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Multisystem inflammatory syndrome in children (MIS-C) is a severe, post-infectious sequela of SARS-CoV-2 infection1,2, yet the pathophysiological mechanism connecting the infection to the broad inflammatory syndrome remains unknown. Here we leveraged a large set of samples from patients with MIS-C to identify a distinct set of host proteins targeted by patient autoantibodies including a particular autoreactive epitope within SNX8, a protein involved in regulating an antiviral pathway associated with MIS-C pathogenesis. In parallel, we also probed antibody responses from patients with MIS-C to the complete SARS-CoV-2 proteome and found enriched reactivity against a distinct domain of the SARS-CoV-2 nucleocapsid protein. The immunogenic regions of the viral nucleocapsid and host SNX8 proteins bear remarkable sequence similarity. Consequently, we found that many children with anti-SNX8 autoantibodies also have cross-reactive T cells engaging both the SNX8 and the SARS-CoV-2 nucleocapsid protein epitopes. Together, these findings suggest that patients with MIS-C develop a characteristic immune response to the SARS-CoV-2 nucleocapsid protein that is associated with cross-reactivity to the self-protein SNX8, demonstrating a mechanistic link between the infection and the inflammatory syndrome, with implications for better understanding a range of post-infectious autoinflammatory diseases.

Purpose: To present an atypical case of severe bilateral ocular toxoplasmosis with systemic involvement that initially mimicked an autoimmune etiology, posing challenges to its diagnosis and treatment. Case Report: A 39-year-old immunocompetent male was admitted to the hospital due to a presumed pulmonary thromboembolism concomitant with an abrupt onset of vision loss. Initial differential diagnoses included antiphospholipid syndrome and systemic lupus erythematosus, prompting the administration of corticosteroid pulses and rituximab. Despite observing a partial systemic response, there was no improvement in visual acuity. Subsequent aqueous humor polymerase chain reaction confirmed Toxoplasma gondii infection, leading to the introduction of oral antibiotic therapy. The patient's condition showed a partially favorable response; however, the treatment could not reverse the permanent retinal damage. Conclusion and importance: This case underscores the importance of ruling out an infectious etiology in all cases of uveitis. Additionally, it alerts clinicians to the possibility that elevated positive autoantibodies may result from a severe inflammatory reaction caused by pathogens rather than an autoimmune or autoinflammatory disease, particularly in instances of poor treatment response or atypical clinical presentation. [ABSTRACT FROM AUTHOR]

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. Epstein–Barr virus (EBV) infection is associated with numerous autoimmune diseases, including rheumatic diseases. In this Review, Robinson and colleagues provide an overview of the biology of EBV, the potential mechanisms through which EBV could promote autoimmune diseases and how EBV might be targeted for the treatment of autoimmune disease. Key points: Epstein–Barr virus (EBV) infection is epidemiologically associated with the autoimmune rheumatic diseases systemic lupus erythematosus, Sjögren syndrome and rheumatoid arthritis, as well as other autoimmune diseases, including multiple sclerosis. There are multiple non-exclusive mechanisms by which EBV might potentiate autoimmunity, including molecular mimicry; B cell reprogramming; genetic factors, including autoimmunity-promoting strains of EBV and host genetics; immune evasion; and lytic reactivation. Ongoing studies are linking EBV infection and EBV reactivation with development of autoimmunity and disease activity. Ongoing studies are defining the molecular and cellular mechanisms by which EBV might mediate autoimmune diseases. Therapeutic targeting of EBV could provide a fundamental treatment approach for EBV-associated autoimmune diseases. [ABSTRACT FROM AUTHOR]

The genus Borrelia encompasses a diverse group of spirochetes transmitted primarily by ticks, with Borrelia burgdorferi causing Lyme disease, which is prevalent in North America and Europe. Borrelia's structural adaptations and ability to persist in diverse host tissues underscore its pathogenic potential. Beyond traditional infectious responses, Borrelia engages in complex interactions with the host immune system, contributing to autoimmune mechanisms such as molecular mimicry and persistent infections. This intricate interplay manifests in symptoms resembling various autoimmune diseases, including systemic lupus erythematosus, dermatomyositis, local scleroderma, and systemic sclerosis. However, these associations lack a precise explanation, emphasizing the need for further investigation. The cases of misdiagnosis between Lyme borreliosis and autoimmune diseases highlight the critical importance of accurate diagnostics and adherence to guidelines. Understanding Borrelia's impact on immune responses is pivotal for advancing diagnostics and targeted therapeutic interventions in Lyme borreliosis and its potential autoimmune implications. [ABSTRACT FROM AUTHOR]

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. Autoantibody immune responses could contribute to acute and post-COVID-19 symptoms. Here, the authors describe longitudinal autoantibody responses in a cohort of healthcare workers and hospitalised COVID-19 patients from Sweden. [ABSTRACT FROM AUTHOR]

Parasites have attained a life-long stigma of being detrimental organisms with deleterious outcomes. Yet, recently, a creditable twist was verified that can dramatically change our perception of those parasites from being a source of misery to millions of people to a useful anti-cancerous tool. Various parasites have shown promise to combat cancer in different experimental models, including colorectal, lung, and breast cancers, among others. Helminths and protozoan parasites, as well as their derivatives such as Echinococcus granulosus protein KI-1, Toxoplasma gondii GRA15II, and Trypanosoma cruzi calreticulin, have demonstrated the ability to inhibit tumor growth, angiogenesis, and metastasis. This article provides an overview of the literature on various cancer types that have shown promising responses to parasite therapy in both in vitro and in vivo animal studies. Parasites have shown anti-neoplastic activity through a variety of mechanisms that collectively contribute to their anti-cancer properties. These include immunomodulation, inhibition of angiogenesis, and molecular mimicry with cancer cells. This review article sheds light on this intriguing emerging field and emphasizes the value of collaborative multidisciplinary research projects with funding agencies and pharmaceutical companies. Thus, these strategies would secure continuous exploration of this new avenue and accelerate the advancement of cancer therapy research. Although experimental studies are heavily conducted by leaps and bounds, further steps are definitely lagging. Upgrading research from the experimental level to the clinical trial would be a wise progression toward efficient exploitation of the anti-neoplastic capabilities of parasites, ultimately saving countless lives. [ABSTRACT FROM AUTHOR]

Key Clinical Message: 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. [ABSTRACT FROM AUTHOR]

Bacteria of the genus Pseudomonas are ubiquitous on Earth due to their great metabolic versatility and adaptation to fluctuating environments and different hosts. Some groups are important animal/human and plant pathogens, whereas others are studied for their biotechnological applications, including bioremediation, biological control of phytopathogens and plant growth promotion. Notably, their adaptability is mediated by various signal transduction systems, with the post‐transcriptional Gac‐Rsm cascade playing a key role. This pervasive Pseudomonas pathway controls major transitions at the population level, such as motile/sessile lifestyle, primary/secondary metabolism or replicative/infective behaviour. A hallmark of the Gac‐Rsm cascade is the participation of small, regulatory, non‐coding RNAs of the Rsm clan. These RNAs are synthetised in response to cell‐density‐dependent autoinducer signals channelled through the GacS/GacA two‐component system, and they counteract, by molecular mimicry, the translational control that RNA‐binding proteins of the RsmA family exert over hundreds of mRNAs. Rsm RNAs have been investigated in a few Pseudomonas model species, evidencing the presence of a variable number and families of genes depending on the taxonomic clade. However, the global picture of the distribution of these riboregulators at the genus level was unknown until now. We have undertaken a comprehensive survey and annotation of the vast array of gene sequences encoding members of the Rsm RNA clan in 245 complete genomes that cover 28 phylogenomic clades across the entire genus. The properties of the different families of rsm genes, their phylogenetic radiation, as well as the features of their promoters and adjacent regions, are discussed. The novel insights presented in our manuscript will significantly boost research on the biology of these prevalent RNAs in understudied species of the genus Pseudomonas and closely related genera. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV) infection has been advocated as a prerequisite for developing multiple sclerosis (MS) and possibly the propagation of the disease. However, the precise mechanisms for such influences are still unclear. A large-scale study investigating the host genetics of EBV serology and related clinical manifestations, such as infectious mononucleosis (IM), may help us better understand the role of EBV in MS pathogenesis. This study evaluates the host genetic factors that influence serological response against EBV and history of IM and cross-evaluates them with MS risk and genetic susceptibility in the Swedish population. Plasma IgG antibody levels against EBV nuclear antigen-1 [EBNA-1, truncated = amino acids (aa) (325–641), peptide = aa(385–420)] and viral capsid antigen p18 (VCAp18) were measured using bead-based multiplex serology for 8744 MS cases and 7229 population-matched control subjects. The MS risk association for high/low EBV antibody levels and history of IM was compared to relevant clinical measures along with sex, age at sampling, and associated HLA allele variants. Genome-wide and HLA allele association analyses were also performed to identify genetic risk factors for EBV antibody response and IM history. Higher antibody levels against VCAp18 [odds ratio (OR) = 1.74, 95% confidence interval (CI) = 1.60–1.88] and EBNA-1, particularly the peptide (OR = 3.13, 95% CI = 2.93–3.35), were associated with an increased risk for MS. The risk increased with higher anti-EBNA-1 IgG levels up to 12× the reference risk. We also identified several independent HLA haplotypes associated with EBV serology overlapping with known MS risk alleles (e.g. DRB1*15:01). Although there were several candidates, no variants outside the HLA region reached genome-wide significance. Cumulative HLA risk for anti-EBNA-1 IgG levels, particularly the peptide fragment, was strongly associated with MS. In contrast, the genetic risk for high anti-VCAp18 IgG levels was not as strongly associated with MS risk. IM history was not associated with class II HLA genes but negatively associated with A*02:01 , which is protective against MS. Our findings emphasize that the risk association between anti-EBNA-1 IgG levels and MS may be partly due to overlapping HLA associations. Additionally, the increasing MS risk with increasing anti-EBNA-1 levels would be consistent with a pathogenic role of the EBNA-1 immune response, perhaps through molecular mimicry. Given that high anti-EBNA-1 antibodies may reflect a poorly controlled T-cell defence against the virus, our findings would be consistent with DRB1*15:01 being a poor class II antigen in the immune defence against EBV. Last, the difference in genetic control of IM supports the independent roles of EBNA-1 and IM in MS susceptibility. [ABSTRACT FROM AUTHOR]

Immune-mediated cerebellar ataxias (IMCAs) represent a group of disorders in which the immune system targets mainly the cerebellum and related structures. We address fundamental questions on the diagnosis and immunological pathogenesis of IMCAs, as illuminated by recent advances in the field. Various types of IMCAs have been identified, including post-infectious cerebellitis, Miller Fisher syndrome, gluten ataxia, paraneoplastic cerebellar degeneration (PCD), opsoclonus and myoclonus syndrome, and anti-GAD ataxia. In some cases, identification of several well-characterized autoantibodies points to a specific etiology in IMCAs and leads to a firm diagnosis. In other cases, various autoantibodies have been reported, but their interpretation requires a careful consideration. Indeed, some autoantibodies have only been documented in a limited number of cases and the causal relationship is not established. In order to facilitate an early treatment and prevent irreversible lesions, new entities have been defined in recent years, such as primary autoimmune cerebellar ataxia (PACA) and latent autoimmune cerebellar ataxia (LACA). PACA is characterized by autoimmune features which do not align with traditional etiologies, while LACA corresponds to a prodromal stage. LACA does not imply the initiation of an immunotherapy but requires a close follow-up. Concurrently, accumulation of clinical data has led to intriguing hypotheses regarding the mechanisms of autoimmunity, such as a pathogenesis of autoimmunity against synapses (synaptopathies), and the vulnerability of the entire nervous system when the immunity targets ion channels and astrocytes. The development of PCD in patients treated with immune-checkpoint inhibitors suggests that molecular mimicry specifically determines the direction of autoimmunity, and that the strength of this response is modulated by co-signaling molecules that either enhance or dampen signals from the antigen-specific T cell receptor. [ABSTRACT FROM AUTHOR]

Lipooligosaccharides are the most abundant cell surface glycoconjugates on the outer membrane of Gram-negative bacteria. They play important roles in host–microbe interactions. Certain Gram-negative pathogenic bacteria cap their lipooligosaccharides with the sialic acid, N -acetylneuraminic acid (Neu5Ac), to mimic host glycans that among others protects these bacteria from recognition by the hosts immune system. This process of molecular mimicry is not fully understood and remains under investigated. To explore the functional role of sialic acid-capped lipooligosaccharides at the molecular level, it is important to have tools readily available for the detection and manipulation of both Neu5Ac on glycoconjugates and the involved sialyltransferases, preferably in live bacteria. We and others have shown that the native sialyltransferases of some Gram-negative bacteria can incorporate extracellular unnatural sialic acid nucleotides onto their lipooligosaccharides. We here report on the expanded use of native bacterial sialyltransferases to incorporate neuraminic acids analogs with a reporter group into the lipooligosaccharides of a variety of Gram-negative bacteria. We show that this approach offers a quick strategy to screen bacteria for the expression of functional sialyltransferases and the ability to use exogenous CMP-Neu5Ac to decorate their glycoconjugates. For selected bacteria we also show this strategy complements two other glycoengineering techniques, Metabolic Oligosaccharide Engineering and Selective Exo-Enzymatic Labeling, and that together they provide tools to modify, label, detect and visualize sialylation of bacterial lipooligosaccharides. [ABSTRACT FROM AUTHOR]

Background: Multiple sclerosis (MS) is a demyelinating disease affecting millions of people worldwide. Hereditary susceptibility and environmental factors contribute to disease risk. Infection with Epstein–Barr virus (EBV) and human herpesvirus 6A (HHV‐6A) have previously been associated with MS risk. Other neurotropic viruses, such as rubella virus (RV), are possible candidates in MS aetiopathogenesis, but previous results are limited and conflicting. Methods: In this nested case–control study of biobank samples in a Swedish cohort, we analysed the serological response towards RV before the clinical onset of MS with a bead‐based multiplex assay in subjects vaccinated and unvaccinated towards RV. The association between RV seropositivity and MS risk was analysed with conditional logistic regression. Results: Seropositivity towards RV was associated with an increased risk of MS for unvaccinated subjects, even when adjusting for plausible confounders including EBV, HHV‐6A, cytomegalovirus and vitamin D (adjusted odds ratio [AOR] = 4.0, 95% confidence interval [CI] 1.8–8.8). Cases also had stronger antibody reactivity towards rubella than controls, which was not seen for other neurotropic viruses such as herpes simplex or varicella zoster. Furthermore, we observed an association between RV seropositivity and MS in vaccinated subjects. However, this association was not significant when adjusting for the aforementioned confounders (AOR = 1.7, 95% CI 1.0–2.9). Conclusions: To our knowledge, these are the first reported associations between early RV seropositivity and later MS development. This suggests a broadening of the virus hypothesis in MS aetiology, where molecular mimicry between rubella epitopes and human central nervous system molecules could be an attractive possible mechanism. [ABSTRACT FROM AUTHOR]

Environmental factors, in particular viral infections, are thought to have an important role in the pathogenesis of type 1 diabetes mellitus (T1DM). The COVID-19 pandemic reinforced this hypothesis as many observational studies and meta-analyses reported a notable increase in the incidence of T1DM following infection with SARS-CoV-2 as well as an association between SARS-CoV-2 infection and the risk of new-onset T1DM. Experimental evidence suggests that human β-cells express SARS-CoV-2 receptors and that SARS-CoV-2 can infect and replicate in β-cells, resulting in structural or functional alterations of these cells. These alterations include reduced numbers of insulin-secreting granules, impaired pro-insulin (or insulin) secretion, and β-cell transdifferentiation or dedifferentiation. The inflammatory environment induced by local or systemic SARS-CoV-2 infection might result in a set of signals (such as pro-inflammatory cytokines) that lead to β-cell alteration or apoptosis or to a bystander activation of T cells and disruption of peripheral tolerance that triggers autoimmunity. Other mechanisms, such as viral persistence, molecular mimicry and activation of endogenous human retroviruses, are also likely to be involved in the pathogenesis of T1DM following SARS-CoV-2 infection. This Review addresses the issue of the involvement of SARS-CoV-2 infection in the development of T1DM using evidence from epidemiological, clinical and experimental studies. Many studies identified an increase in the incidence of type 1 diabetes mellitus (T1DM) during the COVID-19 pandemic, but other reports do not support this association. This Review addresses the issue of the involvement of SARS-CoV-2 infection in the development of T1DM using evidence from epidemiological, clinical and experimental studies. Key points: Epidemiological studies and meta-analyses reported an increase in the incidence of type 1 diabetes mellitus during the COVID-19 pandemic as well as an association between SARS-CoV-2 infection and the risk of new-onset type 1 diabetes mellitus. Angiotensin-converting enzyme 2 (ACE2), transmembrane serine protease 2 (TMPRSS2) and alternative receptors of SARS-CoV-2 have been identified in several human cell types, including pancreatic islet β-cells. SARS-CoV-2 proteins are detected in both exocrine and endocrine cells (including β-cells) of post-mortem pancreas samples from patients with COVID-19 and in samples from non-human primates intranasally or intratracheally infected with SARS-CoV-2. SARS-CoV-2 can infect and replicate in pancreatic β-cells ex vivo, resulting in structural and functional alterations of these cells. Pro-inflammatory cytokines produced during SARS-CoV-2 infection can impair human pancreatic islet function. SARS-CoV-2 infection might promote islet autoimmunity through various mechanisms, including bystander activation of T cells, disruption of peripheral tolerance, viral persistence, molecular mimicry and activation of endogenous human retroviruses. [ABSTRACT FROM AUTHOR]

Breast milk is a vital source of nutrients, prebiotics, probiotics, and protective factors, including antibodies, immune cells and antimicrobial proteins. Using bacterial lipopolysaccharide arrays, we investigated the reactivity and specificity of breast milk antibodies towards microbial antigens, comparing samples from rural Kenya and urban Switzerland. Results showed considerable variability in antibody reactivity both within and between these locations. Kenyan breast milk demonstrated broad reactivity to bacterial lipopolysaccharides, likely due to increased microbial exposure. Antibodies primarily recognized the O-antigens of lipopolysaccharides and showed strong binding to specific carbohydrate motifs. Notably, antibodies against specific Escherichia coli O-antigens showed cross-reactivity with parasitic pathogens like Leishmania major and Plasmodium falciparum, thus showing that antibodies reacting against lipopolysaccharide Oantigens can recognize a wide range of antigens beyond bacteria. The observed diversity in antigen recognition highlights the significance of breast milk in safeguarding infants from infections, particularly those prevalent in specific geographic regions. The findings also offer insights for potential immunobiotic strategies to augment natural antibody-mediated defense against diverse pathogens. [ABSTRACT FROM AUTHOR]

Objectives: Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) is frequently preceded by infections. The underlying pathomechanism, however, remains poorly understood. Here, we present the clinical data of two MOGAD patients with concurrent syphilis infection and investigate the reactivity of patient-derived antibodies to MOG and Treponema pallidum (T. pallidum). Methods: Longitudinal serumsamples and soluble immunoglobulins in single B cell supernatants were measured for MOG reactivity by a live cell-based assay. Reactivity against T. pallidum was assessed by enzyme-linked immunosorbent assay. Results: The two patients presented MOGAD and concurrent latent syphilis infection, manifesting as cervical myelitis and unilateral optic neuritis, respectively. The first patient had been living with HIV on antiretroviral therapy, and the second was concomitantly diagnosed with chronic hepatitis B infection. Upon screening of B cell supernatants, we identified reactivity to MOG or T. pallidum. Notably, one B cell showed reactivity to both antigens. Discussion: The coexistence of MOGAD diagnoses and latent syphilis, alongside the identification of antibody reactivity to MOG and T. pallidum, underscores the potential pathomechanistic link between syphilis infection and subsequent autoimmune neuroinflammation. Cross-reactivity between MOG and T. pallidum antibodies remains to be validated on a molecular level, and further characterization of infectious triggers associated with MOGAD is needed. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

This document provides information on the potential connection between Epstein-Barr virus (EBV) and multiple sclerosis (MS). It explains that while the exact cause of MS is unknown, a combination of genetic factors and environmental triggers, including EBV infection, may play a role. The document discusses epidemiological evidence linking EBV to MS, as well as potential mechanisms by which EBV could contribute to the development of the disease. However, it emphasizes the need for further research and cautions against drawing definitive conclusions based on current studies. The document also includes a list of references that library patrons can use for further research on the topic. [Extracted from the article]

Multiple sclerosis (MS) is a prototypical autoimmune disease of the central nervous system (CNS). In addition to CD4+ T cells, memory B cells are now recognized as a critical cell type in the disease. This is underlined by the fact that the best-characterized environmental risk factor for MS is the Epstein-Barr virus (EBV), which can infect and persist in memory B cells throughout life. Several studies have identified changes in anti-EBV immunity in patients with MS. Examples include elevated titers of anti-EBV nuclear antigen 1 (EBNA1) antibodies, interactions of these with the MS-associated HLA-DR15 haplotype, and molecular mimicry with MS autoantigens like myelin basic protein (MBP), anoctamin-2 (ANO2), glial cell adhesion molecule (GlialCAM), and alpha-crystallin B (CRYAB). In this study, we employ a simple in vitro assay to examine the memory B cell antibody repertoire in MS patients and healthy controls. We replicate previous serological data from MS patients demonstrating an increased secretion of anti-EBNA1380-641 IgG in cell culture supernatants, as well as a positive correlation of these levels with autoantibodies against GlialCAM262-416 and ANO21-275. For EBNA1380-641 and ANO21-275, we provide additional evidence suggesting antibody cross-reactivity between the two targets. Further, we show that two efficacious MS treatments - natalizumab (NAT) and autologous hematopoietic stem cell transplantation (aHSCT) - are associated with distinct changes in the EBNA1- directed B cell response and that these alterations can be attributed to the unique mechanisms of action of these therapies. Using an in vitro system, our study confirms MS-associated changes in the anti-EBNA1 memory B cell response, EBNA1380-641 antibody cross-reactivity with ANO21-275, and reveals treatment-associated changes in the immunoglobulin repertoire in MS. [ABSTRACT FROM AUTHOR]

This article provides an overview of IgA nephropathy (IgAN), a kidney disease characterized by the deposition of IgA antibodies in the glomeruli. The author shares their research findings from the past 20 years, including the establishment of an IgAN mouse model and the development of a monoclonal antibody for a specific type of IgA. The article explores the presence of subclinical IgAN and its progression to symptomatic IgAN, as well as the role of infection in this transition. The author also examines the inflammatory properties of glomerular IgA and the potential formation of immune complexes in IgAN. The study further investigates the role of apoptosis inhibitor of macrophage (AIM) in regulating the clearance of glomerular IgA and the formation of immune complexes in the kidneys. It suggests that not all glomerular IgA is inflammatory and that specific forms of IgA may have inflammatory properties. The article delves into the molecular properties of nephritogenic GdIgA1, including the presence of IgA autoantibodies that target β2 spectrin on mesangial cells. The study proposes a potential molecular mimicry mechanism between oral bacteria and proteins on mesangial cells as a cause of IgA autoantibody production. The article concludes by discussing the potential for early detection and prevention of IgAN through the identification of responsible bacteria and the development of screening systems and vaccinations. [Extracted from the article]

Initial studies using bioinformatics analysis revealed DNA sequence similarities between Trypanosoma cruzi GenBank® M21331, coding for Antigen 36 (Ag 36), and tripartite motif (TRIM) genes. TRIM40 showed 9.7% identity to GenBank M21331, and four additional TRIM genes had identities greater than 5.0%. TRIM37 showed a continuous stretch of identity of 12 nucleotides, that is, at least 25% longer than any of the other TRIMs. When we extended our analysis on the relationships of GenBank M21331 to further innate immune genes, using the Needleman-Wunsch (NW) algorithm for alignment, identities to human IFN-α, IFN-β, and IFN-γ genes of 13.6%, 12.6%, and 17.9%, respectively, were found. To determine the minimum number of genes coding for proteins closely related to Ag 36, a BLAST-p search was conducted with it versus the T. cruzi genome. The BLAST-p search revealed that T. cruzi GenBank M21331 had 14 gene sequences homologous to microtubule-associated protein (MAP) genes with 100% amino acid sequence identity. To verify the similarities in non-human genes, a study comparing TRIM21 region sequences among mammalian species to the comparable human TRIM21 region showed that related sequences were also present in 11 mammalian species. The MAP genes homologous to Ag 36 form a family of at least 14 genes which mimic human immune genes in the IFN and TRIM families. This mimicry is of gene sequences and not their protein products or epitopes. These results appear to be the first description of molecular mimicry of immune genes in humans by a protozoan parasite. [ABSTRACT FROM AUTHOR]

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]

Retinopathy of prematurity (ROP) is a retinal disease‐causing retinal neovascularization that can lead to blindness. Oxygen‐induced retinopathy (OIR) is a widely used ROP animal model. Icariin (ICA) has anti‐oxidative and anti‐inflammation properties; however, whether ICA has a regulatory effect on OIR remains unclear. In this study, ICA alleviated pathological neovascularization, microglial activation and blood–retina barrier (BRB) damage in vivo. Further results indicated that endothelial cell tube formation, migration and proliferation were restored by ICA treatment in vitro. Proteomic microarrays and molecular mimicry revealed that ICA can directly bind to hexokinase 2 (HK2) and decrease HK2 protein expression in vivo and in vitro. In addition, ICA inhibited the AKT/mTOR/HIF1α pathway activation. The effects of ICA on pathological neovascularization, microglial activation and BRB damage disappeared after HK2 overexpression in vivo. Similarly, the endothelial cell function was revised after HK2 overexpression. HK2 overexpression reversed ICA‐induced AKT/mTOR/HIF1α pathway inhibition in vivo and in vitro. Therefore, ICA prevented pathological angiogenesis in OIR in an HK2‐dependent manner, implicating ICA as a potential therapeutic agent for ROP. [ABSTRACT FROM AUTHOR]

Urticarial vasculitis is characterized by persistent urticarial lesions lasting over 24 h. Urticarial vasculitis is often triggered by medications, infections, and autoimmune disorders. However, vaccinations against viral and bacterial pathogens have recently been documented to induce urticarial vasculitis. We describe the case of a 67-year-old woman who was presented with an extensive erythematous and purpuric rash without systemic symptoms 3 days after an influenza vaccination. She was diagnosed with normocomplementemic urticarial vasculitis based on clinical findings, normal complement levels, and histopathological findings of leukocytoclastic vasculitis. After receiving oral histamines, she showed complete resolution 3 months after receiving the influenza vaccination. Although vaccination-associated vasculitis is common, urticarial vasculitis following vaccinations is rare. We reviewed 13 cases of urticarial vasculitis following a wide range of vaccines, including those against Bacillus Calmette–Guérin, serogroup B meningococcus, influenza, and coronavirus disease. We conducted a comprehensive review of various aspects, including age, sex, past medical history, type of vaccination, number of vaccinations, onset time, cutaneous symptoms, place of eruption, systemic symptoms, laboratory disorders, treatment period, and treatment of urticarial vasculitis. Two patients developed hypocomplementemic urticarial vasculitis after vaccination, and both experienced systemic symptoms such as arthralgia and fever. In this review, no significant differences were found in the data, which may be attributed to the small number of cases. The mechanisms underlying the induction of urticarial vasculitis by vaccines remain unknown; however, in addition to immune complex deposition and complement activation due to vaccine components, molecular mimicry may trigger urticarial vasculitis by producing vaccine-derived pathogenic antigen antibodies. This case study emphasizes the need for heightened awareness and further investigation of urticarial vasculitis as a rare adverse effect of vaccination. [ABSTRACT FROM AUTHOR]

Besides genetic susceptibility, infections due to viruses, bacteria and protozoa have been implicated in the development of autoimmune diseases (AD). AD can be triggered in a genetically susceptible individual by infections that disrupt immunological tolerance towards self-antigens. Pathogens can initiate autoimmunity by way of molecular mimicry, bystander activation, epitope spreading or persistent infection with polyclonal activation. This review covers two main topics: (i) the mechanisms by which an infectious agent can trigger or worsen autoimmunity; and (ii) the correlation between specific infectious agents and AD in humans with special emphasis on multisystem inflammatory syndrome in children (MIS-C). [ABSTRACT FROM AUTHOR]

Background/Objective: Multiple cases of postvaccination immune-related adverse events have been reported. We, hereby, present a patient who presented with new-onset type 1 diabetes mellitus (DM) after COVID-19 messenger RNA (mRNA) vaccination. Case Report: A 38-year-old Caucasian man presented with sudden onset of polyuria, polydipsia, and blurry vision for 1 month. The patient received the second dose of the COVID-19 mRNA vaccine (Pfizer-BioNTech) 4 weeks prior to symptom onset. Initial workup revealed glucosuria and hemoglobin A1c of 9.4%. Antibodies against multiple pancreatic beta cell autoantigens were detected. The patient was then initiated on insulin. Discussion: Hypothesized mechanisms for development of type 1 DM after COVID-19 mRNA vaccination include molecular mimicry, autoimmune/inflammatory syndrome induced by adjuvants, and possible interaction between the angiotensin-I converting enzyme-2 receptor on beta cells and viral mRNA. An initial high index of suspicion should be accompanied by early autoantibody testing and initiation of insulin, if indicated. Finally, if diagnosed with type 1 diabetes, patients must have long-term follow-up as there may be brief periods where glycemic control is maintained off insulin. Conclusion: New-onset type 1 DM has been reported after COVID mRNA vaccination. Clinicians should maintain a high index of suspicion and pursue early testing for the same to reduce adverse outcomes and improve long-term prognosis.

Infectious diseases are commonly implicated as potential initiators of autoimmune diseases (ADs) and represent the most commonly known factor in the development of autoimmunity in susceptible individuals. Epidemiological data and animal studies on multiple ADs suggest that molecular mimicry is one of the likely mechanisms for the loss of peripheral tolerance and the development of clinical disease. Besides molecular mimicry, other mechanisms such as defects in central tolerance, nonspecific bystander activation, epitope-determinant spreading, and/or constant antigenic stimuli, may also contribute for breach of tolerance and to the development of ADs. Linear peptide homology is not the only mechanism by which molecular mimicry is established. Peptide modeling (i.e., 3D structure), molecular docking analyses, and affinity estimation for HLAs are emerging as critical strategies when studying the links of molecular mimicry in the development of autoimmunity. In the current pandemic, several reports have confirmed an influence of SARS-CoV-2 on subsequent autoimmunity. Bioinformatic and experimental evidence support the potential role of molecular mimicry. Peptide dimensional analysis requires more research and will be increasingly important for designing and distributing vaccines and better understanding the role of environmental factors related to autoimmunity.

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by immune system dysfunction that can lead to serious health issues and mortality. Recent investigations highlight the role of gut microbiota alterations in modulating inflammation and disease severity in SLE. This review specifically summaries the variations in gut microbiota composition across various murine models of lupus. By focusing on these differences, we aim to elucidate the intricate relationship between gut microbiota dysbiosis and the development and progression of SLE in preclinical settings. [ABSTRACT FROM AUTHOR]

Background Atopic dermatitis (AD) is a chronic inflammatory skin condition that has a significant impact on quality of life. The immune response and allergy symptoms in AD are triggered by the recognition of specific allergens by IgE antibodies. Cross-reactivity can lead to auto-IgE responses, potentially worsening AD symptoms. Our research aimed to enhance our understanding of allergenic sources, including A. fumigatus, and their role in AD. We focused on molecular mimicry between human AQP3 and A. fumigatus aquaporin. Methods In our in-silico analysis, we compared the amino acid sequences of human aquaporin 3 (AQP3) and A. fumigatus aquaporin with 25 aquaporins from various allergenic sources, sourced from the UniProt and NCBI databases. Phylogenetic relationship analysis and homology-based modeling were conducted. We identified conserved antigenic regions located within the 3D structures. Results The global identity levels among the studied aquaporins averaged 32.6%. One antigenic site exhibited a remarkable local region, with a conserved identity of 71.4%. We categorized the aquaporins into five monophyletic clades (A–E), with group B showing the highest identity (95%), including six mammalian aquaporins, including AQP3. When comparing A. fumigatus aquaporins, the highest identity was observed with Malassezia sympodialis at 35%. Both human and A. fumigatus aquaporins have three linear and three discontinuous epitopes. Conclusions We identified potential linear and conformational epitopes of AQP3, indicating a possible molecular mimicry between humans and A. fumigatus aquaporins. This suggests autoreactivity and potential cross-reactivity, although further validation using in vitro and in vivo experiments is required.

Immunotherapy has revolutionized cancer treatment by leveraging the immune system's innate capabilities to combatmalignancies. Despite the promise of tumor antigens in stimulating anti-tumor immune responses, their clinical utility is hampered by limitations in eliciting robust and durable immune reactions, exacerbated by tumor heterogeneity and immune evasion mechanisms. Recent insights into the immunogenic properties of host homologous microbial antigens have sparked interest in their potential for augmenting anti-tumor immunity while minimizing off-target effects. This review explores the therapeutic potential of microbial antigen peptides in tumor immunotherapy, beginning with an overview of tumor antigens and their challenges in clinical translation. We further explore the intricate relationship between microorganisms and tumor development, elucidating the concept of molecular mimicry and its implications for immune recognition of tumor-associated antigens. Finally, we discuss methodologies for identifying and characterizing microbial antigen peptides, highlighting their immunogenicity and prospects for therapeutic application. [ABSTRACT FROM AUTHOR]

Epidemiological studies and meta-analyses have shown a strong association between high seroprevalence of Toxoplasma gondii (T. gondii) and schizophrenia. Schizophrenic patients showed higher levels of anti-Toxoplasma immunoglobulins M and G (IgM and IgG) when compared to healthy controls. Previously, in a rat model, we demonstrated that the progeny of mothers immunized with T. gondii lysates before gestation had behavioral and social impairments during adulthood. Therefore, we suggested that T. gondii infection can trigger autoreactivity by molecularly mimicking host brain proteins. Here, we aimed to identify the occurrence of antigenic mimicry between T. gondii epitopes and host brain proteins. Using a bioinformatic approach, we predicted T. gondii RH-88 B cell epitopes and compared them to human cell-surface proteins involved in brain development and differentiation (BrainS). Five different algorithms for B-cell-epitope prediction were used and compared, resulting in 8584 T. gondii epitopes. We then compared T. gondii predicted epitopes to BrainS proteins by local sequence alignments using BLASTP. T. gondii immunogenic epitopes significantly overlapped with 42 BrainS proteins. Among these overlapping proteins essential for brain development and differentiation, we identified HSP90 and NOTCH receptors as the proteins most likely to be targeted by the maternally generated pathogenic antibodies due to their topological overlap at the extracellular region of their sequence. This analysis highlights the relevance of pregestational clinical surveillance and screening for potential pathogenic anti-T. gondii antibodies. It also identifies potential targets for the design of vaccines that could prevent behavioral and cognitive impairments associated with pre-gestational T. gondii exposure. [ABSTRACT FROM AUTHOR]

The relationship between infectious agents and autoimmune diseases is a complex issue. In recent years, increasing clinical cases have indicated that infectious agents play an important role in the development of autoimmune diseases. Molecular mimicry is currently widely regarded as the primary pathogenic mechanism of various autoimmune diseases in humans. Components of infectious agents can undergo molecular mimicry with components in patients' bodies, leading to the development of various autoimmune diseases. In this article, we provide a brief overview of current research of the current research status on the relationship between infectious agents and autoimmune diseases, and describe our current understanding of their mechanisms of action in order to better understand the pathogenesis, diagnosis, and treatment of autoimmune diseases. [ABSTRACT FROM AUTHOR]

Recurrent Pregnancy Loss (RPL) affects 1–2% of women, and its triggering factors are unclear. Several studies have shown that the vaginal, endometrial, and gut microbiota may play a role in RPL. A decrease in the quantity of Lactobacillus crispatus in local microbiota has been associated with an increase in local (vaginal and endometrial) inflammatory response and immune cell activation that leads to pregnancy loss. The inflammatory response may be triggered by gram-negative bacteria, lipopolysaccharides (LPS), viral infections, mycosis, or atypia (tumor growth). Bacterial structures and metabolites produced by microbiota could be involved in immune cell modulation and may be responsible for immune cell activation and molecular mimicry. Gut microbiota metabolic products may increase the amount of circulating pro-inflammatory lymphocytes, which, in turn, will migrate into vaginal or endometrial tissues. Local pro-inflammatory Th1 and Th17 subpopulations and a decrease in local Treg and tolerogenic NK cells are accountable for the increase in pregnancy loss. Local microbiota may modulate the local inflammatory response, increasing pregnancy success. Analyzing local and gut microbiota may be necessary to characterize some RPL patients. Although oral supplementation of probiotics has not been shown to modify vaginal or endometrial microbiota, the metabolites produced by it may benefit patients. Lactobacillus crispatus transplantation into the vagina may enhance the required immune tolerogenic response to achieve a normal pregnancy. The effect of hormone stimulation and progesterone to maintain early pregnancy on microbiota has not been adequately studied, and more research is needed in this area. Well-designed clinical trials are required to ascertain the benefit of microbiota modulation in RPL. [ABSTRACT FROM AUTHOR]

ABSTRACT The COVID‐19 pandemic drove a uniquely fervent pursuit to explore the potential of peptide, antibody, protein, and small‐molecule‐based antiviral agents against severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2). The interaction between the SARS‐CoV2 spike protein with the angiotensin‐converting enzyme 2 (ACE2) receptor that mediates viral cell entry was a particularly interesting target given its well‐described protein–protein interaction (PPI). This PPI is mediated by an α‐helical portion of ACE2 binding to the receptor binding domain (RBD) of the spike protein and thought to be susceptible to blockade through molecular mimicry. Small numbers of hydrocarbon‐stapled synthetic peptides designed to disrupt or block this interaction were tested individually and were found to have variable efficacy despite having related or overlapping sequences and similarly increased α‐helicity. Reasons for these differences are unclear and reported preclinical successes have been limited. This study sought to better understand reasons for these differences through evaluation of a comprehensive collection of hydrocarbon‐stapled peptides, designed based on four distinct principles: stapling position, number of staples, amino acid sequence, and primary sequence length. Surprisingly, we observed that the helicity and amino acid sequence iterations of hydrocarbon‐stapled peptides did not correlate with their bioactivity. Our results highlight the importance of iterative and combinatorial testing of these compounds to determine a configuration that best mimics natural binding and allows for chain flexibility while sacrificing structural helicity. [ABSTRACT FROM AUTHOR]

The given text is a list of references to various scientific articles related to immunology and autoimmune diseases. The articles cover topics such as the influence of HLA class II molecules on inflammatory diseases, the role of DNases in health and disease, polymorphisms associated with rheumatoid arthritis, and the overlap in neutrophil transcriptome between lupus and COVID-19. Other articles discuss the role of alternative splicing in cancer and autoimmune diseases, the expression of retroviruses in rheumatoid arthritis and lupus, and the presence of autoantibodies in autoimmune diseases. These articles provide valuable insights into the mechanisms and potential therapeutic targets for these diseases. [Extracted from the article]

Background: Immunotherapies, notably immune checkpoints inhibitors that target programmed death 1/programmed death ligand 1(PD‐1/PD‐L1) and cytotoxic T lymphocyte‐associated antigen 4 (CTLA‐4), had profoundly changed the way advanced and metastatic cancers are treated and dramatically improved overall and progression‐free survival. Aims: This review article aimed to explore the underlying molecular mechanisms by which the gut microbiota affects antitumor immunity and the efficacy of cancer immunotherapy. Methods: We summarized the latest knowledge supporting the associations among the gut microbiota, antitumor immunity, and immunotherapy. Moreover, we disscussed the therapeutic strategy for improving immunotherapy efficacy by modulating gut microbiota in cancer treatment. Results: The potential molecular mechanisms underlying these associations are explained in terms of four aspects: immunomodulation, molecular mimicry, mamps, and microbial metabolites. Conclusion: The gut microbiota significantly impacts antitumor immunity and alters the effectiveness of cancer immunotherapy. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

This review delves into the interactions between hepatitis C virus (HCV) and the host immune system, shedding light on how by using the mechanism of molecular mimicry, the virus strategically evades the immune system, resulting in a cascade of diverse complications. HCV, notorious for its ability to persistently infect hepatocytes, employs molecular mimicry to resemble host proteins, thereby avoiding immune detection and mounting an effective defense. This mimicry also triggers systemic autoimmune responses that lead to various sequelae. The objective of this review is to comprehensively explore the role of HCV-induced molecular mimicry, which not only facilitates viral survival but is also instrumental in developing autoimmune and inflammatory disorders. By mimicking host proteins, HCV triggers an immune response that inadvertently attacks the host, fostering the development of autoimmune and other inflammatory disorders. Understanding the nuanced mechanisms of HCV-mediated molecular mimicry provides crucial insights into the multifaceted sequelae of viral infections on host immune responses. Unravelling these complexities is paramount for advancing therapeutic strategies that not only target the virus directly but also mitigate the secondary autoimmune and inflammatory complications induced by HCV. [ABSTRACT FROM AUTHOR]

Background: In the present study we investigated whether peptides derived from the entire SARS-CoV-2 proteome share homology to TAAs (tumor-associated antigens) and cross-reactive CD8+ T cell can be elicited by the BNT162b2 preventive vaccine or the SARS-CoV-2 natural infection. Methods and results: Viral epitopes with high affinity (<100nM) to the HLAA* 02:01 allele were predicted. Shared and variant-specific epitopes were identified. Significant homologies in amino acidic sequence have been found between SARS-CoV-2 peptides and multiple TAAs, mainly associated with breast, liver, melanoma and colon cancers. The molecular mimicry of the viral epitopes and the TAAs was found in all viral proteins, mostly the Orf 1ab and the Spike, which is included in the BNT162b2 vaccine. Predicted structural similarities confirmed the sequence homology and comparable patterns of contact with both HLA and TCR α and β chains were observed. CD8+ T cell clones cross-reactive with the paired peptides have been found by MHC class l-dextramer staining. Conclusions: Our results show for the first time that several SARS-COV-2 antigens are highly homologous to TAAs and cross-reactive T cells are identified in infected and BNT162b2 preventive vaccinated individuals. The implication would be that the SARS-Cov-2 pandemic could represent a natural preventive immunization for breast, liver, melanoma and colon cancers. In the coming years, real-world evidences will provide the final proof for such immunological experimental evidence. Moreover, such SARS-CoV-2 epitopes can be used to develop "multicancer" off-the-shelf preventive/therapeutic vaccine formulations, with higher antigenicity and immunogenicity than over-expressed tumor self-antigens, for the potential valuable benefit of thousands of cancer patients around the World. [ABSTRACT FROM AUTHOR]

The AAA-type ATPase VPS4 is recruited by proteins of the endosomal sorting complex required for transport III (ESCRT-III) to catalyse membrane constriction and membrane fission. VPS4A accumulates at the cytoplasmic viral assembly complex (cVAC) of cells infected with human cytomegalovirus (HCMV), the site where nascent virus particles obtain their membrane envelope. Here we show that VPS4A is recruited to the cVAC via interaction with pUL71. Sequence analysis, deep-learning structure prediction, molecular dynamics and mutagenic analysis identify a short peptide motif in the C-terminal region of pUL71 that is necessary and sufficient for the interaction with VPS4A. This motif is predicted to bind the same groove of the N-terminal VPS4A Microtubule-Interacting and Trafficking (MIT) domain as the Type 2 MIT-Interacting Motif (MIM2) of cellular ESCRT-III components, and this viral MIM2-like motif (vMIM2) is conserved across β-herpesvirus pUL71 homologues. However, recruitment of VPS4A by pUL71 is dispensable for HCMV morphogenesis or replication and the function of the conserved vMIM2 during infection remains enigmatic. VPS4-recruitment via a vMIM2 represents a previously unknown mechanism of molecular mimicry in viruses, extending previous observations that herpesviruses encode proteins with structural and functional homology to cellular ESCRT-III components. Author summary: Enveloped viruses appropriate cellular membranes from infected cells to generate their membrane coats. Many enveloped viruses accomplish the membrane wrapping of new virus particles by recruiting the cellular membrane-remodelling ESCRT machinery to sites of virus assembly. Herpesviruses have a complex assembly pathway and molecular roles of the ESCRT machinery in the production of new herpesvirus particles remains unclear, but previous studies have shown that the ESCRT-associated ATPase VPS4A is recruited to the cytoplasmic assembly site of human cytomegalovirus (HCMV). Here we show that the HCMV protein pUL71 is necessary for this VPS4A recruitment. Using a combination of biochemical, computational and cell-based techniques we demonstrate that a C-terminal segment of pUL71 binds VPS4A via molecular mimicry of cellular 'MIM2' VPS4-binding motifs. Direct binding to VPS4A via a viral MIM2 (vMIM2) represents a previously unknown mechanism of molecular mimicry in viruses, extending previous observations that herpesviruses encode proteins with structural and functional homology to cellular ESCRT-III components. However, mutational analysis reveals that VPS4A recruitment by pUL71 is not required for HCMV particle assembly, indicating that this novel and conserved HCMV vMIM2 has an unknown function of during infection. [ABSTRACT FROM AUTHOR]

The VH6-1 class of antibodies includes some of the broadest and most potent antibodies that neutralize influenza A virus. Here, we elicit and isolate antiidiotype antibodies against germline versions of VH6-1 antibodies, use these to sort human leukocytes, and isolate a new VH6-1-class member, antibody L5A7, which potently neutralized diverse group 1 and group 2 influenza A strains. While its heavy chain derived from the canonical IGHV6-1 heavy chain gene used by the class, L5A7 utilized a light chain gene, IGKV1-9, which had not been previously observed in other VH6-1-class antibodies. The cryo-EM structure of L5A7 in complex with Indonesia 2005 hemagglutinin revealed a nearly identical binding mode to other VH6-1-class members. The structure of L5A7 bound to the isolating anti-idiotype antibody, 28H6E11, revealed a shared surface for binding anti-idiotype and hemagglutinin that included two critical L5A7 regions: an FG motif in the third heavy chain-complementary determining region (CDR H3) and the CDR L1 loop. Surprisingly, the chemistries of L5A7 interactions with hemagglutinin and with anti-idiotype were substantially different. Overall, we demonstrate anti-idiotype-based isolation of a broad and potent influenza A virus-neutralizing antibody, revealing that anti-idiotypic selection of antibodies can involve features other than chemical mimicry of the target antigen. [ABSTRACT FROM AUTHOR]

This letter discusses the importance of molecular mimicry in understanding and treating human diseases. Molecular mimicry occurs when pathogenic microbes express antigens that closely resemble those found in humans, allowing them to evade the immune system. The letter presents a bibliometric analysis of research on molecular mimicry, identifying trends and hotspots in the field. The analysis reveals that the United States is the leading country in molecular mimicry research, and the Journal of Autoimmunity is one of the most active journals in publishing this research. The letter also highlights three main areas of molecular mimicry research: its function in autoimmune diseases, its role in vaccine development, and the discovery of mimics through specificity and computational tools. The analysis suggests a shift in research focus towards specificity and computational tools in recent years. Overall, the letter emphasizes the potential of molecular mimicry in improving our understanding of diseases and developing therapeutic interventions. [Extracted from the article]

Simple Summary: COVID-19, with persistent and new onset of symptoms, such as fatigue, post-exertional malaise, and cognitive dysfunction that impact everyday functioning, is referred to as long-COVID under the general category of post-acute sequelae of the SARS-CoV-2 infection (PASC). It includes a wide range of signs and symptoms that can last weeks, months, or even years after infection, most of which are attributable to dysfunctions of the neurovegetative system. The causative mechanisms are still unknown, but autoimmunity and the production of autoantibodies targeting self-antigens via the molecular mimicry phenomenon seem to have a role. Here we evaluated the presence of autoantibodies against two proteins of vagal nuclei sharing a peptide with SARS-CoV-2 spike glycoprotein in sera from ongoing symptomatic COVID-19 patients (long-COVID) with cardiorespiratory symptoms, subjects vaccinated without a history of SARS-CoV-2 infection, and subjects not vaccinated without a history of SARS-CoV-2. Putative autoantibodies are present in both long-COVID-19 and vaccinated groups, suggesting that both viral infection and vaccination may trigger autoreactivity. However, the presence of autoantibodies is not sufficient for triggering autoimmunity, and other predisposing conditions must co-occur. Therefore, it is necessary to run further investigations to clarify the complex mechanisms involved in the development of long-COVID, providing knowledge which may offer further information for the prevention and treatment of the disease. As reported by the World Health Organization (WHO), about 10–20% of people have experienced mid- to long-term effects following SARS-CoV-2 infection, collectively referred to as post-COVID-19 condition or long-COVID, including some neurovegetative symptoms. Numerous findings have suggested that the onset of these neurovegetative symptoms upon viral infection may be caused by the production of autoantibodies through molecular mimicry phenomena. Accordingly, we had previously demonstrated that 22 of the human proteins sharing putatively immunogenic peptides with SARS-CoV-2 proteins are expressed in the dorsal motor nucleus and nucleus ambiguous. Therefore, if molecular mimicry occurs following severe forms of COVID-19, there could be transitory or permanent damage in some vagal structures, resulting in a lower vagal tone and all the related clinical signs. We investigated the presence of autoantibodies against two proteins of vagal nuclei sharing a peptide with SARS-CoV-2 spike glycoprotein using an immunoassay test on blood obtained from patients with cardiorespiratory symptoms in patients affected by ongoing symptomatic COVID-19 (long-COVID), subjects vaccinated without a history of SARS-CoV-2 infection, and subjects not vaccinated without a history of SARS-CoV-2 infection. Interestingly, putative autoantibodies were present in both long-COVID-19 and vaccinated groups, opening interesting questions about pathogenic mechanisms of the disease. [ABSTRACT FROM AUTHOR]

The development of psoriasis is mainly driven by the dysregulation of T cells within the skin, marking a primary involvement of these cells in the pathogenesis. Although B cells are integral components of the immune system, their role in the initiation and progression of psoriasis is not as pivotal as that of T cells. The paradox of B cell suggests that, while it is crucial for adaptive immunity, B cells may contribute to the exacerbation of psoriasis. Numerous ideas proposed that there are potential relationships between psoriasis and B cells especially within germinal centers (GCs). Recent research projected that B cells might be triggered by autoantigens which then induced molecular mimicry to alter B cells activity within GC and generate autoantibodies and pro‐inflammatory cytokines, form ectopic GC, and dysregulate the proliferation of keratinocytes. Hence, in this review, we gathered potential evidence indicating the participation of B cells in psoriasis within the context of GC, aiming to enhance our comprehension and advance treatment strategies for psoriasis thus inviting many new researchers to investigate this issue. [ABSTRACT FROM AUTHOR]

Evidence of cognition in aneural cells is well‐establish in the literature. This paper extends the exploration of the mechanisms of cognition by considering whether or not aneural cells may be capable of irrational cognition, making associations based on coincidental similarities and circumstantial factors. If aneural cells do harness such semiosic qualities, as with higher‐level creativity, this might be how they are able to overcome old algorithms and invent tools for new situations. I will look at three examples of irrational learning in aneural systems in terms of semiotics: (1) generalisation in the immune system, based on viral molecular mimicry, whereby immune cells attack the self, which seems to be an overgeneralisation of an icon sign based on mere similarity, not identity, (2) the classical conditioning of pea plants to trope toward wind as a sign of light, which seems to be an association of an index sign based on mere temporal proximity, and (3) a pharmaceutical intervention to prevent pregnancy, using a conjugate to encrypt self with non‐self, which seems to be an example of symbol use. We identify irrational cognition easily when it leads to 'wrong' outcomes, but, if it occurs, it may also lead to favourable outcomes and 'creative' solutions. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease characterized by self-immune tolerance breakdown and the production of autoantibodies, causing the deposition of immune complexes and triggering inflammation and immune-mediated damage. SLE pathogenesis involves genetic predisposition and a combination of environmental factors. Clinical manifestations are variable, making an early diagnosis challenging. Heat shock proteins (Hsps), belonging to the chaperone system, interact with the immune system, acting as pro-inflammatory factors, autoantigens, as well as immune tolerance promoters. Increased levels of some Hsps and the production of autoantibodies against them are correlated with SLE onset and progression. The production of these autoantibodies has been attributed to molecular mimicry, occurring upon viral and bacterial infections, since they are evolutionary highly conserved. Gut microbiota dysbiosis has been associated with the occurrence and severity of SLE. Numerous findings suggest that proteins and metabolites of commensal bacteria can mimic autoantigens, inducing autoimmunity, because of molecular mimicry. Here, we propose that shared epitopes between human Hsps and those of gut commensal bacteria cause the production of anti-Hsp autoantibodies that cross-react with human molecules, contributing to SLE pathogenesis. Thus, the involvement of the chaperone system, gut microbiota dysbiosis, and molecular mimicry in SLE ought to be coordinately studied. [ABSTRACT FROM AUTHOR]

One of the probable hypotheses for the onset of autoimmunity is molecular mimicry. This study aimed to determine the HLA-II risk alleles for developing Hashimoto's thyroiditis (HT) in order to analyze the molecular homology between candidate pathogen-derived epitopes and potentially self-antigens (thyroid peroxidase, TPO) based on the presence of HLA risk alleles. HLA-DRB1/-DQB1 genotyping was performed in 100 HT patients and 330 ethnically matched healthy controls to determine the predisposing/protective alleles for HT disease. Then, in silico analysis was conducted to examine the sequence homology between epitopes derived from autoantigens and four potentially relevant pathogens and their binding capacities to HLA risk alleles based on peptide docking analysis. We identified HLA-DRB1*03:01, *04:02, *04:05, and *11:04 as predisposing alleles and DRB1*13:01 as a potentially predictive allele for HT disease. Also, DRB1*11:04 ~ DQB1*03:01 (Pc = 0.002; OR, 3.97) and DRB1*03:01 ~ DQB1*02:01 (Pc = 0.004; OR, 2.24) haplotypes conferred a predisposing role for HT. Based on logistic regression analysis, carrying risk alleles increased the risk of HT development 4.5 times in our population (P = 7.09E-10). Also, ROC curve analysis revealed a high predictive power of those risk alleles for discrimination of the susceptible from healthy individuals (AUC, 0.70; P = 6.6E-10). Analysis of peptide sequence homology between epitopes of TPO and epitopes derived from four candidate microorganisms revealed a homology between envelop glycoprotein D of herpes virus and sequence 151–199 of TPO with remarkable binding capacity to HLA-DRB1*03:01 allele. Our findings indicate the increased risk of developing HT in those individuals carrying HLA risk alleles which can also be related to herpes virus infection. [ABSTRACT FROM AUTHOR]

The ArdA DNA-mimic antirestriction proteins inhibit type I restriction−modification (RMI) systems by binding instead of DNA to RMI. The ArdA specificity to DNA methylation sites recognized by RMI complexes remains poorly understood; i.e., it is unclear whether a particular DNA site is mimicked by ArdA. The ardA genes were cloned from three Gram-positive bacteria: Agrobacterium tumefaciens, Pseudomonas monteilii, and Xanthomonas sp. Antirestriction activities of their products were tested against three Escherichia coli RMI systems differing in DNA recognition/methylation sites. Although similar structures were predicted for the ArdA proteins, the strong specificity to three RMI systems was observed. The results indicate that specific DNA sites may be imitated by DNA mimic ArdA proteins. [ABSTRACT FROM AUTHOR]

Drilling fluid is pivotal for efficient drilling. However, the gelation performance of drilling fluids is influenced by various complex factors, and traditional methods are inefficient and costly. Artificial intelligence and numerical simulation technologies have become transformative tools in various disciplines. This work reviews the application of four artificial intelligence techniques—expert systems, artificial neural networks (ANNs), support vector machines (SVMs), and genetic algorithms—and three numerical simulation techniques—computational fluid dynamics (CFD) simulations, molecular dynamics (MD) simulations, and Monte Carlo simulations—in drilling fluid design and performance optimization. It analyzes the current issues in these studies, pointing out that challenges in applying these two technologies to drilling fluid gelation performance research include difficulties in obtaining field data and overly idealized model assumptions. From the literature review, it can be estimated that 52.0% of the papers are related to ANNs. Leakage issues are the primary concern for practitioners studying drilling fluid gelation performance, accounting for over 17% of research in this area. Based on this, and in conjunction with the technical requirements of drilling fluids and the development needs of drilling intelligence theory, three development directions are proposed: (1) Emphasize feature engineering and data preprocessing to explore the application potential of interpretable artificial intelligence. (2) Establish channels for open access to data or large-scale oil and gas field databases. (3) Conduct in-depth numerical simulation research focusing on the microscopic details of the spatial network structure of drilling fluids, reducing or even eliminating data dependence. [ABSTRACT FROM AUTHOR]

Aquaporin-4 (AQP4)-specific Th17 cells are thought to have a central role in neuromyelitis optica (NMO) pathogenesis. When modeling NMO, only AQP4-reactive Th17 cells from AQP4-deficient (AQP4-/-), but not wild-type (WT) mice, caused CNS autoimmunity in recipient WT mice, indicating that a tightly regulated mechanism normally ensures tolerance to AQP4. Here, we found that pathogenic AQP4 T cell epitopes bind MHC II with exceptionally high affinity. Examination of T cell receptor (TCR) α/β usage revealed that AQP4-specific T cells from AQP4-/- mice employed a distinct TCR repertoire and exhibited clonal expansion. Selective thymic AQP4 deficiency did not fully restore AQP4-reactive T cells, demonstrating that thymic negative selection alone did not account for AQP4-specific tolerance in WT mice. Indeed, AQP4-specific Th17 cells caused paralysis in recipient WT or B cell-deficient mice, which was followed by complete recovery that was associated with apoptosis of donor T cells. However, donor AQP4-reactive T cells survived and caused persistent paralysis in recipient mice deficient in both T and B cells or mice lacking T cells only. Thus, AQP4 CNS autoimmunity was limited by T cell-dependent deletion of AQP4-reactive T cells. In contrast, myelin oligodendrocyte glycoprotein (MOG)-specific T cells survived and caused sustained disease in WT mice. These findings underscore the importance of peripheral T cell deletional tolerance to AQP4, which may be relevant to understanding the balance of AQP4-reactive T cells in health and in NMO. T cell tolerance to AQP4, expressed in multiple tissues, is distinct from tolerance to MOG, an autoantigen restricted in its expression.

Background Atopic dermatitis (AD) is a chronic inflammatory skin condition that has a significant impact on quality of life. The immune response and allergy symptoms in AD are triggered by the recognition of specific allergens by IgE antibodies. Cross-reactivity can lead to auto-IgE responses, potentially worsening AD symptoms. Our research aimed to enhance our understanding of allergenic sources, including A. fumigatus, and their role in AD. We focused on molecular mimicry between human AQP3 and A. fumigatus aquaporin. Methods In our in-silico analysis, we compared the amino acid sequences of human aquaporin 3 (AQP3) and A. fumigatus aquaporin with 25 aquaporins from various allergenic sources, sourced from the UniProt and NCBI databases. Phylogenetic relationship analysis and homology-based modeling were conducted. We identified conserved antigenic regions located within the 3D structures. Results The global identity levels among the studied aquaporins averaged 32.6%. One antigenic site exhibited a remarkable local region, with a conserved identity of 71.4%. We categorized the aquaporins into five monophyletic clades (A–E), with group B showing the highest identity (95%), including six mammalian aquaporins, including AQP3. When comparing A. fumigatus aquaporins, the highest identity was observed with Malassezia sympodialis at 35%. Both human and A. fumigatus aquaporins have three linear and three discontinuous epitopes. Conclusions We identified potential linear and conformational epitopes of AQP3, indicating a possible molecular mimicry between humans and A. fumigatus aquaporins. This suggests autoreactivity and potential cross-reactivity, although further validation using in vitro and in vivo experiments is required.