Viral Triggers of Autoimmune Diabetes: Mechanisms, Clinical Implications, and Future Directions

Primary biliary cirrhosis, bacteria and molecular mimicry: what's the molecule and where's the mimic?

Role of coxsackievirus B4 in the pathogenesis of type 1 diabetes

The Enigmatic Role of Viruses in Multiple Sclerosis: Molecular Mimicry or Disturbed Immune Surveillance?

Numerous infectious agents may trigger autoimmunity or even result in autoimmune diseases. Several mechanisms have been proposed for pathogen-triggered autoimmunity including molecular mimicry, cryptic antigens, epitope spreading, bystander activation and polyclonal activation. In the case of dengue virus infection which causes serious public health problems, the mechanisms regarding the pathogenesis of dengue hemorrhagic syndrome are not fully resolved. Our previous studies suggest a mechanism of molecular mimicry in which antibodies directed against dengue virus non-structural protein 1 (NS1) cross-react with human platelets and endothelial cells and cause their damage and dysfunction, which may be related to the clinical features of dengue disease. Several cell surface proteins recognized by patient serum samples and anti-NS1 antibodies have been identified. Based on proteomic studies and sequence analysis, the C-terminal region of dengue virus NS1 shows sequence homology with target proteins. In addition, different regions of dengue virus proteins including core, prM, E and NS1 proteins show sequence homology with different coagulatory molecules. As an example, the amino acid sequence 101-106 of E protein (WGNGCG) shows sequence homology with factors XI, X, IX, VII, II (thrombin), plasminogen and tissue plasminogen activator. Furthermore, single chain variable region against NS1 can interfere with fibrin formation, which leads to prolonged thrombin time. We hypothesize that molecular mimicry between dengue virus proteins and coagulatory molecules may induce cross-reactive autoantibodies that can interfere with coagulation activation. A molecular mimicry pathogenesis for dengue disease which involves cross-reactivity of dengue virus with human endothelial cells, platelets and coagulatory molecules is proposed.

BACKGROUNDMultiple pathogenic mechanisms have been implicated in autoimmune hepatitis, but they have not fully explained susceptibility, triggering events, and maintenance or escalation of the disease. Furthermore, they have not identified a critical defect that can be targeted. The goals of this review are to examine the diverse pathogenic mechanisms that have been considered in autoimmune hepatitis, indicate investigational opportunities to validate their contribution, and suggest interventions that might evolve to modify their impact. English abstracts were identified in PubMed by multiple search terms. Full length articles were selected for review, and secondary and tertiary bibliographies were developed. Genetic and epigenetic factors can affect susceptibility by influencing the expression of immune regulatory genes. Thymic dysfunction, possibly related to deficient production of programmed cell death protein-1, can allow autoreactive T cells to escape deletion, and alterations in the intestinal microbiome may help overcome immune tolerance and affect gender bias. Environmental factors may trigger the disease or induce epigenetic changes in gene function. Molecular mimicry, epitope spread, bystander activation, neo-antigen production, lymphocytic polyspecificity, and disturbances in immune inhibitory mechanisms may maintain or escalate the disease. Interventions that modify epigenetic effects on gene expression, alter intestinal dysbiosis, eliminate deleterious environmental factors, and target critical pathogenic mechanisms are therapeutic possibilities that might reduce risk, individualize management, and improve outcome. In conclusion, diverse pathogenic mechanisms have been implicated in autoimmune hepatitis, and they may identify a critical factor or sequence that can be validated and used to direct future management and preventive strategies.

Multiple sclerosis (MS) is a chronic neurodegenerative and autoimmune disease of the central nervous system (CNS). While the exact etiology remains unclear, emerging evidence suggests that bacterial toxins play significant roles in MS pathogenesis and progression. We aimed to review mechanisms by which bacterial toxins influence MS development, focusing on molecular mimicry, epitope spreading, bystander activation, and blood-brain barrier (BBB) disruption. Specific toxins, including Clostridium perfringens epsilon toxin, Staphylococcus aureus superantigens, and Chlamydia pneumoniae heat shock proteins, demonstrate distinct pathogenic mechanisms in promoting CNS inflammation. Crucially, several toxins disrupt BBB integrity, making it easier for immune cells and cytokines that promote inflammation to enter the CNS and exacerbate neural inflammation. Furthermore, through molecular mimicry and epitope dissemination, bacterial antigens can initiate cross-reacting immune responses that may lead to autoimmune attacks on myelin. This review highlights the complex interplay between bacterial toxins, immune modulation, and genetic susceptibility in MS. Understanding these toxin-mediated pathways reveals the complex interplay between the microbiome and MS pathogenesis, potentially leading to novel therapeutic interventions targeting bacterial contributions to autoimmune neurodegeneration.

SUMMARY: Antibiotics have been applied for the treatment of autoimmune diseases for over five decades, based on the premise that infections play a role in the initiation and propagation of these entities. The mechanisms by which an infection may trigger an autoimmune reaction include the so-called ‘molecular mimicry’, ‘epitope spreading’ or ‘bystander activation’. The association between infection and autoimmunity may be directly evident, as in cases of reactive arthritis, or in a more roundabout manner, as exemplified by the association between anaerobic bacterial infection of the gums and rheumatoid arthritis. Moreover, some antibiotics have, in addition to their antibacterial effects, anti-inflammatory and immunomodulatory properties. In this review we focus on the rationale and possible benefits of antibiotic treatment in various autoimmune diseases, including rheumatoid arthritis, reactive arthritis, granulomatosis with polyangitis, immune thrombocytopenia purpura and the antiphospholipid syndrome.

Type 1 diabetes (T1D) is caused by aberrant activation of autoreactive T cells specific for the islet beta cells. How islet‐specific T cells evade tolerance to become effector T cells is unknown, but it is believed that an altered gut microbiota plays a role. Possible mechanisms include bystander activation of autoreactive T cells in the gut or “molecular mimicry” from cross‐reactivity between gut microbiota‐derived peptides and islet‐derived epitopes. To investigate these mechanisms, we use two islet‐specific CD8+ T cell clones and the non‐obese diabetic mouse model of type 1 diabetes. Both insulin‐specific G9C8 cells and IGRP‐specific 8.3 cells underwent early activation and proliferation in the pancreatic draining lymph nodes but not in the Peyer's patches or mesenteric lymph nodes. Mutation of the endogenous epitope for G9C8 cells abolished their CD69 upregulation and proliferation, ruling out G9C8 cell activation by a gut microbiota derived peptide and molecular mimicry. However, previously activated islet‐specific effector memory cells but not naïve cells migrated into the Peyer's patches where they increased their cytotoxic function. Oral delivery of butyrate, a microbiota derived anti‐inflammatory metabolite, reduced IGRP‐specific cytotoxic function. Thus, while initial activation of islet‐specific CD8+ T cells occurred in the pancreatic lymph nodes, activated cells trafficked through the gut lymphoid tissues where they gained additional effector function via non‐specific bystander activation influenced by the gut microbiota.

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

For a long time, viruses have been shown to modify the clinical picture of several autoimmune diseases, including type 1 diabetes (T1D), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjögren’s syndrome (SS), herpetic stromal keratitis (HSK), celiac disease (CD), and multiple sclerosis (MS). Best examples of viral infections that have been proposed to modulate the induction and development of autoimmune diseases are the infections with enteric viruses such as Coxsackie B virus (CVB) and rotavirus, as well as influenza A viruses (IAV), and herpesviruses. Other viruses that have been studied in this context include, measles, mumps, and rubella. Epidemiological studies in humans and experimental studies in animal have shown that viral infections can induce or protect from autoimmunopathologies depending on several factors including genetic background, host-elicited immune responses, type of virus strain, viral load, and the onset time of infection. Still, data delineating the clear mechanistic interaction between the virus and the immune system to induce autoreactivity are scarce. Available data indicate that viral-induced autoimmunity can be activated through multiple mechanisms including molecular mimicry, epitope spreading, bystander activation, and immortalization of infected B cells. Contrarily, the protective effects can be achieved via regulatory immune responses which lead to the suppression of autoimmune phenomena. Therefore, a better understanding of the immune-related molecular processes in virus-induced autoimmunity is warranted. Here we provide an overview of the current understanding of viral-induced autoimmunity and the mechanisms that are associated with this phenomenon.

Infectious agents especially viruses e.g. Epstein Barr virus contribute to systemic lupus erythematosus (SLE) pathogenesis and can trigger lupus disease activity by driving autoimmunity through molecular mimicry, bystander activation and...

Type 1 diabetes (T1D) is an organ-specific autoimmune disease caused by altered immune tolerance to specific proteins leading to a selective destruction of insulin-producing beta cells in genetically predisposed individuals. T1D is likely to be triggered by environmental factors, including virus infections in genetically predisposed individuals. Rotaviruses are the main cause of severe diarrhea among children worldwide, but they seem to have a role also in T1D induction. Epidemiological data may be consistent with a similar hypothesis. Mechanisms hypothesized include molecular mimicry, bystander activation (with or without epitope spreading), and viral persistence. In this review the authors analyze the factors accounting for rotavirus ability to prime islet autoimmunity and cause T1D. A thorough comprehension of their potential pathogenetic mechanisms may allow preventive strategies to be designed.

Type 1 diabetes (T1D) is usually caused by immune-mediated destruction of islet β cells, and genetic and environmental factors are thought to trigger autoimmunity. Convincing evidence indicates that viruses are associated with T1D development and progression. During the COVID-19 pandemic, cases of hyperglycemia, diabetic ketoacidosis, and new diabetes increased, suggesting that SARS-CoV-2 may be a trigger for or unmask T1D. Possible mechanisms of β-cell damage include virus-triggered cell death, immune-mediated loss of pancreatic β cells, and damage to β cells because of infection of surrounding cells. This article examines the potential pathways by which SARS-CoV-2 affects islet β cells in these 3 aspects. Specifically, we emphasize that T1D can be triggered by SARS-CoV-2 through several autoimmune mechanisms, including epitope spread, molecular mimicry, and bystander activation. Given that the development of T1D is often a chronic, long-term process, it is difficult to currently draw firm conclusions as to whether SARS-CoV-2 causes T1D. This area needs to be focused on in terms of the long-term outcomes. More in-depth and comprehensive studies with larger cohorts of patients and long-term clinical follow-ups are required.

Polymicrobial infections have been associated with plausible immune mediated diseases, including multiple sclerosis (MS). Virus infection can prime autoimmune T cells specific for central nervous system (CNS) antigens, if virus has molecular mimicry with CNS proteins. On the other hand, infection of irrelevant viruses will induce two types of cytokine responses. Infection with a virus such as lymphocytic choriomeningitis virus (LCMV), can induce interferon (IFN)-α/β production and suppress autoimmunity, while infection with a virus, such as murine cytomegalovirus (MCMV), can activate natural killer (NK), NKT and dendritic cells, resulting in interleukin (IL)-12 and IFN-γ production. These cytokines can cause bystander activation of autoreactive T cells. We established an animal model, where mice infected with vaccinia virus encoding myelin protein can mount autoimmune responses. However, the mice develop clinical disease only after irrelevant immune activation either with complete Freund's adjuvant or MCMV infection. In this review, we propose that a combination of two mechanisms, molecular mimicry and bystander activation, induced by virus infection, can lead to CNS demyelinating diseases, including MS. Viral proteins having molecular mimicry with self-proteins in the CNS can prime genetically susceptible individuals. Once this priming has occurred, an immunologic challenge could result in disease through bystander activation by cytokines.

Type 1 Diabetes Mellitus (T1DM) is an autoimmune disorder characterized by the progressive destruction of pancreatic beta cells. Coxsackie B Virus (CVB), particularly CVB1, CVB3, and CVB4, has been identified as a key environmental trigger in the pathogenesis of T1DM, particularly in genetically predisposed individuals. This narrative review synthesizes two decades of evidence (2005–2025) to explore the mechanisms by which CVB contributes to autoimmunity and emerging prevention strategies. CVB induces beta cell autoimmunity through molecular mimicry, bystander activation, and persistent viral infections that promote chronic inflammation and immune-mediated beta cell damage. Specific serotypes, such as CVB3 and CVB4, have been shown to have stronger associations with T1DM onset, emphasizing the importance of targeted interventions for these serotypes. Recent advancements in prevention strategies include multivalent CVB vaccines, antiviral agents such as pleconaril, and immune-modulating therapies like tolerogenic vaccines and regulatory T cell (Treg) expansion. However, challenges remain regarding their safety, timing of administration, and immune cross-reactivity. Early diagnostic efforts focused on biomarkers such as CVB-specific antibodies, islet autoantibodies (e.g., GAD65, ICA, ZnT8), and HLA risk alleles are crucial for identifying individuals in the latent phase of T1DM. To mitigate the risk of CVB-induced T1DM, an integrated public health approach—combining virological surveillance, vaccination campaigns, and early immunological screening—is essential. We recommend prioritizing longitudinal cohort studies, the development of safe multivalent vaccines, and investment in community-based early detection programs. A collaborative, multidisciplinary approach is vital to prevent or delay T1DM onset in at-risk populations