Molecular Mimicry Research Articles

Viral intruders in the heart: A review of RNA viruses and their role in cardiac disorders.

Viral cardiac diseases have a significant impact on global health, and RNA viruses play a crucial role in their pathogenesis. This literature review aims to provide a comprehensive understanding of the complex relationship between RNA viruses and cardiac diseases, focusing on the molecular processes and clinical implications of these interactions. The paper begins by discussing the various RNA viruses that have been linked to cardiac infections. Subsequently, the study explores the mechanisms through which RNA viruses can cause cardiac injury, including direct viral invasion, immune-mediated responses, and molecular mimicry. The review extensively examines the intricate interplay between the host immune system and RNA viruses, shedding light on both protective and harmful immune responses. Additionally, it investigates the role of viral persistence and chronic inflammation in the long-term effects on cardiac health. The thorough analysis presented not only enhances our scientific understanding of how RNA viruses contribute to the development of cardiac diseases but also highlights potential avenues for future research and breakthroughs in this field. Given the significant global health threat posed by viral cardiac disorders, unraveling the molecular foundations of these diseases is essential for advancing diagnostic capabilities and therapeutic interventions.

Activation in Autoimmunity: Mechanisms and Clinical Implications

Autoimmunity arises when the immune system mistakenly targets the body’s own tissues, leading to chronic inflammatory diseases that can affect multiple organs. The central event in autoimmunity is the inappropriate activation of immune cells, which normally tolerate self-antigens. This review examines the mechanisms underlying immune activation in autoimmunity, focusing on the loss of immune tolerance, molecular mimicry, bystander activation, and epitope spreading. Genetic predispositions and environmental triggers, such as infections, play key roles in this process, contributing to the dysregulation of immune responses. Specific immune cells, including autoreactive T cells, B cells producing autoantibodies, and dendritic cells presenting self-antigens, drive disease pathogenesis by perpetuating inflammation and tissue damage. Dysfunctions in regulatory T cells (Tregs) further exacerbate immune activation by failing to suppress autoreactive lymphocytes. Clinically, understanding these activation mechanisms is crucial for developing diagnostic biomarkers and targeted therapies. Current treatments focus on modulating immune responses through biologic agents that block pro-inflammatory cytokines (e.g., TNF-α, IL-6), deplete B cells (e.g., rituximab), or restore immune regulation (e.g., Treg therapies). Emerging therapies aim to restore immune tolerance, offering hope for more effective and personalized interventions. This review highlights the critical role of immune activation in autoimmunity and discusses therapeutic strategies to prevent or reverse this process. The ongoing exploration of these mechanisms is key to improving outcomes for patients with autoimmune diseases. Keywords: Autoimmunity, immune tolerance, molecular mimicry, T cells, autoantibodies, targeted therapy

Characterization of anti-EBNA-1 antibodies and exploration of their molecular mimicry potential in an EBV-infected Sjögren's syndrome patient

There is a potential link between autoimmune diseases and Epstein-Barr virus (EBV) infections, with EBV playing a substantial role in the onset of Sjögren's syndrome (SjS). Some EBV proteins could mimic host self-antigens post-infection, leading to molecular mimicry. This similarity may cause the immune system to attack its tissues mistakenly. Among the various proteins associated with EBV, nuclear antigen 1 (EBNA-1) is essential for the latent replication of infected cells and is prevalent in all EBV-related diseases. In the study, single-chain variable fragment (scFv) antibodies targeting EBNA-1 were isolated using phage display technology from a primary SjS patient who also had a chronic active EBV infection. The specific clones were enriched after panning, and the binding activity of selected scFvs targeting EBNA-1 was confirmed. Sequence analysis indicated that the scFvs exhibiting positive signals could be grouped into five clones, all of which used homologous heavy chain V regions derived from germline Vh4-39, and two types of light chain V regions stemming from germline Vλ1-44 and Vλ3-15. These scFvs were found to exhibit a high degree of somatic mutations, likely indicative of antigen selection. Of the scFvs, P1-3 demonstrated the strongest binding affinity to EBNA-1, exhibiting a determined value of 7.3 x 10-8 M, and showed cross-reactivity to the SjS associated La/SSB self-antigen. The experimental results combined with AlphaFold 3 predictions revealed a potential epitope for scFv P1-3 binding to EBNA-1. Additionally, scFv P1-3 could also cross-bind to the modeled structure of La/SSB. We inferred a possible structural correlation between EBNA-1 and La/SSB involving an X2AX6PG epitope motif. This research contributes to our understanding of the structural basis of the interactions between antibodies and EBNA-1, shedding light on the VH and VL gene usage of anti-EBNA-1 antibodies in EBV-infected SjS patients and the potential origins of autoantibodies.

Gut microbiome metabolites, molecular mimicry, and species-level variation drive long-term efficacy and adverse event outcomes in lung cancer survivors

The influence of the gut microbiota on long-term immune checkpoint inhibitor (ICI) efficacy and immune-related adverse events (irAEs) is poorly understood, as are the underlying mechanisms. We performed gut metagenome and metabolome sequencing of gut microbiotas from patients with lung cancer initially treated with anti-PD-1/PD-L1 therapy and explored the underlying mechanisms mediating long-term (median follow-up 1167 days) ICI responses and immune-related adverse events (irAEs). Results were validated in external, publicly-available datasets (Routy, Lee, and McCulloch cohorts). The ICI benefit group was enriched for propionate (P=0.01) and butyrate/isobutyrate (P=0.12) compared with the resistance group, which was validated in the McCulloch cohort (propionate P<0.001, butyrate/isobutyrate P=0.002). The acetyl-CoA pathway (P=0.02) in beneficial species mainly mediated butyrate production. Microbiota sequences from irAE patients aligned with antigenic epitopes found in autoimmune diseases. Microbiotas of responsive patients contained more lung cancer-related antigens (P=0.07), which was validated in the Routy cohort (P=0.02). Escherichia coli and SGB15342 of Faecalibacterium prausnitzii showed strain-level variations corresponding to clinical phenotypes. Metabolome validation reviewed more abundant acetic acid (P=0.03), propionic acid (P=0.09), and butyric acid (P=0.02) in the benefit group than the resistance group, and patients with higher acetic, propionic, and butyric acid levels had a longer progression-free survival and lower risk of tumor progression after adjusting for histopathological subtype and stage (P<0.05). Long-term ICI survivors have coevolved a compact microbial community with high butyrate production, and molecular mimicry of autoimmune and tumor antigens by microbiota contribute to outcomes. These results not only characterize the gut microbiotas of patients who benefit long term from ICIs but pave the way for "smart" fecal microbiota transplantation. Registered in the Chinese Clinical Trial Registry (ChiCTR2000032088). This work was supported by Beijing Natural Science Foundation (7232110), National High Level Hospital Clinical Research Funding (2022-PUMCH-A-072, 2023-PUMCH-C-054), CAMS Innovation Fund for Medical Sciences (CIFMS) (2022-I2M-C&T-B-010).

Molecular mimicry as a mechanism of viral immune evasion and autoimmunity

Mimicry of host protein structures, or ‘molecular mimicry’, is a common mechanism employed by viruses to evade the host’s immune system. Short linear amino acid (AA) molecular mimics can elicit cross-reactive antibodies and T cells from the host, but the prevalence of such mimics throughout the human virome has not been fully explored. Here we evaluate 134 human-infecting viruses and find significant usage of linear mimicry across the virome, particularly those in the Herpesviridae and Poxviridae families. Furthermore, host proteins related to cellular replication and inflammation, autosomes, the X chromosome, and thymic cells are enriched as viral mimicry targets. Finally, we find that short linear mimicry from Epstein-Barr virus (EBV) is higher in auto-antibodies found in patients with multiple sclerosis than previously appreciated. Our results thus hint that human-infecting viruses leverage mimicry in the course of their infection, and that such mimicry may contribute to autoimmunity, thereby prompting potential targets for therapies.

Cognitive Impact of Neurotropic Pathogens: Investigating Molecular Mimicry through Computational Methods

Neurotropic pathogens, notably, herpesviruses, have been associated with significant neuropsychiatric effects. As a group, these pathogens can exploit molecular mimicry mechanisms to manipulate the host central nervous system to their advantage. Here, we present a systematic computational approach that may ultimately be used to unravel protein–protein interactions and molecular mimicry processes that have not yet been solved experimentally. Toward this end, we validate this approach by replicating a set of pre-existing experimental findings that document the structural and functional similarities shared by the human cytomegalovirus-encoded UL144 glycoprotein and human tumor necrosis factor receptor superfamily member 14 (TNFRSF14). We began with a thorough exploration of the Homo sapiens protein database using the Basic Local Alignment Search Tool (BLASTx) to identify proteins sharing sequence homology with UL144. Subsequently, we used AlphaFold2 to predict the independent three-dimensional structures of UL144 and TNFRSF14. This was followed by a comprehensive structural comparison facilitated by Distance-Matrix Alignment and Foldseek. Finally, we used AlphaFold-multimer and PPIscreenML to elucidate potential protein complexes and confirm the predicted binding activities of both UL144 and TNFRSF14. We then used our in silico approach to replicate the experimental finding that revealed TNFRSF14 binding to both B- and T-lymphocyte attenuator (BTLA) and glycoprotein domain and UL144 binding to BTLA alone. This computational framework offers promise in identifying structural similarities and interactions between pathogen-encoded proteins and their host counterparts. This information will provide valuable insights into the cognitive mechanisms underlying the neuropsychiatric effects of viral infections.Graphical

Modulation of the Immune Environment in Glioblastoma by the Gut Microbiota

Studies increasingly support the role of the gut microbiota in glioma development and treatment, although the exact mechanisms remain unclear. Research indicates that the gut microbiota can influence glioma progression, response to therapies, and the effectiveness of treatments like immunotherapy, with certain microbial compositions being linked to better outcomes. Additionally, the gut microbiota impacts the tumor microenvironment, affecting both tumor growth and the response to treatment. This review will explore glioma, the gut microbiota, and how their interaction shapes glioma development and therapy responses. Additionally, this review examines the influence of gut microbiota metabolites, such as short-chain fatty acids (SCFAs) and tryptophan, on glioma development and treatment. It also explores gut microbiome signaling via pattern recognition receptors, and the role of molecular mimicry between microbial and tumor antigens in glioblastoma, and if these interactions affect glioma development and treatment.

Hepatitis E Virus Infection in Patients with Systemic and Cutaneous Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by a multifactorial etiology in which genetic and environmental factors interplay. An exclusively cutaneous condition has been described and defined as cutaneous lupus erythematosus (CLE). In Italy, a nationwide blood donor survey found an overall HEV prevalence of 8.7%, with an interregional variation from 2.2% to 22.8%. In this study, we aimed to estimate HEV seroprevalence in a cohort of patients affected by SLE and CLE attending the Lupus Clinic, Sapienza University of Rome. Serum samples were tested for anti-HEV immunoglobulin Ig G and M antibodies using commercial enzyme-linked immunosorbent assay (ELISA) kits. Statistical analysis was performed. In total, 138 patients were enrolled, 92 (67%) affected by SLE and 46 by CLE. The prevalence of HEV infection was 23.9% in the CLE group and 7.6% in the SLE group. The anti-HEV+ prevalence was significantly more frequent in CLE. Some mechanisms may be linked to increased susceptibility to HEV such as a molecular mimicry associated with the CLE condition or with the skin compartment/skin self-antigens, as well as the involvement of the genetic background. Regarding the possible risk factors, no association was found, although, of note, the odds of HEV+ relative to contact with animals and to eating raw seafood were strongly higher than the unit in the CLE group.

Prevalent and persistent new-onset autoantibodies in mild to severe COVID-19

Autoantibodies have been shown to be implied in COVID-19 but the emerging autoantibody repertoire remains largely unexplored. We investigated the new-onset autoantibody repertoire in 525 healthcare workers and hospitalized COVID-19 patients at five time points over a 16-month period in 2020 and 2021 using proteome-wide and targeted protein and peptide arrays. Our results show that prevalent new-onset autoantibodies against a wide range of antigens emerged following SARS-CoV-2 infection in relation to pre-infectious baseline samples and remained elevated for at least 12 months. We found an increased prevalence of new-onset autoantibodies after severe COVID-19 and demonstrated associations between distinct new-onset autoantibodies and neuropsychiatric symptoms post-COVID-19. Using epitope mapping, we determined the main epitopes of selected new-onset autoantibodies, validated them in independent cohorts of neuro-COVID and pre-pandemic healthy controls, and identified sequence similarities suggestive of molecular mimicry between main epitopes and the conserved fusion peptide of the SARS-CoV-2 Spike glycoprotein. Our work describes the complexity and dynamics of the autoantibody repertoire emerging with COVID-19 and supports the need for continued analysis of the new-onset autoantibody repertoire to elucidate the mechanisms of the post-COVID-19 condition.

Epstein-Barr virus as a potentiator of autoimmune diseases.

The Epstein-Barr virus (EBV) is epidemiologically associated with development of autoimmune diseases, including systemic lupus erythematosus, Sjögren syndrome, rheumatoid arthritis and multiple sclerosis. Although there is well-established evidence for this association, the underlying mechanistic basis remains incompletely defined. In this Review, we discuss the role of EBV infection as a potentiator of autoimmune rheumatic diseases. We review the EBV life cycle, viral transcription programmes, serological profiles and lytic reactivation. We discuss the epidemiological and mechanistic associations of EBV with systemic lupus erythematosus, Sjögren syndrome, rheumatoid arthritis and multiple sclerosis. We describe the potential mechanisms by which EBV might promote autoimmunity, including EBV nuclear antigen 1-mediated molecular mimicry of human autoantigens; EBV-mediated B cell reprogramming, including EBV nuclear antigen 2-mediated dysregulation of autoimmune susceptibility genes; EBV and host genetic factors, including the potential for autoimmunity-promoting strains of EBV; EBV immune evasion and insufficient host responses to control infection; lytic reactivation; and other mechanisms. Finally, we discuss the therapeutic implications and potential therapeutic approaches to targeting EBV for the treatment of autoimmune disease.

Immunogenic Sulfated l-Idose Homo Oligosaccharides Elicit Neutralizing Antibody against Native Heparan Sulfate with Biomarker and Therapeutic Possibilities.

Heparan sulfate (HS) is a non-immunogenic antigen, and developing antibodies against specific sulfated patterns in HS poses significant challenges. Herein, we employed an innovative immunization strategy that exploits the molecular mimicry of HS to generate antibodies against HS sequences. Mice were immunized with synthetic sulfated oligo-l-idose (ID49) that mimics optimum 67% of the conserved structure of HS ligands. This immunization of ID49@CRM197 with alum and Freund's adjuvant resulted in the production of robust IgG antibody responses targeting ID49 and cross-reactivity with the N-sulfated HS ligands compared to N-unsubstituted and N-acetate domain synthetic HS ligands. Such a pharmacological agent exhibited distinct staining of tissue sections and cell lines and induced complement-dependent cell cytotoxicity against SK-BR-3 cancer cells. Moreover, these antibodies inhibited heparin-mediated anticoagulation activity similar to that of protamine. These findings highlight the biomarker and possible therapeutic capability of the antibodies.

8090 A Gut Commensal, Parabacteroides distasonis, and Molecular Mimicry in Type 1 Diabetes

Abstract Disclosure: A. Randall: None. Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by the destruction of pancreatic, insulin-producing beta cells by autoreactive T-cells. The trigger(s) of T1D are unclear and genetics alone cannot explain the recent increase in T1D incidence. The gut microbiome composition in T1D patients is altered and thought to play a key role in T1D pathogenesis. Most longitudinal studies have been descriptive. However, a direct cause-and-effect relationship hasn't been established yet. Insulin is a key autoantigen in T1D autoimmunity, and insulin B-chain amino acids 9-23 (insB:9-23) is an important, commonly recognized T-cell epitope. Molecular mimicry is an autoimmunity mechanism where host-like microbial proteins trigger autoimmune responses. We previously identified a peptide mimic of insB:9-23, amino acids 4-18 of hypoxanthine phosphoribosyl transferase (HPRT:4-18) of Parabacteroides distasonis (Girdhar et al., 2022). HPRT:4-18 stimulated insB:9-23-specific human and non-obese diabetic (NOD) mice T-cells. We hypothesize that P. distasonis HPRT:4-18 is required to accelerate diabetes via molecular mimicry of insB:9-23. By orally gavaging NOD mice (n=40 mice/group), we showed that P. distasonis accelerated diabetes onset. Next, we colonized NOD mice with another common gut commensal, Bacteroides fragilis, as a control, and did not observe any effect on islet infiltration. In addition, P. distasonis colonization increased infiltration of immune cells into the islets of germ-free NOD mice (n=6-8 mice/group), while the diabetes incidence experiment in mice is ongoing. P. distasonis-colonized mice had significantly more splenic CD8 and naïve T-cells, dendritic cells and macrophages but fewer FOXP3 cells (n=3-6 mice/group). To determine whether P. distasonis’s effect is specific to the pancreas, we checked intestinal barrier function and intestinal immune cell composition. Disruption of intestinal barrier function has been associated with diabetes. P. distasonis colonization did not alter gut permeability. Furthermore, P. distasonis did not increase intestinal inflammation. Among the intestinal intraepithelial lymphocytes (IELs), there were fewer naïve, central and effector T-cells and B-cells. The findings indicate that P. distasonis does not stimulate an unspecific immune response and its inflammatory effect is specific to the pancreas, supporting our initial hypothesis. Taken together, our results indicate that exposure to P. distasonis in the first years of life has the potential to stimulate molecular mimicry mechanism and cause T1D onset. Reference: Girdhar, K., Huang, Q., Chow, I. T., Vatanen, T., Brady, C., Raisingani, A., . . . Altindis, E. (2022). A gut microbial peptide and molecular mimicry in the pathogenesis of type 1 diabetes. Proc Natl Acad Sci U S A, 119(31), e2120028119. doi:10.1073/pnas.2120028119 Presentation: 6/2/2024

6441 Hyperthyroidism in a patient with Lyme disease

Abstract Disclosure: J. Epstein: None. C. Berman: None. Background: Lyme disease is known to cause inflammation in many organs. There are few case reports in the literature that discuss the association between Lyme disease and thyroiditis. This case underscores the need to further research the association between Lyme disease and thyroid physiology. Clinical Case: A 15-year-old female with a history of polycystic kidney disease is referred to a pediatric endocrinologist for primary amenorrhea and hyperthyroidism. Initial thyroid function tests demonstrated suppressed TSH of 0.03 mIU/L with an elevated free T4 level of 4.0 ng/dL and total T3 of 437 ng/dL. The patient was asymptomatic with normal vital signs, and physical exam was normal without goiter, tremor, tongue fasciculations, or exophthalmos. Thyroid ultrasound demonstrated a mildly heterogenous appearance without nodules. Incidentally, Lyme disease was concurrently diagnosed based on a positive screen confirmed with immunoblot. There was no known tick exposure or rash, but the patient had recently spent time outdoors in upstate New York. Doxycycline was started for the treatment of Lyme disease and repeat thyroid tests one week later showed a decrease in free T4 and total T3 levels, although still elevated. Thyroid antibodies including thyroid peroxidase (TPO), thyroglobulin and thyroid-stimulating immunoglobulin (TSI) were negative. After finishing doxycycline treatment, she developed a hypothyroid state with a TSH of 6.39 mIU/L, free T4 of 0.6 ng/dL, and a normal total T3 of 148 ng/dL. Free T4 has since normalized however TSH remains elevated. The patient continues to be monitored closely without pharmacologic treatment. The evolution of this patient’s thyroid function is consistent with thyroiditis and appears similar to the course of Hashitoxicosis, however antibodies remain negative. There is literature that suggests molecular mimicry between Borrelia proteins and thyroid autoantigens due to amino acid sequence homology. Some Borrelial proteins are found to share antigenic properties with multiple thyroid related proteins, specifically the TSH receptor, TPO, thyroglobulin and sodium iodine symporter, potentially leading to thyroiditis. Three case reports describe adults with hyperthyroidism in the setting of Lyme disease, however in these cases thyroid antibodies (TPO +/- thyroglobulin) were positive. Two of these patients were asymptomatic, similar to our patient. This phenomenon has never been described in a pediatric patient and illustrates the need to consider Lyme disease as a potential cause of destructive, transient, thyroiditis. Presentation: 6/1/2024

Post-Vaccine Myocarditis: Clinical Insights and Epidemiological Trends

Myocarditis is a rare but key adverse event linked to mRNA COVID-19 vaccines, predominantly in young males. Epidemiological data indicate an incidence of approximately 12.6 cases per million doses administered to patients aged 12-39 years, mostly following the second dose of the vaccine. Most patients present with elevated levels of cardiac biomarkers, chest pain, and abnormal ECG findings within a few days of vaccination. Proposed mechanisms for the exact pathophysiology of this include molecular mimicry between the SARS-CoV-2 spike protein and cardiac antigens, activation of immune pathways, and dysregulated cytokine expression. Despite these findings, the overall benefit-risk balance for COVID-19 vaccination remains positive, as the majority of patients recover fully. In contrast, COVID-19-associated myocarditis is more common and more severe, with an estimated incidence of 1,000-1,400 cases per 100,000 infections. Clinical presentation of vaccine-associated myocarditis is usually mild and self-limiting, and most patients do recover without significant long-term effects. Treatment is usually supportive in nature and has an emphasis on ruling out acute coronary syndrome and symptomatic management for heart failure or arrhythmias if present. Given its low incidence and the generally good outcome, vaccination against COVID-19 is recommended from 12 years of age and above, with provision for ongoing surveillance for monitoring and management of rare adverse events like myocarditis.

Acute disseminated encephalomyelitis (ADEM) in a patient with post streptococcal glomerulonephritis (PSGN): A case report.

Concurrent recurrence of acute disseminated encephalomyelitis (ADEM) and poststreptococcal glomerulonephritis (PSGN) in a thalassemia intermedia patient is rare and underscores the complexity of autoimmune disorders. This case emphasizes the importance of considering ADEM in the differential diagnosis of children presenting with PSGN accompanied by neurological symptoms. Post-streptococcal glomerulonephritis (PSGN) is a common group A streptococcal (GAS) infection sequela. The pathophysiology of PSGN involves immune complex deposition, with type 3 hypersensitivity reaction triggered by GAS. Certain neurological conditions may also arise following a GAS infection, possibly due to molecular mimicry in the brain, a pathophysiology similar to rheumatic fever, another common sequel of GAS infection. We present the case of a child with β-thalassemia intermedia who exhibited the classic triad (edema, hypertension, hematuria) of PSGN along with neurological manifestations, including a low glasgow coma scale (GCS) score and seizures. Magnetic resonance imaging (MRI) of the brain indicated changes consistent with acute disseminated encephalomyelitis (ADEM). Initially treated with methylprednisolone, the patient eventually received intravenous immunoglobulin (IVIG) due to lack of response. The patient had a good outcome, with complete resolution of all symptoms and no residual neurological deficits. This case underscores the importance of considering ADEM in the differential diagnosis for patients presenting with neurological signs and symptoms following a recent throat infection with GAS. Furthermore, given the increased risk of infection in thalassemia, patients with thalassemia who have a throat infection and neurological symptoms should be evaluated for the possible presence of ADEM.

Mechanisms that potentially contribute to the development of post-streptococcal glomerulonephritis.

Post-streptococcal glomerulonephritis (PSGN) is primarily associated with preceding Group A streptococcal skin or throat infections, now mainly observed in economically disadvantaged communities. This condition significantly predisposes individuals to later-life chronic kidney disease and concurrent renal complications, with the elderly experiencing increased severity and less favourable outcomes. Streptococcal pyrogenic exotoxin B and nephritis associated plasmin receptor are identified nephritogenic antigens (nephritogens). Pathogenesis of PSGN is multifactorial. It can involve the formation of antigen-antibody immune complexes, causing inflammatory damage to renal glomeruli. Deposition of circulating immune complexes or in situ formation of immune complexes in glomeruli, or both, results in glomerulonephritis. Additionally, molecular mimicry is hypothesised as a mechanism, wherein cross-reactivity between anti-streptococcal antibodies and glomerular intrinsic matrix proteins leads to glomerulonephritis. Besides, as observed in clinical studies, streptococcal inhibitor of complement, a streptococcal-secreted protein, can also be associated with PSGN. However, the interplay between these streptococcal antigens in the pathogenesis of PSGN necessitates further investigation. Despite the clinical significance of PSGN, the lack of credible animal models poses challenges in understanding the association between streptococcal antigens and the disease process. This review outlines the postulated mechanisms implicated in the development of PSGN with possible therapeutic approaches.

Do Vaccines Cause Postural Orthostatic Tachycardia Syndrome? Review of Cases in the National Vaccine Injury Compensation Program

BackgroundThe National Childhood Vaccine Injury Act of 1986 created the National Vaccine Injury Compensation Program (VICP), a no-fault alternative to the traditional tort system. Since 1988, the total compensation paid exceeds $6 billion. Although postural orthostatic tachycardia syndrome (POTS) is a frequent reason for filing a claim, there has been no review of the process and validity of the legal outcomes given current medical information. The purpose of this study was to review vaccine-related POTS and assess the rationale behind decisions made by the court. MethodsWe identified 102 unique cases with POTS. All published reports were reviewed for petitioner's theories supporting vaccine-induced POTS, respondent's counterarguments, the final decision regarding compensation, and the rationale underlying these decisions. The primary goal was to determine which factors went into decisions regarding whether vaccines cause POTS. ResultsIn deciding the cases the Special Masters hearing the cases place a high reliance on expert witnesses for both the petitioners and respondents. Petitioners’ experts frequently implicated vaccines, primarily human papillomavirus vaccine, as causing POTS through autoimmunity induced by molecular mimicry. However, in none of the 102 cases was POTS considered to be directly caused by a vaccine. ConclusionsDespite the lack of epidemiologic or mechanistic evidence indicating that childhood vaccines covered by the VICP result in POTS, these cases continue to be adjudicated, at considerable cost to the government. Unless there is emerging scientific support for implicating vaccines in POTS it is time that the VICP stop considering these cases.

The role of Helicobacter pylori in the development of inflammatory eyelid diseases

Background. Blepharitis is one of the most common eye diseases: it accounts for 23.3 % of the total number of patients with inflammatory eye diseases worldwide. 40.2 % of these patients seek outpatient care. The incidence of blepharitis is 1.5–2 times higher in women than in men. The leading factors in the development of blepharitis are both general (gastrointestinal tract diseases, diabetes mellitus, hypertension, systemic use of corticosteroids, etc.) and local (atopic and seborrheic dermatitis or rosacea). The main causative agents of this disease are Staphylococcus spp. (S. aureus, S. epidermidis). As a rule, the disease manifests itself in patients aged 30–50 years, while in women aged 40 to 45 years, 80 % of blepharitis are of staphylococcal origin. Currently, there are reports in the literature about apotential link between Helicobacter pylori infection and the development of chronic blepharitis, but the data are very contradictory.The aim of the study. To analyze the features of the relationship between Helicobacter pylori and inflammatory eyelid diseases.Materials and methods. We conducted a search and analysis of literary sources in the Web of Science, PubMed and Google Scholar databases, as well as in the Russian Science Citation Index database for the period from 2000 to 2022.Conclusion. The review analyzes and summarizes the pathogenic mechanisms of the relationship between chronic blepharitis and Helicobacter pylori. We carried out an analysis of numerous studies, which give grounds to assume a possible role of Helicobacter pylori infection in the development and course of inflammatory eyelid diseases (blepharitis). The main pathogenic aspects in these studies are: chronic inflammation of the eyelids and gastrointestinal tract (antigenic mimicry); excretion of toxic substances from the oral cavity (ammonia, hydrogen nitrite, hydrogen cyanide and other substances causing indirect inflammation of the conjunctiva and eyelid cartilage); the presence of Helicobacter pylori in tears.

Autoantigens of Small Nerve Fibers and Human Coronavirus Antigens: Is There a Possibility for Molecular Mimicry?

In post-COVID-19 syndrome, clinical presentation of the nerve fiber dysfunction plays an important role. The possibility of autoantigen cross-mimicry of human coronaviruses and the peripheral nervous system needs to be investigated. The bioinformatic analysis was applied to search for possible common protein sequences located in the immunoreactive epitopes. Among the autoantigens of the human nervous system, fibroblast growth factor receptor protein 3, myelin protein P0, myelin protein P2, sodium channel protein type 9, alpha protein subunit, plexin-D1 protein and ubiquitin-carboxyl-terminal hydrolase protein of the L1 isoenzyme were selected. The original "Alignmentaj" analytical program was created. The UniProt database, Protein Data Bank, and AlphaFold databases were used. The analysis of protein sequence similarities of spike glycoproteins in human coronaviruses revealed common pentapeptides of the MERS-CoV-2 virus with the fibroblast growth factor receptor 3 and myelin protein P2. Among seasonal coronaviruses, common peptide sequences were identified in HCoV-HKU-1 virus with sodium channel protein type 9 subunit alpha and Plexin-D1, HCoV-OC43 with Plexin-D1, as well as HCoV-NL63 with Plexin-D1 and Ubiquitin carboxyl-terminal hydrolase isozyme L1. Some shared peptides belong to immunoreactive epitopes. The most important targets for the molecular similarities are the sodium channel subunits and fibroblast growth factor receptor 3, both for seasonal and highly pathogenic coronaviruses. The data obtained make it possible to identify new potential targets for the development of autoimmune reactions that may occur against the background of the infections with highly pathogenic as well as seasonal coronaviruses.

HLA A*24:02-restricted T cell receptors cross-recognize bacterial and preproinsulin peptides in type 1 diabetes.

CD8+ T cells destroy insulin-producing pancreatic β cells in type 1 diabetes through HLA class I-restricted presentation of self-antigens. Combinatorial peptide library screening was used to produce a preferred peptide recognition landscape for a patient-derived T cell receptor (TCR) that recognized the preproinsulin-derived (PPI-derived) peptide sequence LWMRLLPLL in the context of disease risk allele HLA A*24:02. Data were used to generate a strong superagonist peptide, enabling production of an autoimmune HLA A*24:02-peptide-TCR structure by crystal seeding. TCR binding to the PPI epitope was strongly focused on peptide residues Arg4 and Leu5, with more flexibility at other positions, allowing the TCR to strongly engage many peptides derived from pathogenic bacteria. We confirmed an epitope from Klebsiella that was recognized by PPI-reactive T cells from 3 of 3 HLA A*24:02+ patients. Remarkably, the same epitope selected T cells from 7 of 8 HLA A*24+ healthy donors that cross-reacted with PPI, leading to recognition and killing of HLA A*24:02+ cells expressing PPI. These data provide a mechanism by which molecular mimicry between pathogen and self-antigens could have resulted in the breaking of self-tolerance to initiate disease.