Molecular Mimicry Research Articles

Concomitant Polymyalgia Rheumatica and Giant Cell Arteritis Associated with Cystic Echinococcosis: A Rare Geriatric Case.

Parasitic infections could be an important triggering factor for autoimmune diseases. We present a clinical case of concomitant polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) induced with cystic echinococcosis (CE). A 74-year-old male was admitted with a 2-month history of progressive pain at the shoulders and hip, movement restriction, and constitutional symptoms. As a result of the examinations performed due to rheumatological complaints, PMR and GCA were diagnosed. The cystic appearance, which was incidentally detected in the liver 6months ago and not examined at that time, was found to be hydatid cyst. Medical treatment was initiated for all three conditions and the patient's symptoms improved significantly. Parasite infections may cause various autoimmune diseases because of molecular mimicry or sustained immune activation. Echinococcus granulosus is a very complex multicellular parasite and highly immunogenic for humans. Some body parts of the parasite, the outer surface and secreted particles, stimulate the host immune system strongly. The first case in the literature of coexistence of PMR and GCA associated with CE. Autoimmune diseases should be evaluated in patients with CE. Furthermore, CE should be considered in patients with autoimmune diseases in the presence of a cyst.

How persistent infection overcomes peripheral tolerance mechanisms to cause T cell-mediated autoimmune disease.

T cells help orchestrate immune responses to pathogens, and their aberrant regulation can trigger autoimmunity. Recent studies highlight that a threshold number of T cells (a quorum) must be activated in a tissue to mount a functional immune response. These collective effects allow the T cell repertoire to respond to pathogens while suppressing autoimmunity due to circulating autoreactive T cells. Our computational studies show that increasing numbers of pathogenic peptides targeted by T cells during persistent or severe viral infections increase the probability of activating T cells that are weakly reactive to self-antigens (molecular mimicry). These T cells are easily re-activated by the self-antigens and contribute to exceeding the quorum threshold required to mount autoimmune responses. Rare peptides that activate many T cells are sampled more readily during severe/persistent infections than in acute infections, which amplifies these effects. Experiments in mice to test predictions from these mechanistic insights are suggested.

Galectin-4 Antimicrobial Activity Primarily Occurs Through its C-Terminal Domain

Although immune tolerance evolved to reduce reactivity with self, it creates a gap in the adaptive immune response against microbes that decorate themselves in self-like antigens. This is particularly apparent with carbohydrate-based blood group antigens, wherein microbes can envelope themselves in blood group structures similar to human cells. In this study, we demonstrate that the innate immune lectin, galectin-4 (Gal-4), exhibits strain-specific binding and killing behavior towards microbes that display blood group–like antigens. Examination of binding preferences using a combination of microarrays populated with ABO(H) glycans and a variety of microbial strains, including those that express blood group–like antigens, demonstrated that Gal-4 binds mammalian and microbial antigens that have features of blood group and mammalian-like structures. Although Gal-4 was thought to exist as a monomer that achieves functional bivalency through its two linked carbohydrate recognition domains, our data demonstrate that Gal-4 forms dimers and that differences in the intrinsic ability of each domain to dimerize likely influences binding affinity. While each Gal-4 domain exhibited blood group–binding activity, the C-terminal domain (Gal-4C) exhibited dimeric properties, while the N-terminal domain (Gal-4N) failed to similarly display dimeric activity. Gal-4C not only exhibited the ability to dimerize but also possessed higher affinity toward ABO(H) blood group antigens and microbes expressing glycans with blood group–like features. Furthermore, when compared to Gal-4N, Gal-4C exhibited more potent antimicrobial activity. Even in the context of the full-length protein, where Gal-4N is functionally bivalent by virtue of Gal-4C dimerization, Gal-4C continued to display higher antimicrobial activity. These results demonstrate that Gal-4 exists as a dimer and exhibits its antimicrobial activity primarily through its C-terminal domain. In doing so, these data provide important insight into key features of Gal-4 responsible for its innate immune activity against molecular mimicry.

Імунопатологічні аспекти етіопатогенезу міокардиту

Myocarditis is a group of inflammatory diseases of the heart muscle against the background of the absence of acute or chronic ischemic heart disease, which are diagnosed according to established histological, immunological and immunohistochemical criteria.Objective. Summarize current information on the immunopathogenesis of myocarditis based on data from open sources of information.Methods. Publications were selected based on PubMed, Clinical Key Elsevier, Cochrane Library, eBook Business Collection and Google Scholar databases, which covered information on the immunopathogenesis of myocarditis.Results. Viral infections are the most common cause of myocarditis, along with some bacteria and protozoa. Chronic immune stimulation or autoimmunity in chronic viral myocarditis results from incomplete resolution of the viral infection or response to a previous virus or immune-mediated chronic tissue injury. An active autoimmune response in human myocarditis, both at the cellular and humoral levels, is the immunological basis for the development of this pathology. Myocarditis caused by COVID-19 is a new entity. At the moment, four main manifestations of myocarditis in the context of SARS-CoV-2 have been identified: myocarditis associated with an acute infection of COVID-19, post-acute syndrome of COVID-19 (or prolonged syndrome of COVID-19), multisystem inflammatory syndrome, and myocarditis due to related to vaccination. Autoimmune reactions probably contribute to molecular mimicry – they activate virus-specific T-cells that attack the myocardium. During this phase, high concentrations of cytokines (eg, tumor necrosis factor, interleukins 1a, 1b, 2, and interferon-γ) are produced. These cytokines, together with antibodies against viral and cardiac proteins, further exacerbate cardiac damage and systolic dysfunction due to contractile dysfunction and matrix proteins.Conclusions. CD4+T-cells are defined as the main driving forces of heart-specific autoimmunity in myocarditis. Dysregulated CD4+ T-cell populations and their associated cytokines are critical for the development and progression of myocarditis and may serve as therapeutic targets and the development of new treatment approaches.

An active learning card game to teach microbial pathogenesis to undergraduate biology majors.

Interactive classroom activities are an effective way to reinforce knowledge and promote student engagement. In this paper, we introduce the Pathogenesis Card Game (PCG), an innovative card game that engages students in a battle between microbial pathogens and the host immune system. Each student is given a set of cards that consist of either common host defenses or common pathogen evasion strategies. In pairs, students play a host defense card versus a pathogenesis card. Host defense cards include neutralize (antibody production), eat (phagocytosis), and destroy (degranulation). Pathogenesis cards present evasive strategies including mimic (molecular mimicry), escape (hemolysin production), hide (polysaccharide capsule), block (antioxidant defense), cut (protease secretion), and disguise (antigenic variation). Students develop a mastery of microbial pathogenesis through active gameplay by deliberating the outcome of each unique host-pathogen interaction. Furthermore, they learn the role of cells in the immune system and how pathogens can evade these immune defenses. PCG was piloted in a 300-level introductory microbiology course for 22 undergraduate students, comprising primarily biology and nursing majors. Both quantitative and qualitative student evaluations of the activity strongly suggest that PCG is an engaging, effective, and useful way to teach microbial pathogenesis. This activity provides a 60-minute lesson plan and corresponding materials that can be used to facilitate the introduction of pathogenesis to a typical undergraduate microbiology course. PCG offers instructors a framework to teach microbial pathogenesis and gives students the opportunity to construct their own knowledge about pathogen immune evasion in an engaging and interactive way.

Connection between gut microbiota and Anorexia Nervosa. Literature review

Introduction: Anorexia Nervosa (AN) stands as a severe mental disorder characterized by the highest mortality rate within the realm of psychiatric conditions. Its etiology encompasses genetic, neurobiological, environmental, and developmental factors. Recent investigations have shed light on the potential impact of the gut microbiota on the genesis and progression of AN.
 Aim of the Study: The aim of this paper is to provide a comprehensive review of the existing findings on relationship between gut dysbiosis and AN. The intention is to present new perspectives that contribute to a more detailed understanding of the multifaceted nature of this serious disorder.
 Description of the State of Knowledge: The gut microbiota takes a central role in modulating various physiological processes. Dysbiosis, which refers to an imbalance in gut microbiota composition, has recently drawn attention because of its association with several mental disorders. In the context of AN, studies have shown reduced microbial diversity and notable changes in specific bacterial populations. The influence of the gut microbiota on AN includes disturbances in the digestive system, changes in eating behaviours, and associations with related conditions such as anxiety and depression. Mechanisms such as the gut-brain axis, hormonal regulation and molecular mimicry contribute to these associations.
 Conclusions: Recognition of the pivotal role played by the gut microbiota in AN opens up avenues for potential therapeutic interventions. Pro- and prebiotics, along with fecal transplantation, emerge as promising modalities in the treatment of AN. Ongoing research is essential to further elucidate this evolving field, ultimately facilitating the development of targeted interventions for individuals with AN.

Evolution of parasitism genes in the plant parasitic nematodes

The plant-parasitic nematodes are considered as one of the most destructive pests, from which the migratory and sedentary endoparasitic plant parasitic nematodes infect more than 4000 plant species and cause over $100 billion crop losses annually worldwide. These nematodes use multiple strategies to infect their host and to establish a successful parasitism inside the host such as cell-wall degradation enzymes, inhibition of host defense proteins, and molecular mimicry. In the present study, the main parasitism-associated gene families were identified and compared between the migratory and sedentary endoparasitic nematodes. The results showed that the migratory and sedentary endoparasitic nematodes share a core conserved parasitism mechanism established throughout the evolution of parasitism. However, genes involved in pectin degradation and hydrolase activity are rapidly evolving in the migratory endoparasitic nematodes. Additionally, cell-wall degrading enzymes such as GH45 cellulases and pectate lyase and peptidase and peptidase inhibitors were expanded in the migratory endoparasitic nematodes. The molecular mimicry mechanism was another key finding that differs between the endoparasitic and sedentary parasitic nematodes. The PL22 gene family, which is believed to play a significant role in the molecular mechanisms of nematode parasitism, has been found to be present exclusively in migratory endoparasitic nematodes. Phylogenetic analysis has suggested that it was de novo born in these nematodes. This discovery sheds new light on the molecular evolution of these parasites and has significant implications for our understanding of their biology and pathogenicity. This study contributes to our understanding of core parasitism mechanisms conserved throughout the nematodes and provides unique clues on the evolution of parasitism and the direction shaped by the host.

Prediction of motif-mediated viral mimicry through the integration of host–pathogen interactions

One of the mechanisms viruses use in hijacking host cellular machinery is mimicking Short Linear Motifs (SLiMs) in host proteins to maintain their life cycle inside host cells. In the face of the escalating volume of virus-host protein–protein interactions (vhPPIs) documented in databases; the accurate prediction of molecular mimicry remains a formidable challenge due to the inherent degeneracy of SLiMs. Consequently, there is a pressing need for computational methodologies to predict new instances of viral mimicry. Our present study introduces a DMI-de-novo pipeline, revealing that vhPPIs catalogued in the VirHostNet3.0 database effectively capture domain-motif interactions (DMIs). Notably, both affinity purification coupled mass spectrometry and yeast two-hybrid assays emerged as good approaches for delineating DMIs. Furthermore, we have identified new vhPPIs mediated by SLiMs across different viruses. Importantly, the de-novo prediction strategy facilitated the recognition of several potential mimicry candidates implicated in the subversion of host cellular proteins. The insights gleaned from this research not only enhance our comprehension of the mechanisms by which viruses co-opt host cellular machinery but also pave the way for the development of novel therapeutic interventions.

[In Silico analysis of molecular mimic between Der p 23 against allergenic sources].

To identify through In Silico analysis the possible molecular mimicry between Der p 23 and antigens from allergenic sources. Identity was sought between Der p 23 and proteins from the mite families Pyroglyphidae, Acaridae, Chortoglyphidae and Echimyopodidae, through PSI-BLAST and They used PRALINE and EMBOSS for the alignments. Antigens with resolved experimental structure were obtained from Protein Data Bank and those not reported were generated using Swiss Model server and ALPHAFOLD 2. Epitope prediction was carried out with the Ellipro server and Pymol 2.3 was used to visualize the 3D models. The analysis between Pyroglyphidae allergens and Der p 23 showed identity with the endochitinase-like protein of D. pteronyssinus, and the type 2 chitin binding domain of D. farinae, with identities between 85 and 100%, with coverage of 100%, and 75% respectively. The allergens Der f 23 and Der p 23 of D. farinae and D. pteronyssinus had 100% coverage with identities of 85.42% and 79.59%, respectively. Among the allergens of Tyrophagus putrescentiae, binding to chitin, oviduct-specific glycoprotein and Cda4p were included, which had identity values corresponding to 40%, 42.22% and 34.78%, with coverage values that did not exceed the 55%. No results were found for Chortoglyphidae and Echimyopodidae. There is molecular mimicry and structural homology between Der P 23 and allergens from allergic sources of the Pyroglyphidae and Acaridae families. Potential epitopes were identified in Der p 23, which could present cross-reactivity with the proteins of the allergenic sources studied, which must be demonstrated in In vitro and In vivo studies. In vitro and in vivo work is needed to demonstrate the results obtained in the In Silico analysis.

[In silico analysis of molecular mimicry between human aquaporin 3, Aspergillus fumigatus aquaporin and aquaporins from allergic sources].

Conduct an in-silico assessment of potential molecular mimicry between human aquaporins, A. fumigatus, and diverse allergenic sources. Amino acid sequences of human AQP3 and A. fumigatus aquaporin were compared through multiple alignments with 25 aquaporins from diverse allergenic sources. Phylogenetic analysis and homology-based modeling were executed, and the ElliPro server predicted conserved antigenic regions on 3D structures. Global identity among studied aquaporins was 32.6%, with a specific conserved local region at 71.4%. Five monophyletic clades (A-E) were formed, and Group B displayed the highest identity (95%), including 6 mammalian aquaporins, notably AQP3. A. fumigatus aquaporin exhibited the highest identity with Malassezia sympodialis (35%). Three linear and three discontinuous epitopes were identified in both human and A. fumigatus aquaporins. The Root Mean Square Deviation (RMSD) from overlapping aquaporin structures was 1.006. Identification of potential linear and conformational epitopes on human AQP3 suggests likely molecular mimicry with A. fumigatus aquaporins. High identity in a specific antigenic region indicates potential autoreactivity and a probable antigenic site involved in cross-reactivity. Validation through in vitro and in vivo studies is essential for further understanding and confirmation.

[Molecular mimicry between human thyroid peroxidase, thyroglobulin, cosinophil peroxidase, IL-24 and microorganisms antigens].

Identify molecular mimicry between TPO, eosinophil peroxidase (EPX), thyroglobulin and IL24 and microorganism antigens. Through in silico analysis, we performed local alignments between human and microorganism antigens with PSI-BLAST. Proteins that did not present a 3D structure were modeled by homology through the Swiss Modeller server and epitope prediction was performed through Ellipro. Epitopes were located in the 3D models using PYMOL software. A total of 38 microorganism antigens (parasites, bacteria) had identities between 30% and 45%, being the highest with Anisakis simplex. The alignment between 2 candidate proteins from A. simplex and EPX presented significant values, with identities of 43 and 44%. In bacteria, Campylobacter jejuni presented the highest identity with thyroglobulin (35%). 220 linear and conformational epitopes of microorganism antigens were predicted. Peroxidasin-like proteins from Toxocara canis and Trichinella pseudospiralis presented 10 epitopes similar to TPO and EPX, as possible molecules triggering cross-reactivity. No virus presented identity with the human proteins studied. TPO and EPX antigens shared potential cross-reactive epitopes with bacterial and nematode proteins, suggesting that molecular mimicry could be a mechanism that explains the relationship between infections and urticaria/hypothyroidism. In vitro work is needed to demonstrate the results obtained in the in silico analysis.

Potential clinical implications of molecular mimicry-induced autoimmunity.

Molecular mimicry is hypothesized to be a mechanism by which autoimmune diseases are triggered. It refers to sequence or structural homology between foreign antigens and self-antigens, which can activate cross-reactive lymphocytes that attack host tissues. Elucidating the role of molecular mimicry in human autoimmunity could have important clinical implications. To review evidence for the role of molecular mimicry in major autoimmune diseases and discuss potential clinical implications. Comprehensive literature review of clinical trials, observational studies, animal models, and immunology studies on molecular mimicry in multiple sclerosis, type 1 diabetes, rheumatoid arthritis, lupus, Guillain-Barre syndrome, autoimmune myocarditis, and primary biliary cirrhosis published from 2000-2023. Substantial indirect evidence supports molecular mimicry as a contributor to loss of self-tolerance in several autoimmune conditions. Proposed microbial triggers include Epstein-Barr virus, coxsackievirus, Campylobacter jejuni, and bacterial commensals. Key mechanisms involve cross-reactive T cells and autoantibodies induced by epitope homology between microbial and self-antigens. Perpetuation of autoimmunity involves epitope spreading, inflammatory mediators, and genetic factors. Molecular mimicry plausibly explains initial stages of autoimmune pathogenesis induced by infection or microbiota disturbances. Understanding mimicry antigens and pathways could enable improved prediction, monitoring, and antigen-specific immunotherapy for autoimmune disorders. However, definitive proof of causation in humans remains limited. Further research should focus on establishing clinical evidence and utility.

Insights into the interplay between Epstein-Barr virus (EBV) and multiple sclerosis (MS): A state-of-the-art review and implications for vaccine development.

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS). MS results from an inflammatory process leading to the loss of neural tissue and increased disability over time. The role of Epstein Barr Virus (EBV), as one of the most common global viruses, in MS development has been the subject of several studies. However, many related questions are still unanswered. This study aimed to review the connection between MS and EBV and provide a quick outline of MS prevention using EBV vaccination. For this narrative review, an extensive literature search using specific terms was conducted across online databases, including PubMed/Medline, Scopus, Web of Science, and Google Scholar, to identify pertinent studies. Several studies proved that almost 100% of people with MS showed a history of EBV infection, and there was an association between high titers of EBV antibodies and an increased risk of MS development. Various hypotheses are proposed for how EBV may contribute to MS directly and indirectly: (1) Molecular Mimicry, (2) Mistaken Self, (3) Bystander Damage, and (4) Autoreactive B cells infected with EBV. Given the infectious nature of EBV and its ability to elude the immune system, EBV emerges as a strong candidate for being the underlying cause of MS. The development of an EBV vaccine holds promise for preventing MS; however, overcoming the challenge of creating a safe and efficacious vaccine presents a significant obstacle.

IMMUNOLOGICAL FEATURES OF COVID-19 IN PATIENTS WITH NEUROPSYCHIATRIC SYMPTOMS AND HHV-6-INFECTION

SARS-CoV-2 infection in most cases is characterised by mild symptoms of fever, tiredness and dry cough. Coronaviruses can also induce cognitive, emotional, neurovegetative and behavioral dysregulation due to direct neurological injury through hypoxic damage and neuroinvasion. Most SARS-CoV-2 infections resolve within two weeks. However, the infection, which is characterized by neurological and neuropsychiatric symptoms, may last longer than 12 weeks. This phenomenon has been termed as Long COVID (LC) – a multisystemic condition, associated with acute phase disease severities. Several hypotheses for its pathogenesis have been suggested, including immune dysregulation with or without reactivation of herpesviruses. The inflammation is central to pathogenesis of psychiatric symptoms in COVID-19 patients, which is often associated with presence of neural autoantibodies.
 The following changes are established of innate immunity in patients with SARS-CoV-2 infection and long COVID: 1) cytokine storm, which manifests itself in high concentration of proinflammatory cytokines and chemokines (IFN-β, IFN-λ1, IFN-γ, CXCL9, CXCL10, IL-8, IL-1α/β, IP-10, MCP-1); 2) elevated level C-reactive protein; 3) decreased number of NK, NKT cells and its exhaustion; 4) lower expression of NKG2C, upregulation of checkpoint receptors (LAG3, TIGIT and TIM3) on NK cells; 5) poor interacting between monocytes, infectious agents and Tolllike receptor (TLR) ligands; 6) reinforced products of thromboxane-A2, resulting in increased platelet aggregation, which mediate thrombus formation. It was also found in such patients the changes of adaptive immunity: 1) T cell alterations, including exhausted T cells; 2) reduced CD4+ and CD8+ effector memory cell numbers, which mainly express PD-1, CTLA-4, TIGIT and Tim-3; 3) a lack of naive T and B cells; 4) increases in the numbers of IL-4- and IL-6-secreting CD4+ T cells; 5) higher expression of cytotoxic granules (GrA, GrB, perforin) on CD8+ T cells.
 The exact mechanisms underlying the immune response after SARS-CoV-2 infection remain unclear. The count of helper T cells, regulatory T cells and memory T cells are all diminished in severe COVID- 19 cases, though Th1 and Th2 cytokine levels remain high. T cell activation (indicated by CD38 and HLA-DR) occur during severe COVID-19. Besides, T cells are overactivated in COVID-19 patients, leading to cytokine storm, and decreased Treg cells are a reason for severe disease. A subset of T cell expressed at the same time both: T cell immunoglobulin and mucin domain-3 (Tim-3) and programmed death-1 (PD-1).
 The overproduction of several inflammatory cytokines, overactivated and exhausted T cells, overstimulation of immune system and loss of self-tolerance alone can cause the production of autoantibodies. In addition, are activated the extrafollicular B cells in conjunction with autoantibody-secreting B cells. As seen in COVID-19 patients with autoantibodies and autoreactive CD4+ and CD8+ cells, probably promotes the development of neural autoantibody-associated psychiatric disease. The neural autoantibodies probably promote the development of psychiatric disease according to such pathomechanisms: 1) molecular mimicry: 2) NETs; 3) altered blood-brain barrier permeability; 4) coagulopathy and endothelial dysfunction (brain microhaemorrhages); 5) neuronal injury and apoptosis; 6) chronic hypoxia; 7) oxidative stress.
 Some features of COVID-19 resemble clinical diseases that accompany certain acute and chronic viral diseases, including diseases caused by HHV-6. Virus HHV-6 act in the following ways: 1) downregulation of CD3; 2) induction of IL-10-producing T-regulatory type 1 cells; 3) inhibition of IFN-β, IL-2, IL-12, and molecules MHC class I production; 4) immunomodulation – alterations in cell surface receptor expression and cytokine/chemokine production. Infection with SARS-CoV-2 causes overproduction of inflammatory cytokines that activate the inflammatory cascade. The hyperinflammatory processes in COVID-19 patients reactivate latent HHV-6, and that this is related to the inflammatory status of the patient. HHV-6 infects a broad array of immune and non-immune cell types and may introduce changes in T cell expression profiles and differential proliferation rates. The subclinical reactivation HHV-6 may affect the degree or severity of the SARS-CoV-2 infection. The severity of the course of the SARS-CoV-2 infection against the background of reactivation of HHV-6 threatens the formation of immunopathological syndromes, first of all is autoimmune syndrome. Long COVID could be induced by different mechanisms, including viral persistence that leads to disorders of immune response regulation, the release of superantigens that overactivate the immune system, destroys the blood-brain barriers which collectively may result in autoimmunity and polyautoimmunity, including neuroautoimmunity. This process was accompanied by the production of autoantibodies against thyroglobulin, thyroid peroxidase, insulin, double-stranded DNA, topoisomerase 1, glomerular basement membrane, and myoloperoxidase, which are detected in many autoimmune diseases. The production of antibodies against autoantigens that are detected mainly in polyautoimmunity through a completely new mechanism which involves the disruption of central tolerance Therefore, neuropsychiatric disorders in patients who have experienced moderate and severe forms of the course of COVID-19 are in the vast majority caused by deep immune changes and concominant lymphotropic/ neurotropic infection (HHV-6). The depth of disorders is often associated with autoimmunity to neuronal and other autoantigens.

[Molecular mimicry between Plasmodium sp and Guillain-Barre syndrome antigens].

Analyze the molecular mimicry between Plasmodium spp. and autoantigens associated with GBS, identifying possible antigenic epitopes. PSI-Blast, Praline, Emboss, Protein Data Bank, Swiss Model Server, AlphaFold 2, Ellipro and PyMol 2.3 were used to search for homologies, perform alignments, obtain protein structures, and predict epitopes. 17 autoantigens and seven immunological targets of the peripheral nervous system were included, identifying 72 possible epitopes associated with GBS. From the proteome of Plasmodium spp. (298 proteins), only two showed similarities close to 30% with TRIM21 and BACE1, generating seven possible epitopes. No significant homologies were observed between the proteome of GBS and Plasmodium spp. The exploration of other mechanisms such as immune-mediated capillary damage, Epitope Spreading or Bystander Activation is suggested to explain the mentioned association. These findings underscore the need to clarify the etiology of autoimmune diseases and the role of pathogens. The need for experimental studies to validate these results is emphasized.

[Molecular mimic between cardiovascular diseases and microorganism antigens].

Cardiovascular diseases are the result of genetic and environmental interaction that conditions the integrity of the heart and blood vessels. Risk factors include infections. The inflammatory response against the infectious agent is a trigger of autoimmune cardiovascular diseases due to the similarity between the pathogen proteins and human antigens, since the immune response can present cross-reactivity caused by molecular mimicry. We performed a search for pathogens involved in autoimmune heart diseases and autoantigens 9 associated with these diseases in the Pubmed and Google Scholar search engines. Identity between proteins was performed through global alignments using PSI-BLAST. The 3D structures of the proteins were obtained by Uniprot or NCBI and, if not found, the structure was modeled by homology using the Swiss Model server. Epitope prediction was performed through Ellipro and the Immunological Epitope Database (IEDB). In addition, the PYMOL program was used to visualize proteins in 3D and position the epitopes in the structure. A total of ten cardiovascular proteins showed identity (30-88,24%) in their amino acid sequences with antigens from 10 pathogens. Actin proteins and heat shock protein (HSP) families had higher levels of identity with Trypanosoma Cruzi, Cryptococcus neoformans, and Chlamydia trachomatis, 71,47%, 88,24%, and 80,61%, respectively. Other pathogens, such as Streptococcus pyogenes, Bacillus sp, Magnetospirillum gryphiswaldense, Helicobacter pylori and Chlamydia pneumoniae, presented a moderate identity with a maximum value of 65,79%. Human actin and HSPs share a high degree of conservation with epitopes from various microorganisms, such as bacteria, fungi and protozoa, suggesting molecular mimicry and cross-reactivity as a mechanism for the development of atherosclerosis, heart disease rheumatic disease, myocarditis and Chagas heart disease. In vitro and in vivo work is needed to demonstrate the results obtained in the In Silico analysis.

A rare case of streptococcal pharyngitis in an adult male causing hemophagocytic lymphohistiocytosis

Hyperinflammatory responses due to cytokine storms involve multiple systems in hemophagocytic lymphohistiocytosis (HLH) leading to morbidities. Multiple bacterial etiologies have been suggested as a cause of secondary HLH but streptococcal infection has only been reported in pediatric cases. Streptococcus has been considered a notorious pathogen due to its ability to interfere with host immunity through the phenomenon of molecular mimicry. This case report shows the sequence of events post-streptococcal pharyngitis in a 28-year-old male, which lead to HLH and fatality to life, and how a timely intervention of steroids salvaged the patient.

The Rapidly Changing Patterns in Bacterial Co-Infections Reveal Peaks in Limited Gram Negatives during COVID-19 and Their Sharp Drop Post-Vaccination, Implying Potential Evolution of Co-Protection during Vaccine-Virus-Bacterial Interplay.

SARS-CoV-2 has caused the most devastating pandemic of all time in recent human history. However, there is a serious paucity of high-quality data on aggravating factors and mechanisms of co-infection. This study aimed to identify the trending patterns of bacterial co-infections and types and associated outcomes in three phases of the pandemic. Using quality hospital data, we have investigated the SARS-CoV-2 fatality rates, profiles, and types of bacterial co-infections before, during, and after COVID-19 vaccination. Out of 389 isolates used in different aspects, 298 were examined before and during the pandemic (n = 149 before, n = 149 during). In this group, death rates were 32% during compared to only 7.4% before the pandemic with significant association (p-value = 0.000000075). However, the death rate was 34% in co-infected (n = 170) compared to non-co-infected patients (n = 128), indicating a highly significant value (p-value = 0.00000000000088). However, analysis of patients without other serious respiratory problems (n = 28) indicated that among the remaining 270 patients, death occurred in 30% of co-infected patients (n = 150) and only 0.8% of non-co-infected (n = 120) with a high significant p-value = 0.00000000076. The trending patterns of co-infections before, during, and after vaccination showed a significant decline in Staphylococcus aureus with concomitant peaks in Gram negatives n = 149 before/n = 149 during, including Klebsiella pneumonian = 11/49 before/during, E. coli n = 10/24, A. baumannii n = 8/25, Ps. aeruginosa n = 5/16, and S. aureus 13/1. Nevertheless, in the post-vaccination phase (n = 91), gender-specific co-infections were examined for potential differences in susceptibility. Methicillin-resistant S. aureus dominated both genders followed by E. coli in males and females, with the latter gender showing higher rates of isolations in both species. Klebsiella pneumoniae declined to third place in male patients. The drastic decline in K. pneumoniae and Gram negatives post-vaccination strongly implied a potential co-protection in vaccines. Future analysis would gain more insights into molecular mimicry.

Virus-reactive T cells expanded in aplastic anemia eliminate hematopoietic progenitor cells by molecular mimicry

AbstractAcquired aplastic anemia is a bone marrow failure syndrome characterized by hypocellular bone marrow and peripheral blood pancytopenia. Frequent clinical responses to calcineurin inhibition and antithymocyte globulin strongly suggest critical roles for hematopoietic stem/progenitor cell–reactive T-cell clones in disease pathophysiology; however, their exact contribution and antigen specificities remain unclear. We determined differentiation states and targets of dominant T-cell clones along with their potential to eliminate hematopoietic progenitor cells in the bone marrow of 15 patients with acquired aplastic anemia. Single-cell sequencing and immunophenotyping revealed oligoclonal expansion and effector differentiation of CD8+ T-cell compartments. We reexpressed 28 dominant T-cell receptors (TCRs) of 9 patients in reporter cell lines to determine reactivity with (1) in vitro–expanded CD34+ bone marrow, (2) CD34− bone marrow, or (3) peptide pools covering immunodominant epitopes of highly prevalent viruses. Besides 5 cytomegalovirus-reactive TCRs, we identified 3 TCRs that recognized antigen presented on hematopoietic progenitor cells. T cells transduced with these TCRs eliminated hematopoietic progenitor cells of the respective patients in vitro. One progenitor cell–reactive TCR (11A5) also recognized an epitope of the Epstein-Barr virus–derived latent membrane protein 1 (LMP1) presented on HLA-A∗02:01. We identified 2 LMP1-related mimotopes within the human proteome as activating targets of TCR 11A5, providing proof of concept that molecular mimicry of viral and self-epitopes can drive T cell–mediated elimination of hematopoietic progenitor cells in aplastic anemia.

Gene-environment interaction in the pathophysiology of type 1 diabetes.

Type 1 diabetes (T1D) is a complex metabolic autoimmune disorder that affects millions of individuals worldwide and often leads to significant comorbidities. However, the precise trigger of autoimmunity and disease onset remain incompletely elucidated. This integrative perspective article synthesizes the cumulative role of gene-environment interaction in the pathophysiology of T1D. Genetics plays a significant role in T1D susceptibility, particularly at the major histocompatibility complex (MHC) locus and cathepsin H (CTSH) locus. In addition to genetics, environmental factors such as viral infections, pesticide exposure, and changes in the gut microbiome have been associated with the development of T1D. Alterations in the gut microbiome impact mucosal integrity and immune tolerance, increasing gut permeability through molecular mimicry and modulation of the gut immune system, thereby increasing the risk of T1D potentially through the induction of autoimmunity. HLA class II haplotypes with known effects on T1D incidence may directly correlate to changes in the gut microbiome, but precisely how the genes influence changes in the gut microbiome, and how these changes provoke T1D, requires further investigations. These gene-environment interactions are hypothesized to increase susceptibility to T1D through epigenetic changes such as DNA methylation and histone modification, which in turn modify gene expression. There is a need to determine the efficacy of new interventions that target these epigenetic modifications such as "epidrugs", which will provide novel avenues for the effective management of T1D leading to improved quality of life of affected individuals and their families/caregivers.