimmune conditions. • Thus, we discuss autoimmunity as a plausible mechanism for extrapulmonary effects of COVID-19. Underlying mechanisms of multi-organ manifestations and exacerbated inflammation in COVID-19 are yet to be delineated. The hypothesis of SARS-CoV-2 triggering autoimmunity is gaining attention and, in the present study, we have identified 28 human proteins harbouring regions homologous to SARS-CoV-2 peptides that could possibly be acting as autoantigens in COVID-19 patients displaying autoimmune conditions. Interestingly, these conserved regions are amongst the experimentally validated B cell epitopes of SARS-CoV-2 proteins. The reported human proteins have demonstrated presence of autoantibodies against them in typical autoimmune conditions which may explain the frequent occurrence of autoimmune conditions following SARS-CoV-2 infection. Moreover, the proposed autoantigens' widespread tissue distribution is suggestive of their involvement in multi-organ manifestations via molecular mimicry. We opine that our report may aid in directing subsequent necessary antigen-specific studies, results of which would be of long-term relevance in management of extrapulmonary symptoms of COVID-19. [ABSTRACT FROM AUTHOR]

• The gut-brain axis is attracting much attention in the field of medical science. • Recent research revealed the bidirectional causality between multiple sclerosis (MS) and the gut microbiome. • Microbiome holds the key to understand the mechanisms of onset and progression of MS. • The enhancement of oxidative stress in the gut of MS patients is a promising target of therapy. Recent studies identified specific gut microbial species linked to various human diseases, and gut-brain axis is currently attracting much attention in the field of microbiome science clinically and biologically. Research on multiple sclerosis (MS) and its mouse model, experimental autoimmune encephalomyelitis is one of the most active research subjects. Notably, recent achievements established the bidirectional causality between MS and gut microbiome. The reduction of gut microbiome-derived short chain fatty acids and the enrichment of gut-associated oxidative stress appear to be promoting for neurodegenerative processes. Also, researchers are trying to elucidate the mechanisms by which the microbiome regulates the onset and progression of MS. The new findings achieved by the analysis of the causal relationship between MS and the gut microbiome will provide a new therapeutic strategy for MS. These results will contribute to our understanding of the cause, prevention, and treatment of MS, and will lead to a complete cure for this disease in the future. In MS, for which no curative treatment has yet to be established, the unmet needs may be overcome through the analysis of gut microbiome. [ABSTRACT FROM AUTHOR]

Autoimmune encephalitis (AE) is an increasingly recognized inflammatory disorder of the central nervous system and is most often characterized by antibodies against intracellular and neuronal surface antigens. AE is a devastating disease that may result in developmental delay or regression in children. However, the pathogenesis of AE is not clear, and immune system disorders after infection likely play an important role in AE. Many studies have reported that patients with herpes simplex virus encephalitis develop anti-N-methyl-d-aspartate receptor encephalitis after antiviral treatment. It is critical to recognize pediatric AE early and to distinguish it from infectious forms because AE is treatable and responsive to immunotherapies. In this review, we discuss the clinical features of pediatric AE and focus on the relationship between AE and postinfection status. In addition, we review the probable mechanisms underlying infection-triggered AE, which include molecular mimicry, bystander activation, epitope spreading, immune system disorder, and genetic susceptibility. [ABSTRACT FROM AUTHOR]

Acute rheumatic fever (ARF) is an autoimmune disease caused by group A β-hemolytic streptococci (GAS) and may develop into rheumatic heart disease (RHD). The pathogenesis of ARF and RHD involves molecular mimicry and antibody-mediated mechanisms. T cell involvement is described in various stages of the disease. Mucosal associated invariant T (MAIT) cells are enriched at the mucosa and are present in the blood and may be activated by GAS. In this study, we investigated the quantity and activity of CD3+TCRVα7.2+CD161+ cells in the active and recovered ARF patients and healthy controls. Twenty newly diagnosed, 20 recovered-ARF children, and 20 healthy controls were enrolled in the study. Peripheral blood (PB) mononuclear cells were isolated by Ficoll-Paque density gradient. CD4+, CD4− subsets of CD3+CD161+TCRVα7.2+ cells and IFN-γ and TNF-α production were quantified by Flow cytometry. Acute and recovered ARF patients had significantly elevated the number of CD3+TCRVα7.2+CD161+ cells in their PB. Both CD4+ and CD4− subsets were increased. Moreover, total CD3+TCRVα7.2+CD161+ cell numbers were significantly higher in the recovered patients' PB compared with active ARF patients. In addition, CD3+TCRVα7.2+CD161+ cells in both acute and recovered patients produced significantly more IFN-γ and TNF-α. Non-MAIT total CD3+ T cell, CD4+ and CD4− T cell subsets were also increased in active and recovered ARF patients and they also produced more IFN-γ and TNF-α. Our data reveal that CD3+TCRVα7.2+CD161+ cells are elevated and actively producing IFN-γ and TNF-α in acute and recovered ARF patients and may contribute to ARF pathology. • CD3+TCR Vα7.2+CD161+ MAIT cells may comprise up to 10% of human peripheral blood (PB) T cells. • Acute and recovered ARF patients have elevated number of PB CD3+TCR Vα7.2+CD161+ cells. • PB CD3+TCR Vα7.2+CD161+ cells in acute and recovered ARF patients produce more IFN-γ and TNF-α. • CD3+TCR Vα7.2+CD161+ cell-derived IFN-γ and TNF-α may contribute to ARF pathology. [ABSTRACT FROM AUTHOR]

Few studies have pointed to the possible role of infectious diseases in triggering Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP). Given the association of Hepatitis E Virus (HEV) with Guillain Barrè syndrome, we conducted a case-control study to determine the possible association of HEV infection with CIDP, analyzing possible risk factors for acquiring HEV infection in both CIDP patients and controls. 82 CIDP and 260 from the general population have provided some personal information (demographics, anamnestic data and recognized risk factors for HEV infection) and underwent venipuncture blood sampling for virological assays testing for anti-HEV IgG and IgM with ELISA and RNA-HEV performing RT-PCR. Anti-HEV IgG seropositivity resulted in 32 CIDP patients (39.0%) and in 45 controls (17.3%), indicating a significant association between anti-HEV IgG positivity and CIDP (OR 3.04; 95% CI 1.70–5.43, p -value <0.001), but in multivariate logistic regression the only significant associations with anti-HEV positivity were eating pork liver sausages (OR 10.443, 95% CI 2.268–60.12, p -value 0.004) and IVIg/SCIg administration (OR 31.32, 95% CI 7.914–171.7, p-value <0.001). The higher prevalence of anti-HEV IgG in CIDP patients than in controls could be justified by chronically administering IVIg/SCIg with a passive acquisition of anti-HEV antibodies. Furthermore, all the 20 CIDP patients who underwent IVIg/SCIg administration reported HEV risk factors, so that they could have acquired the infection. Further studies in a larger CIDP patient sample in treatment with therapy other than IVIg/SCIg are necessary to rule out the possible confounding effect of IVIg/SCIg. • Some infections could precede the symptoms' onset in CIDP. • In Guillain Barrè syndrome there is an association with HEV infection. • The are some similarities in antigenic terms between aminoacidic sequences of HEV proteins and myelin and paranodal proteins. • The molecular mimicry mechanism is probably involved in the immunopathogenesis of CIDP. [ABSTRACT FROM AUTHOR]

Although autoimmunity and autoimmune disease (AID) are relatively common, the repertoire of autoantigens is paradoxically very limited. Highly enriched in this autoantigen repertoire are nucleic acids and their binding proteins, which together form large macromolecular structures. Most of these complexes are of ancient evolutionary origin, with homologs throughout multiple kingdoms of life. Why and if these nucleic acid–protein particles drive the development of autoimmunity remains unresolved. Recent advances in our understanding of the microbiome may provide clues about the origins of autoimmunity – and the particular puzzle of why the autoantigen repertoire is so particularly enriched in ribonucleoprotein particles (RNPs). We discuss the possibility that autoimmunity to some RNPs may arise from molecular mimicry to microbial orthologs. Many autoantigens consist of RNA-binding proteins complexed with RNA molecules. These ribonucleoproteins are highly conserved, and many have microbial orthologs. There is increasing evidence that the microbiome plays an important role in the development of many autoimmune diseases. Immune responses to microbial orthologs of RNA-binding proteins, followed by molecular mimicry, may be a common pathway for the development of autoimmunity. [ABSTRACT FROM AUTHOR]

• Monoclonal Antibodies to EBNA-1, that cross-react with dsDNA. • Can bind to isolated glomeruli and can deposit in the kidney when injected into mice. • Can induce proteinuria and histopathologic alterations in the kidney consistent with glomerulonephritis. • Can bind extracellular matrix antigens found in the GBM and mesangial matrix. • Have pathogenic potential and may play a significant role in triggering SLE and lupus nephritis. Pathogens such as the Epstein Barr virus (EBV) have long been implicated in the etiology of systemic lupus erythematosus (SLE). The Epstein Barr virus nuclear antigen I (EBNA-1) has been shown to play a role in the development of anti-nuclear antibodies characteristic of SLE. One mechanism by which EBV may play a role in SLE is molecular mimicry. We previously generated two monoclonal antibodies (mAbs) to EBNA-1 and demonstrated that they cross-react with double-stranded DNA (dsDNA). In the present study, we demonstrate that these mAbs have pathogenic potential. We show that they can bind to isolated rat glomeruli and that binding can be greatly diminished by pretreatment of glomeruli with DNase I, suggesting that these mAbs bind dsDNA in the kidney. We also demonstrate that these antibodies can deposit in the kidney when injected into mice and can induce proteinuria and elicit histopathological alterations consistent with glomerulonephritis. Finally, we show that these antibodies can cross-react with laminin and collagen IV in the extracellular matrix suggesting that direct binding to the glomerular basement membrane or mesangial matrix may also contribute to the antibody deposition in the kidney. In summary, our results indicate that EBNA-1 can elicit antibodies that cross-react with dsDNA, that can deposit in the kidney, and induce kidney damage. These results are significant because they support the role of a viral protein in SLE and lupus nephritis. [ABSTRACT FROM AUTHOR]

Adhesive pili in Gram-positive bacteria represent a variety of extracellular multiprotein polymers that mediate bacterial colonization of specific host tissues and associated pathogenesis. Pili are assembled in two distinct but coupled steps, an orderly crosslinking of pilin monomers and subsequent anchoring of the polymer to peptidoglycan, catalyzed by two transpeptidase enzymes – the pilus-specific sortase and the housekeeping sortase. Here, we review this biphasic assembly mechanism based on studies of two prototypical models, the heterotrimeric pili in Corynebacterium diphtheriae and the heterodimeric pili in Actinomyces oris , highlighting some newly emerged basic paradigms. The disparate mechanisms of protein ligation mediated by the pilus-specific sortase and the spatial positioning of adhesive pili on the cell surface modulated by the housekeeping sortase are among the notable highlights. Covalently linked pili are assembled on the cell surface of many Gram-positive bacteria via a biphasic mechanism whereby pilus polymerization is catalyzed by the pilus-specific sortase followed by cell wall anchoring of pili by the housekeeping sortase. Pilus-mediated adhesion depends on pilus length, which is modulated by the housekeeping sortase via unique structural features. Some Gram-positive surface proteins with the LPXTG motif may hijack a pilus assembly machine via molecular mimicry to be displayed at the pilus tip. Pilus-specific sortase enzymes provide a bioconjugation tool via the formation of an isopeptide bond that is mechanically stable and less susceptible to proteolytic cleavage. [ABSTRACT FROM AUTHOR]

Type 1 diabetes (T1D) is a multifactorial autoimmune disease that combines genetics and environmental factors. The aim of this study is to determine the environmental risk factors and to investigate how virals infections are risks factors for type 1 diabetics whom have HLA DR3/DR4 predisposition in our population. This study includes 233 subjects, 145 diabetics and 88 controls from regions of the extreme western of Algeria. All the informations related to the disease were collected using predesigned questionnaire. Using in silico approach, we attempt to improve the understanding of this analytical result by molecular mimicry, which is associated with the breakdown of several autoimmune pathologies. The statistical study showed that history of varicella and measles infection and T1D related inheritance and type 2 diabetes are risk factors for T1D in the population of Tlemcen. We have determined the homologous antigenic regions between the glycoprotein "gE" of the varicella virus, the "hemagglutinin" of measles and the human protein "HSP60" at the level of their sequence and 3D structure. These cross-reactive epitopes bind to MHC class II molecules (HLA DR3/DR4) that predispose to T1D but not to MHC class II molecules (HLA DR2) that protect against T1D. This epitopes induce Th2 cells but only "hemagglutinin" and "Hsp60" can activate Th1 differentiation. This indicates their potential to destroy pancreatic cells β. Our study can allow us to adapt biological markers to genetically predisposed T1D and to establish a preventive strategy for healthy genetic predisposed individuals in Tlemcen population. • Infection by varicella and measles are risk factors to develop type 1 diabetes. • The epitope peptide of gE (varicella) and hemagglutinin peptide (measles) are homologue with the human peptide of HSP-60. • These homologous peptides bind to HLA class II molecules (HLADR3/DR4). • These mimicking peptides can induce humoral immune response. • Hemagglutinin peptide and Hsp60 peptide induce the cellular immune response. [ABSTRACT FROM AUTHOR]

The pathogenesis of autoimmune diseases (AIDs) is not only attributed to genetic susceptibilities but also environmental factors, among which, disturbed gut microbiota has attracted increasing attention. Compositional and functional changes of gut microbiota have been reported in various AIDs, and increasing evidence suggests that disturbed gut microbiota contributes to their immunopathogenesis. The accepted mechanisms include abnormal microbial translocation, molecular mimicry, and dysregulation of both local and systemic immunity. Studies have also suggested microbiota-based classification models and therapeutic interventions for patients with AIDs. Further in-depth mechanistic studies on microbiota–autoimmunity interplay in AIDs are urgently needed and underway to explore novel and precise diagnostic biomarkers and develop disease and patient-tailored therapeutic strategies. The compositional and functional changes of gut microbiota have been implicated in various autoimmune diseases (AIDs) by high-throughput techniques such as metagenomic sequencing. Correlation studies in humans and interventional studies in animal models have suggested that disturbed gut microbiota is involved in the immunopathogenesis of AIDs. The mechanisms of disturbed gut microbiota include abnormal microbial translocation, molecular mimicry, and dysregulation of both local and systemic immunity. In-depth deciphering of gut microbiota will help us to develop new microbiota-based assessments and interventions for patients with AIDs, which can help with their diagnosis, prognosis and treatment. [ABSTRACT FROM AUTHOR]

Previously, a distinct MHC class II Luminex-single antigen bead (SAB) pattern was described and attributed to antibodies targeting denatured antigens. In this study, we describe a distinct MHC class I reactivity pattern observed in 1.8% (105/5992) of samples resulted in 2017. The pattern displays reactivity to the following Luminex-SABs: HLA-A*33:03, A*36:01, A*80:01, B*54:01, B*53:01, C*06:02, C*07:02, C*18:02, C*14:02, C*03:03, C*03:04, and C*15:02. This pattern was identified in patients with no sensitization history, negative FlowPRA results, and antibody to self-antigen(s). Epitope analysis failed to reveal a common determinant(s) to explain this pattern of reactivity. Additionally, we found this pattern to be prevalent in female patients (62%) and also those with systemic lupus erythematosus (62%). Given these findings, we speculate this pattern likely represents false-positive reactivity, possibly due to antibody targeting denatured antigens or a specific peptide, molecular mimicry, autoimmunity, or a combination thereof. [ABSTRACT FROM AUTHOR]

Viral proteins evade host immune function by molecular mimicry, often achieved by short linear motifs (SLiMs) of three to ten consecutive amino acids (AAs). Motif mimicry tolerates mutations, evolves quickly to modify interactions with the host, and enables modular interactions with protein complexes. Host cells cannot easily coordinate changes to conserved motif recognition and binding interfaces under selective pressure to maintain critical signaling pathways. SLiMs offer potential for use in synthetic biology, such as better immunogens and therapies, but may also present biosecurity challenges. We survey viral uses of SLiMs to mimic host proteins, and information resources available for motif discovery. As the number of examples continues to grow, knowledge management tools are essential to help organize and compare new findings. • Short linear motifs (SLiMs) are patterns of three to ten consecutive AAs used by eukaryotic cells for tasks that include: signaling, localization, degradation, and proteolytic cleavage. • Viruses use SLiMs to their advantage, including interference with antiviral innate immune pathways. • Viral SLiMs can tolerate mutations, evolve quickly to modify host interactions, and co-occur in a modular manner or involve multiprotein complexes. • SLiMs are useful in synthetic biology, where minor edits can alter target specificity, modulate persistence, reprogram interactions with cell-signaling domains, and alter protein function in myriad other ways. • Aside from possible beneficial uses, for example, to produce better immunogens and develop therapeutic interventions against infectious disease, SLiMs may help characterize new and emerging threats to global health. [ABSTRACT FROM AUTHOR]

• Molecular basis for likely autoimmune origin of multiple sclerosis investigated. • Human endogenous retrovirus envelope and Epstein Barr virus proteins implicated. • Mimicry between brain and virus-derived proteins proposed. • HLA DR2b binding pairs of potential T H cell epitopes identified. • Modelling shows HLA DR2b binding similar to established T H cell epitope. The aetiology of multiple sclerosis (MS) is as yet poorly understood. Multiple mechanisms in different disease stages are responsible for immunopathology in MS. HLA Class II DR2b (DRB1*1501 β, DRA1*0101 α) is the strongest genetic risk factor for MS. Remnants of ancient retroviruses in the human genome, termed human endogenous retroviruses (HERV), and Epstein-Barr virus (EBV) infection are also associated with MS. In silico analyses of human endogenous retroviral envelope (HERV env) proteins and three myelin proteins that are principal targets of an autoimmune response in MS showed sequence similarities between potential T H epitopes within pairs of viral and myelin peptides predicted to bind HLA DR2b. This led to the proposal that such molecular mimicry may potentially trigger MS. HLA DR2b binding characteristics of previously identified peptides from the three myelin proteins and HERV env proteins as well as additional in silico predicted peptides from other encephalitogenic brain proteins and EBV proteins were studied to further investigate molecular mimicry. Peptides containing potential T H epitopes from the myelin oligodendrocyte glycoprotein and HERV env previously predicted to bind HLA DR2b as well as other pertinent potential HLA DR2b-restricted T H epitopes were confirmed to bind HLA DR2b molecules. Molecular modelling of HLA DR2b in complex with high affinity peptides derived from MOG and HERV env proteins showed that their binding could occur in a similar manner to a HLA DR2b-binding peptide containing a known T H epitope. A structurally related pair of peptides predicted to bind HLA DR2b from the EBV protein EBNA1 and β synuclein, a brain protein implicated in MS, were also shown to similarly bind HLA DR2b. The findings justify investigating CD4+ T cell responses to the identified peptides. [ABSTRACT FROM AUTHOR]

Glaucoma is a common irreversible vision loss disorder because of the gradual loss of retinal ganglion cells (RGCs) and the optic nerve axons. Major risk factors include elder age and high intraocular pressure (IOP). However, high IOP is neither necessary nor sufficient to cause glaucoma. Some non-IOP signaling cascades can mediate RGC degeneration. In addition, gender, diet, obesity, depression, or anxiety also contribute to the development of glaucoma. Understanding the mechanism of glaucoma development is crucial for timely diagnosis and establishing new strategies to improve current IOP-reducing therapies. The microbiota exerts a marked influence on the human body during homeostasis and disease. Many glaucoma patients have abnormal compositions of the microbiota (dysbiosis) in multiple locations, including the ocular surface, intraocular cavity, oral cavity, stomach, and gut. Here, we discuss findings in the last ten years or more about the microbiota and metabolite changes in animal models, patients with three risk factors (aging, obesity, and depression), and glaucoma patients. Antigenic mimicry and heat stress protein (HSP)-specific T-cell infiltration in the retina may be responsible for commensal microbes contributing to glaucomatous RGC damage. LPS-TLR4 pathway may be the primary mechanism of oral and ocular surface dysbiosis affecting glaucoma. Microbe-derived metabolites may also affect glaucoma pathogenesis. Homocysteine accumulation, inflammatory factor release, and direct dissemination may link gastric H. pylori infection and anterior chamber viral infection (such as cytomegalovirus) to glaucoma. Potential therapeutic protocols targeting microbiota include antibiotics, modified diet, and stool transplant. Later investigations will uncover the underlying molecular mechanism connecting dysbiosis to glaucoma and its clinical applications in glaucoma management. • The prevalence of glaucoma is rising. Lowering IOP can prevent its progression in some but not all patients. • An association between the microbiota and risk factors (aging, obesity, and depression) or glaucoma is established. • Glaucoma is linked to dysbiosis in the ocular surface, intraocular cavity, oral cavity, stomach, and gut. • It involves homocysteine, inflammation, metabolites, molecular mimicry, LPS-TLR4, and direct dissemination of microbe. • Targeting dysbiosis could be essential to glaucoma management in the future. [ABSTRACT FROM AUTHOR]

COVID-19, caused by infection with the SARS-CoV-2 has become a global health problem due to significant mortality rates; the exact pathophysiological mechanism remains uncertain. Articles reporting patient data are quite heterogeneous and have several limitations. Surviving patients develop a CD4 and CD8 T-cell response to the virus SARS-CoV-2 during COVID-19. Interestingly, pre-existing virus-reactive T-cells have been found in patients that were not infected before, suggesting some form of cross-reactivity or immunological mimicry. To better understand this phenomenon, we performed a bioinformatic study, which was aimed to identify antigenic structures that may explain the presence of such "reactive" T-cells, which may support or modulate the immune response to SARS-CoV-2 infections. Seven different common environmental allergen epitopes identical to the SARS-CoV-2 S-protein were identified that share affinity to 8 MHCI-specific epitope regions. Pollen showed the greatest similarity with the S protein epitope. In the epitope similarity analysis between the S protein and MHC-II / T helper epitopes, the highest similarity was determined for mites. When S-protein that stimulates B cells and identical epitope antigens are examined, the most common allergens were hornbeam and wheat. The high epitope similarity observed for the allergens examined and S protein epitopes suggest that these allergens may be a reason for pre-existing SARS-CoV-2 – reactive T-cells in previously non-infected subjects and such a previous exposure may affect the course of the disease in COVID-19 infection. It remains to be determined whether such a previous existence of SARS-CoV-2 reactive cells can support the clearance of the virus or if they, in contrast, may even aggravate the disease course. (Table 4, Ref 54) [Display omitted] • Significant portions of subjects with NO previous contact to SARS-CoV19 present with virus-specific T-cells. The origin of such T-cell specificity is unknown so far. • This research study evaluated potential immune molecular mimicry between the epitopes on the SARS-CoV19 S protein and naturally occurring allergens • Bioinformatics was used to identify sequence similarities for potential immune response against the SARS-CoV19 • Significant protein sequence similarities between SARS-CoV19 S-protein and naturally occurring allergens were found • Environmental allergens with epitope similarity to the SARS-CoV19 S-protein may contribute to the immune response and may explain T-cell reactivity to SARS-CoV19 even in the absence of previous virus encounter. [ABSTRACT FROM AUTHOR]

• Most of genetic variants affecting the mimicked ANO2 peptide are rare in the human population. • The mimicking EBNA1 peptide has only two variants on reference Epstein-Barr virus strains. • Bionformatic analysis did not suggest any association between different variants of ANO/EBNA1 peptides and the HLA allele DRB1*15:01. [ABSTRACT FROM AUTHOR]

Molecular mimicry is a common mechanism used by many bacteria to evade immune responses. In recent years, it has become evident that bacteria also decorate the extracellular matrix (ECM) of their biofilms with molecules that resemble those of the host. These molecules include amyloids and other proteins, polysaccharides, and extracellular DNA. Bacterial amyloids, like curli, and extracellular DNA are found in the biofilms of many species. Recent work demonstrated that curli and DNA form unique molecular structures that are recognized by the immune system, causing activation of autoimmune pathways. Although a variety of mechanisms have been suggested as the means by which infections initiate and/or exacerbate autoimmune diseases, the mechanism remains unknown. In this article, we discuss recent work on biofilms that highlight the role of amyloids as a carrier for DNA and potentiator of autoimmune responses, and we propose a novel link between bacterial infections and autoimmune diseases. Autoimmune responses are generated during many bacterial infections. Most bacteria that cause autoimmune sequelae postinfection produce amyloid proteins. Amyloids are detected in biofilms produced by many bacterial species. The incorporation of amyloid and DNA into the biofilm ECM enhances biofilm stability. Amyloid/DNA complexes are dominant molecular signatures that the immune system recognizes. Systemic exposure to amyloid/DNA complexes leads to an autoimmune response via Toll-like receptor (TLR)2 and TLR9. Biofilm-associated infections have the potential to generate autoimmunity via presentation of amyloid/DNA complexes to the immune system. [ABSTRACT FROM AUTHOR]

• Dermatomyositis is the main myositis phenotype related with cancer. • Molecular mimicry and shared antigens are involved in cancer-associated myositis. • Tumor-infiltrating lymphocytes may play a role in cancer-associated myositis. Cancer-associated dermatomyositis provides a unique opportunity to explore the relationship between autoimmunity and cancer. In this review, we describe the related epidemiological issues, considering the various currently accepted myositis phenotypes, their link with cancer, and the possible mechanisms leading to this relationship. We discuss current evidence regarding the role of molecular mimicry, somatic DNA tumor mutations, and the PD-1/PD-L1 pathway in the association between cancer and myositis. We also review tumor-infiltrating lymphocytes as a relevant factor to be evaluated in cancer-associated myositis, their interaction with tumor neoantigens, and the tumor mutational burden, all of which have implications for the treatment of these patients with immunotherapy. Finally, we discuss clinical scenarios related to the relationship between cancer and myositis, delineating a comprehensive theory linking autoimmunity and cancer. [ABSTRACT FROM AUTHOR]

• Established role of molecular mimicry in microbial pathogenesis. • Proposed novel drug targets based on a pathogen's molecular-mimicry-inducing proteins. • Repurposing of known drugs against Mycobacterium tuberculosis. Several microbial pathogens cause autoimmune diseases in humans by exhibiting molecular mimicry with the host proteins. However, the contribution of autoimmunity in microbial pathogenesis has not been evaluated critically. Clinical and experimental observations have supported and corroborated that autoimmunity was a fundamental process underlying pathology of human tuberculosis bacteria. In the current review, we propose novel drug targets based on a pathogen's molecular-mimicry-inducing proteins. The process for identification of drug targets has been explained using Mycobacterium tuberculosis as a model organism. The procedure described here can be applied for repurposing other known drugs and/or discovery of novel therapeutics against other pathogenic bacteria that exhibit molecular mimicry with the host's proteins. [ABSTRACT FROM AUTHOR]

Highlights • Adhesion force between MOG and HERV-W proteins and anti-MSRV/HERV-W were similar. • The shapes of force curves presented a typical pattern of a specific interaction. • AFS measurements demonstrate the molecular mimicry hypothesis. • The silver nanoparticles method corroborated the AFS results. • The antigen-antibody interaction was visible to the naked eye by color changing. Abstract Multiple sclerosis (MS) is an autoimmune and inflammatory demyelinating disease of the central nervous system. Experimental evidence supports the reactivity of autoantibodies against components of myelin sheath including the myelin oligodendrocyte glycoprotein (MOG). The MS etiology is still unknown, but some risk factors associated with immune dysregulation, genetic susceptibility, and environmental factors are under investigation. The last consider the hypothesis of molecular mimicry mechanism, which is potentially triggered by viral antigen inducing MS autoimmunity. The Human Endogenous Retroviruses W family (HERV-W) is the subject of studies within this field, based on the detection of HERV-W envelope gene proteins in MS patients' samples. In the biomedical field of diagnosis and therapeutics, nanotechnology is of great use for the detailed study of molecular mechanisms involving specific interactions between biomolecules providing high specificity and sensitivity of response. In view of the significance of etiological aspects for the comprehension of MS mechanisms of action, we applied a nanotechnological approach designed for antibody detection. For this, we analyzed MOG peptide sequences similar to the HERV-W protein. These sequences were subjected to interaction with anti-HERV-W antibodies using atomic force spectroscopy (AFS) and silver nanoparticles (AgNPs) methods to survey the potential occurrence of molecular mimicry. Our results revealed the molecular recognition between the anti-HERV-W antibody and the HERV-W and MOG epitopes by AFS and AgNPs approaches. Specific non-linear shape of force curves and median adhesion force values within the expected range for an antigen-antibody interaction were obtained for HERV-W and MOG peptides, 163 pN and 178 pN, respectively, suggesting the occurrence of cross-reactivity in these systems. [ABSTRACT FROM AUTHOR]

Abstract The central nervous system (CNS) in neurodegenerative diseases is a battlefield in which microglia fight a highly atypical battle. During the inflammatory process microglia themselves become dysfunctional and even with all the available immune arsenal including cytokine or/and antibody production, the battle is eventually lost. A closer look into the picture will reveal the fact that this is mainly due to the atypical characteristics of the infectious agent. The supramolecular assemblies of misfolded proteins carry unique features not encountered in any of the common pathogens. Through misfolding, proteins undergo conformational changes which make them become immunogenic, neurotoxic and highly infective. The immunogenicity appears to be triggered by the exposure of previously hidden hydrophobic portions in proteins which act as damage-associated molecular patters (DAMPs) for the immune system. The neurotoxicity and infectivity are promoted by the small oligomeric forms of misfolded proteins/peptides. Oligomers adopt conformations such as tubular-like, beta-barrel-like, etc., that penetrate cell membranes through their hydrophobic surfaces, thus destabilizing ionic homeostasis. At the same time, oligomers act as a seed for protein misfolding through a prion/prion-like mechanism. Here, we propose the hypothesis that oligomers have catalytic surfaces and exercise their capacity to infect native proteins through specific characteristics such as hydrophobic, electrostatic and π-π stacking interactions as well as the specific surface area (SSA), surface curvature and surface chemistry of their nanoscale supramolecular assemblies. All these are the key elements for prion/prion-like mechanism of self-replication and disease spreading within the CNS. Thus, understanding the mechanism of prion's templating activity may help us in the prevention and development of novel therapeutic strategies for neurodegenerative diseases. Highlights • The atypical nature of infectious agent as main culprit behind the unorthodox inflammation in neurodegenerative diseases. • The presence of autoantibodies and the molecular mimicry point to an autoimmune component in neurodegenerative diseases. • The revealed hydrophobicity in proteins triggers inflammation, aggregation and perturbs the dynamic of water in the brain. • Oligomers and protofibrils in disease may have catalytic surfaces promoting protein destabilization onto their surfaces. [ABSTRACT FROM AUTHOR]

An increase in the incidence of inflammatory arthritis after COVID-19 has been reported. Since many diseases exhibit population-specific causal effect sizes, we aimed to evaluate the incidence trends of inflammatory arthritis, including rheumatoid arthritis (RA), after COVID-19 in a large admixed Colombian population. Data analysis for this retrospective, population-based cohort study was carried out using the COOSALUD EPS registry. The following codes were selected for analyses: M059, seropositive RA, M069, unspecified RA, M060 seronegative RA, and other RA-related diagnoses: M064, M139, M068, M058, M130 and M053. The study period was limited to January 01, 2018, through December 31, 2022. Incidence rates (IRs) and incidence rate ratios (IRRs) were assessed. A Cox survival model was built to evaluate the influence of age, gender, and COVID-19 vaccination status on the development of inflammatory arthritis. A bioinformatic analysis was performed to evaluate the homology between SARS-CoV-2 and autoantigen peptides related to RA. The entire population study comprised 3,335,084 individuals. During the pandemic period (2020−2022) the total IIR for seropositive and unspecified RA were 1.60 (95% CI, 1.16–2.22) and 2.93 (95% CI, 2.04–4.19), respectively, and the IIR for overall RA-related diagnosis was 2.01 (95% CI 1.59–2.53). The age groups hazard ratios (HRs) were increased until the age group of 51–60 years (HR: 9.16; 95% CI, 7.24–11.59) and then decreased slightly in the age group 61 years or older (HR: 5.364; 95% CI, 4.24–6.78) compared to those within 18–30 years. Men were less at risk than women to develop inflammatory arthritis (HR: 0.21; 95% CI, 0.18–0.24). The greater time since COVID-19 diagnosis was associated with a lower likelihood of developing inflammatory arthritis (HR: 0.99; 95% CI:0.998–0.999). Vaccination (all types of COVID-19 vaccines included) did not prevent the development of inflammatory arthritis after COVID-19. Low identity was found between the SARS-CoV-2 ORF1ab antigen and the human antigens Poly ADP-ribose polymerase 14 and Protein mono-ADP-ribosyltransferase PARP9 isoform D (39% and 29%, respectively). In conclusion, our study confirms increased incidence of inflammatory arthritis, including RA, after COVID-19, with the greatest increase occurring before the first year post-covid. Women in their fifties were more susceptible. Further research is required to examine the effectiveness of vaccination in preventing post-COVID inflammatory arthritis and the mechanisms implicated in the development of RA after COVID-19. • Our study confirms an increase incidence of inflammatory arthritis, including rheumatoid arthritis, after COVID-19. • Women are at greater risk of developing inflammatory arthritis post-COVID than men. • Most cases of inflammatory arthritis occur before the first year following the diagnosis of COVID-19. • The effect of vaccination, additional covariables and long-term outcomes deserve further research. [ABSTRACT FROM AUTHOR]

There is a continuous arms race between pathogens and their host plants. However, successful pathogens, such as phytopathogenic oomycetes, secrete effector proteins to manipulate host defense responses for disease development. Structural analyses of these effector proteins reveal the existence of regions that fail to fold into three-dimensional structures, intrinsically disordered regions (IDRs). Because of their flexibility, these regions are involved in important biological functions of effector proteins, such as effector–host protein interactions that perturb host immune responses. Despite their significance, the role of IDRs in phytopathogenic oomycete effector–host protein interactions is not clear. This review, therefore, searched the literature for functionally characterized oomycete intracellular effectors with known host interactors. We further classify regions that mediate effector–host protein interactions into globular or disordered binding sites in these proteins. To fully appreciate the potential role of IDRs, five effector proteins encoding potential disordered binding sites were used as case studies. We also propose a pipeline that can be used to identify, classify as well as characterize potential binding regions in effector proteins. Understanding the role of IDRs in these effector proteins can aid in the development of new disease-control strategies. [ABSTRACT FROM AUTHOR]

Mimicry of host proteins is a strategy employed by pathogens to hijack host functions. Domain and motif mimicry was explored in the experimental and predicted SARS-CoV-2-human interactome. The host first interactor proteins were also added to capture the continuum of the interactions. The domains and motifs of the proteins were annotated using NCBI CD Search and ScanProsite, respectively. Host and pathogen proteins with a common host interactor and similar domain/motif constitute a mimicry pair indicating global structural similarity (domain mimicry pair; DMP) or local sequence similarity (motif mimicry pair; MMP). 593 DMPs and 7,02,472 MMPs were determined. AAA, DEXDc and Macro domains were frequent among DMPs whereas glycosylation, myristoylation and RGD motifs were abundant among MMP. The proteins involved in mimicry were visualised as a SARS-CoV-2 mimicry interaction network. The host proteins were enriched in multiple CVD pathways indicating the role of mimicry in COVID-19 associated CVDs. Bridging nodes were identified as potential drug targets. Approved antihypertensive and anti-inflammatory drugs are proposed for repurposing against COVID-19 associated CVDs. The SARS-CoV-2 mimicry data has been updated in ImitateDB (http://imitatedb.sblab-nsit.net/SARSCoV2Mimicry). Determination of key mechanisms, proteins, pathways, drug targets and repurposing candidates is critical for developing therapeutics for SARS CoV-2 associated CVDs. [Display omitted] [ABSTRACT FROM AUTHOR]

Bacteroidetes are the largest phylum of Gram-negative bacteria inhabiting our gastrointestinal tract and are considered the leading players of the healthy state and sophisticated homeostasis safeguarded by gut microbiota. Furthermore, specific roles have been attributed to some Bacteroidetes genera in the development of immune dysregulation, systemic disease such as metabolic syndrome and also neurological disorders. Glycoproteins secretion, short fatty acids imbalance, toxins production and molecular mimicry are only a part of the functions exerted by these commensals interacting with the host. The aim of this review is to summarize the current knowledge on the recognized role of Bacteroidetes in physiological functions and pathological networks in order to define the needs for future research and clarify the potential role for targeted microbial therapies. [ABSTRACT FROM AUTHOR]

The post-infectious autoimmune polyradiculoneuropathy Guillain-Barré syndrome (GBS) is triggered by molecular mimicry between microbial glycolipid antigens and human peripheral nerve gangliosides. Single nucleotide polymorphisms in exon 2 of CD1A ( *01/*02 ) and CD1E ( *01/*02 ) were assessed using PCR-RFLP; no significant differences in genotype or allele frequency were observed between 200 patients with GBS and 200 healthy controls. CD1 gene polymorphisms cannot be recognized as a susceptibility or disease-causative factor for GBS in the Bangladeshi population. However, further studies are necessary to investigate the CD1A*01/CD1E*01 haplotype distribution and its potential causative role in the axonal form of GBS. [ABSTRACT FROM AUTHOR]

Background and aims Periodontitis, a common polymicrobial inflammatory disease in the tooth supporting tissues, is a risk factor for coronary artery disease. One of the proposed underlying mechanisms is the systemic immune response to periodontal infection. We studied how serum antibodies against seven periodontal pathogens and their subgingival levels associate with each other, periodontitis, and coronary artery disease. Methods The Parogene cohort included 505 Finnish patients (mean age 63 y) who underwent coronary angiography, and clinical and radiographic oral examinations. Coronary diagnosis was defined as no significant coronary artery disease (<50% stenosis, n = 152), stable coronary artery disease (≥50% stenosis, n = 184) and acute coronary syndrome (n = 169). Levels of subgingival Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Porphyromonas endodontalis, Prevotella intermedia, Tannerella forsythia, Campylobacter rectus, and Fusobacterium nucleatum were determined by checkerboard DNA-DNA hybridization. Serum antibody (IgA/IgG) levels were analyzed with enzyme-linked immunosorbent assay (ELISA). Aggregate IgA/IgG burdens were calculated by summing and standardizing the serum antibody levels. Results Patients with active periodontitis were characterized by higher levels of subgingival bacteria and corresponding IgA/IgG response. Quartiles 2–4 of serum IgA/IgG burden indicated higher risk for acute coronary syndrome (OR 1.84, 95%CI 1.01–3.35 for IgA; OR 1.87, 95%CI 1.01–3.46 for IgG) independently of established cardiovascular risk factors, body mass index, number of teeth, subgingival bacterial levels and periodontal diagnosis. Conclusions Our findings support the hypothesis that the association between periodontitis and cardiovascular diseases is partly mediated by the immunologic response for periodontal pathogens. [ABSTRACT FROM AUTHOR]

Some patients with a history of Borrelia burgdorferi infection develop a chronic symptomatology characterized by cognitive deficits, fatigue, and pain, despite antibiotic treatment. The pathogenic mechanism that underlines this condition, referred to as post-treatment Lyme disease syndrome (PTLDS), is currently unknown. A debate exists about whether PTLDS is due to persistent infection or to post-infectious damages in the immune system and the nervous system. We present the case of a patient with evidence of exposure to Borrelia burgdorferi sl and a long history of debilitating fatigue, cognitive abnormalities and autonomic nervous system issues. The patient had a positive Western blot for anti-basal ganglia antibodies, and the autoantigen has been identified as γ enolase, the neuron-specific isoenzyme of the glycolytic enzyme enolase. Assuming Borrelia own surface exposed enolase as the source of this autoantibody, through a mechanism of molecular mimicry, and given the absence of sera reactivity to α enolase, a bioinformatical analysis was carried out to identify a possible cross-reactive conformational B cell epitope, shared by Borrelia enolase and γ enolase, but not by α enolase. Taken that evidence, we hypothesize that this autoantibody interferes with glycolysis in neuronal cells, as the physiological basis for chronic symptoms in at least some cases of PTLDS. Studies investigating on the anti-γ enolase and anti-Borrelia enolase antibodies in PTLDS are needed to confirm our hypotheses. [ABSTRACT FROM AUTHOR]

Neuromyelitis optica (NMO) is a rare, disabling, sometimes fatal central nervous system inflammatory demyelinating disease that is associated with antibodies ("NMO IgG") that target the water channel protein aquaporin-4 (AQP4) expressed on astrocytes. There is considerable interest in identifying environmental triggers that may elicit production of NMO IgG by AQP4-reactive B cells. Although NMO is considered principally a humoral autoimmune disease, antibodies of NMO IgG are IgG1, a T-cell-dependent immunoglobulin subclass, indicating that AQP4-reactive T cells have a pivotal role in NMO pathogenesis. When AQP4-specific proliferative T cells were first identified in patients with NMO it was discovered that T cells recognizing the dominant AQP4 T-cell epitope exhibited a T helper 17 (Th17) phenotype and displayed cross-reactivity to a homologous peptide sequence within a protein of Clostridium perfringens, a commensal bacterium found in human gut flora. The initial analysis of gut microbiota in NMO demonstrated that, in comparison to healthy controls (HC) and patients with multiple sclerosis, the microbiome of NMO is distinct. Remarkably, C. perfringens was the second most significantly enriched taxon in NMO, and among bacteria identified at the species level, C. perfringens was the one most highly associated with NMO. Those discoveries, along with evidence that certain Clostridia in the gut can regulate the balance between regulatory T cells and Th17 cells, indicate that gut microbiota, and possibly C. perfringens itself, could participate in NMO pathogenesis. Collectively, the evidence linking microbiota to humoral and cellular immunity in NMO underscores the importance for further investigating this relationship. [ABSTRACT FROM AUTHOR]

Infections often precede the onset of autoimmune disease and molecular (or epitope) mimicry is a plausible link. Cross-reacting epitopes are common between an infecting microorganism and the host because negative selection of self-reactive T-cells and B-cells is frequently incomplete. Complete eradication could lead to major voids in the immunologic repertoire. The association of an autoimmune disease with a microbial epitope may signify a causal relationship with the organism, an indirect connection through bystander effects, persistent infection or coincidence. There are well-established examples of a microbial mimic inducing a defined model of autoimmune disease in experimental animals but such instances are still relatively rare in humans. Establishing epitope mimicry as a direct cause opens opportunities for preventing the disease. Current approaches to cancer immunotherapy provides new examples of epitope mimicry between cancer antigens and normal tissue antigens. [ABSTRACT FROM AUTHOR]

Cancer prevention is one of the aim with the highest priority in order to reduce the burden of cancer diagnosis and treatment on individuals as well as on healthcare systems. To this aim, vaccines represent the most efficient primary cancer prevention strategy. Indeed, anti-cancer immunological memory elicited by preventive vaccines might promptly expand and prevent tumor from progressing. Antigens derived from microorganisms (MoAs), represent the obvious target for developing highly effective preventive vaccines for virus-induced cancers. In this respect, the drastic reduction in cancer incidence following HBV and HPV preventive vaccines are the paradigmatic example of such evidence. More recently, experimental evidences suggest that MoAs may represent a "natural" anti-cancer preventive vaccination or can be exploited for developing vaccines to prevent cancers presenting highly homologous tumor-associated antigens (TAAs) (e.g. molecular mimicry). The present review describes the different preventive anti-cancer vaccines based on antigens derived from pathogens at the different stages of development. [ABSTRACT FROM AUTHOR]

[Display omitted] • Immunoinformatics enables exploring the microbial impact on Type 1 Diabetes etiology. • Molecular mimicry as a triggering and pace-determining factor of disease progression. • Ubiquitous gut pathogens/commensals successfully mimic epitopes in Type 1 Diabetes. • Heat shock proteins most potent autoantigens for T-cell priming by molecular mimicry. • Gut dysbiosis clearly differentiates disease onset from controls and diagnosed cases. Type 1 diabetes is characterized by steadily increasing incidence and largely obscured pathogenesis. Molecular mimicry is well-established as trigger for different autoimmune pathologies, but obscurely explored in the context of T1D. The presented study explores the underestimated role of molecular mimicry in T1D-etiology/progression in search for etiologic factors among human pathogens and commensals. A comprehensive immunoinformatics analysis of T1D-specific experimental T-cell epitopes across bacterial, fungal, and viral proteomes was performed, coupled with MHC-restricted mimotope validation and docking of most potent epitopes/mimotopes to T1D-high-risk MHCII molecules. In addition, re-analysis of the publicly available T1D-microbiota dataset was performed, including samples at the pre-T1D disease stage. A number of bacterial pathogens/commensals were tagged as putative T1D triggers/boosters, including ubiquitous gut residents. The prediction of most likely mimicked epitopes revealed heat-shock proteins as most potent autoantigens for autoreactive T-cell priming via molecular mimicry. Docking revealed analogous interactions for predicted bacterial mimotopes and corresponding experimental epitopes. Finally, re-analysis of T1D gut microbiota datasets prompted pre-T1D as most significantly different/dysbiotic, compared to other explored categories (T1D stage/controls). Obtained results support the unrecognized role of molecular mimicry in T1D, suggesting that autoreactive T-cell priming might be the triggering factor of disease development. [ABSTRACT FROM AUTHOR]

Angiogenesis in healthy tissue and within malignant tumors differs on many levels, which may partly be explained by vascular mimicry formation resulting in altered contrast material or different radiopharmaceuticals distributions. Failed remodulation results in changes in the molecular exchange through the capillary wall and those consequences affect the behavior of contrast agents and radiopharmaceuticals. One of the most indicative signs of malignant tissue is the increased permeability and the faster molecular exchange that occurs between the extracellular and intravascular spaces. Dynamic imaging can help to assess the changed microenvironment. The fast-distribution of molecules reflects newly developed conditions in blood-flow redistribution inside a tumor and within the affected organ during the early stages of tumor formation. Tumor development, as well as aggressiveness, can be assessed based on the change to the vascular bed development, the level of molecular exchange within the tissue, and/or indicative distribution within the organ. The study of the vascular network organization and its impact on the distribution of molecules is important to our understanding of the image pattern in several imaging methods, which in turn influences our interpretation of the findings. A hybrid imaging approach (including PET/MRI) allows the quantification of vascularization and/or its pathophysiological impressions in structural and metabolic images. It might optimize the evaluation of the pretreatment imaging, as well as help assess the effect of therapy targeting neovascularization; antiVEGF drugs and embolization-based therapies, for example. [ABSTRACT FROM AUTHOR]

We hypothesize that the immune response to Epstein-Barr virus (EBV) drives the autoimmune damage in multiple sclerosis (MS). We investigated whether antibodies to two EBV proteins targeted by MS patients cross-react with self proteins. Using affinity columns, immunoprecipitation, and mass spectrometry, we found that antibodies to the EBV protein BFRF3 cross-react with the cytoplasmic protein septin-9, and antibodies to BRRF2 also bind mitochondrial proteins. Using Western blots and ELISA, we demonstrated that MS patients were more likely to have high levels of antibodies to one or another of these self antigens. [ABSTRACT FROM AUTHOR]