Identification and characterization of a nonbiological small-molecular mimic of a Zika virus conformational neutralizing epitope.

Antigenic similarities between Zika virus (ZIKV) and other flaviviruses pose challenges to the development of virus-specific diagnostic tools and effective vaccines. Starting with a DNA-encoded one-bead-one-compound combinatorial library of 508,032 synthetic, non-natural oligomers, we selected and characterized small molecules that mimic ZIKV epitopes. High-throughput fluorescence-activated cell sorter-based bead screening was used to select molecules that bound IgG from ZIKV-immune but not from dengue-immune sera. Deep sequencing of the DNA from the "Zika-only" beads identified 40 candidate molecular structures. A lead candidate small molecule "CZV1-1" was selected that correctly identifies serum specimens from Zika-experienced patients with good sensitivity and specificity (85.3% and 98.4%, respectively). Binding competition studies of purified anti-CZV1-1 IgG against known ZIKV-specific monoclonal antibodies (mAbs) showed that CZV1-1 mimics a nonlinear, neutralizing conformational epitope in the domain III of the ZIKV envelope. Purified anti-CZV1-1 IgG neutralized infection of ZIKV in cell cultures with potencies comparable to highly specific ZIKV-neutralizing mAbs. This study demonstrates an innovative approach for identification of synthetic non-natural molecular mimics of conformational virus epitopes. Such molecular mimics may have value in the development of accurate diagnostic assays for Zika, as well as for other viruses.

[Molecular mimicry between Plasmodium sp and Guillain-Barre syndrome antigens]. / Mimetismo molecular entre el Plasmodium sp y los antígenos del síndrome de Guillain-Barre.

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

OBJETIVO: Analizar el mimetismo molecular entre Plasmodium spp. y autoantígenos asociados al SGB, identificando posibles epítopos antigénicos. MÉTODOS: Se emplearon PSI-Blast, Praline, Emboss, Protein Data Bank, Swiss Model Server, AlphaFold 2, Ellipro y PyMol 2.3 para buscar homologías, realizar alineamientos, obtener estructuras proteicas y predecir epítopos. RESULTADOS: Se incluyeron 17 autoantígenos y siete objetivos inmunológicos del sistema nervioso periférico, identificándose 72 posibles epítopos asociados al SGB. Del proteoma de Plasmodium spp. (298 proteínas), solo dos mostraron similitud cercana al 30% con TRIM21 y BACE1, generando siete posibles epítopos. CONCLUSIÓN: No se observaron homologías significativas entre el proteoma de SGB y Plasmodium spp. Se sugiere la exploración de otros mecanismos como el daño capilar inmunomediado, Epitope Spreading o Bystander Activation para explicar la asociación mencionada. Estos hallazgos subrayan la necesidad de aclarar la etiología de las enfermedades autoinmunes y el papel de los patógenos. Se enfatiza la necesidad de estudios experimentales para validar estos resultados.

[Molecular mimic between cardiovascular diseases and microorganism antigens]. / Mimetismo molecular entre enfermedades cardiovasculares y antígenos de microorganismos.

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

INTRODUCCIÓN: Las enfermedades cardiovasculares son el resultado de la interacción genética y ambiental que condiciona la integridad del corazón y los vasos sanguíneos. Los factores de riesgo incluyen infecciones. La respuesta inflamatoria contra el agente infeccioso es un desencadenante de las enfermedades cardiovasculares autoinmunes, debido a la similitud entre las proteínas del patógeno y los antígenos humanos, pues la respuesta inmunitaria puede presentar reactividad cruzada causada por mimetismo molecular. MÉTODOS: Realizamos una búsqueda de patógenos involucrados en enfermedades cardíacas autoinmunes y de autoantígenos asociados a estas enfermedades en los buscadores Pubmed y Google Scholar. La identidad entre proteínas se realizó a través de alineamientos globales utilizando PSI-BLAST. Las estructuras 3D de las proteínas fue obtenida por Uniprot o NCBI y, si no se encontraban, las estructuras se modelaban por homología, utilizando el servidor Swiss Model. La predicción de los epítopes se realizó a través de Ellipro, y la Base de Datos de Epítopos Inmunológicos (IEDB). Además, se utilizó el programa PYMOL para la visualización de proteínas en 3D, y el posicionamiento de los epítopes en la estructura. RESULTADOS: Diez proteínas cardiovasculares mostraron una identidad (30-88,24%) en sus secuencias de aminoácidos con antígenos de diez patógenos. Las proteínas de actina y las familias de proteínas de choque térmico (HSP, por sus siglas en inglés), presentaron niveles de identidad más altos con Trypanosoma Cruzi, Cryptococcus neoformans y Chlamydia trachomatis, 71,47%, 88,24% y 80,61%, respectivamente. Otros patógenos, como Streptococcus pyogenes, Bacillus sp, Magnetospirillum gryphiswaldense, Helicobacter pylori y Chlamydia pneumoniae, presentaron identidad moderada con un valor máximo del 65,79%. CONCLUSIÓN: La actina humana y las HSP comparten un alto grado de conservación con epítopos de varios microorganismos, como bacterias, hongos y protozoos; lo que sugiere la imitación molecular y la reactividad cruzada como mecanismos para el desarrollo de la aterosclerosis, la enfermedad cardíaca reumática, la miocarditis y la enfermedad cardíaca de Chagas. Se necesitan trabajos in vitro e in vivo, que demuestren los resultados obtenidos en el análisis In Silico.

[Molecular mimicry between human thyroid peroxidase, thyroglobulin, cosinophil peroxidase, IL-24 and microorganisms antigens]. / Mimetismo molecular entre peroxidasa tiroidea humana, tiroglobulina, peroxidasa de eosinófilos, IL-24 y antígenos de microorganismos.

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

OBJETIVO: Identificar mimetismo molecular entre TPO, eosinofil peroxidasa (EPX), tiroglobulina e IL24 y antígenos de microorganismos. MÉTODOS: A través de análisis in silico, realizamos los alineamientos locales entre los antígenos humanos y de microorganismos con PSI-BLAST. Las proteínas que no presentaban estructura 3D, fueron modeladas por homología a través del servidor Swiss Modeller y se realizó una predicción de epítopes a través de Ellipro. Los epítopes se localizaron en los modelos 3D utilizando el software PYMOL. RESULTADOS: Un total de 38 antígenos de microorganismos (parásitos y bacterias), tuvieron identidades entre 30 y 45%, siendo los más altos con Anisakis simplex. El alineamiento entre dos proteínas candidatas de A. simplex y EPX presentaron valores importantes, con identidades de 43 y 44%. En las bacterias, Campylobacter jejuni presentó la mayor identidad con tiroglobulina (35%). Se predijeron 220 epítopes lineales y conformacionales de antígenos de microorganismos. Las proteínas similares a la peroxidasina de Toxocara canis y Trichinella pseudospiralis presentaron diez epítopes similares a TPO y EPX, como posibles moléculas desencadenantes de una reactividad cruzada. Ningún virus presentó identidad con las proteínas humanas estudiadas. CONCLUSIÓN: Los antígenos TPO y EPX compartieron potenciales epítopes de reacción cruzada con proteínas bacterianas y nematodos, lo que sugiere que el mimetismo molecular podría ser un mecanismo que explique la relación entre infecciones y la urticaria/hipotiroidismo. Se necesitan trabajos in vitro que demuestren los resultados obtenidos en el análisis in silico.

[In Silico analysis of molecular mimic between Der p 23 against allergenic sources]. / Análisis in silico del mimetismo molecular entre Der p 23 contra fuentes alergénicas.

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

OBJETIVO: Identificar, a través de análisis In Silico, el posible mimetismo molecular entre Der p 23 y antígenos de fuentes alergénicas. MÉTODOS: Se buscó identidad entre Der p 23 y proteínas de las familias de ácaros Pyroglyphidae, Acaridae, Chortoglyphidae y Echimyopodidae, a través de PSI-BLAST, y se utilizaron PRALINE y EMBOSS para los alineamientos. Los antígenos con estructura experimental resuelta se obtuvieron de Protein Data Bank, y aquellos no informados, se generaron mediante Swiss Model Server y ALPHAFOLD 2. La predicción de epítopes se realizó con el servidor Ellipro y para la visualización de los modelos en 3D, se utilizó Pymol 2.3. RESULTADOS: El análisis entre alérgenos de Pyroglyphidae y Der p 23, mostró identidad con la proteína parecida a endoquitinasa de D. pteronyssinus, y el dominio de unión a quitina tipo 2 de D. farinae, con identidades entre 85 y 100%, con coberturas de 100% y 75%, respectivamente. Los alérgenos Der f 23 y Der p 23 de D. farinae y D. pteronyssinu,s tuvieron una cobertura del 100% con identidades del 85,42% y 79,59%, respectivamente. Entre los alérgenos de Tyrophagus putrescentiae, se incluyeron la unión a quitina, glicoproteína específica del oviducto y Cda4p, las cuales tuvieron valores de identidad correspondientes al 40%, 42,22% y 34,78%, con valores de cobertura que no superan el 55%. No se encontraron resultados para Chortoglyphidae y Echimyopodidae. CONCLUSIÓN: Existe mimetismo molecular y homología estructural entre Der P 23 y alérgenos de fuentes alérgicas de las familias Pyroglyphidae y Acaridae. Se identificaron potenciales epítopes en Der p 23, los cuales podrían presentar reactividad cruzada con las proteínas de las fuentes alergénicas estudiadas, lo cual debe ser demostrado en estudios In Vitro e In Vivo. Se necesitan trabajos In Vitro e In Vivo que demuestren los resultados obtenidos en el análisis In Silico.

Antigen mimicry as an effective strategy to induce CSPG4-targeted immunity in dogs with oral melanoma: a veterinary trial.

BACKGROUND: Melanoma is the most lethal form of skin cancer in humans. Conventional therapies have limited efficacy, and overall response is still unsatisfactory considering that immune checkpoint inhibitors induce lasting clinical responses only in a low percentage of patients. This has prompted us to develop a vaccination strategy employing the tumor antigen chondroitin sulfate proteoglycan (CSPG)4 as a target. METHODS: To overcome the host's unresponsiveness to the self-antigen CSPG4, we have taken advantage of the conservation of CSPG4 sequence through phylogenetic evolution, so we have used a vaccine, based on a chimeric DNA molecule encompassing both human (Hu) and dog (Do) portions of CSPG4 (HuDo-CSPG4). We have tested its safety and immunogenicity (primary objectives), along with its therapeutic efficacy (secondary outcome), in a prospective, non-randomized, veterinary clinical trial enrolling 80 client-owned dogs with surgically resected, CSPG4-positive, stage II-IV oral melanoma. RESULTS: Vaccinated dogs developed anti-Do-CSPG4 and Hu-CSPG4 immune response. Interestingly, the antibody titer in vaccinated dogs was significantly associated with the overall survival. Our data suggest that there may be a contribution of the HuDo-CSPG4 vaccination to the improvement of survival of vaccinated dogs as compared with controls treated with conventional therapies alone. CONCLUSIONS: HuDo-CSPG4 adjuvant vaccination was safe and immunogenic in dogs with oral melanoma, with potential beneficial effects on the course of the disease. Thanks to the power of naturally occurring canine tumors as predictive models for cancer immunotherapy response, these data may represent a basis for the translation of this approach to the treatment of human patients with CSPG4-positive melanoma subtypes.

Mouse Models of Antigen Presentation in Hematopoietic Stem Cell Transplantation.

Allogeneic stem cell transplantation (alloSCT) is a curative therapy for hematopoietic malignancies. The therapeutic effect relies on donor T cells and NK cells to recognize and eliminate malignant cells, known as the graft-versus-leukemia (GVL) effect. However, off target immune pathology, known as graft-versus-host disease (GVHD) remains a major complication of alloSCT that limits the broad application of this therapy. The presentation of recipient-origin alloantigen to donor T cells is the primary process initiating GVHD and GVL. Therefore, the understanding of spatial and temporal characteristics of alloantigen presentation is pivotal to attempts to separate beneficial GVL effects from detrimental GVHD. In this review, we discuss mouse models and the tools therein, that permit the quantification of alloantigen presentation after alloSCT.

A case of Graves' disease and type 1 diabetes mellitus following SARS-CoV-2 vaccination.

Autoimmune diseases, including autoimmune endocrine diseases (AIED), are thought to develop following environmental exposure in patients with genetic predisposition. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and vaccines against it could represent new environmental triggers for AIED. We report a patient, with history of vitiligo vulgaris and 8 years of type 2 diabetes, who came to our institution because of fever, weight loss, asthenia and thyrotoxicosis occurred 4 weeks later the administration of BNT162B2 (Pfizer-BioNTech) SARS-CoV-2 vaccine. Clinical, biochemical and instrumental work-up demonstrated Graves' disease and autoimmune diabetes mellitus. The occurrence of these disorders could be explained through different mechanism such as autoimmune/inflammatory syndrome induced by adjuvants (ASIA syndrome), mRNA "self-adjuvant" effect, molecular mimicry between human and viral proteins and immune disruption from external stimuli. However further studies are needed to better understand the underlying pathogenesis of AIED following SARS-CoV-2 vaccine.

Autoimmune hepatitis after COVID-19 vaccine - more than a coincidence.

The COVID-19 pandemic is still raging across the world and vaccination is expected to lead us out of this pandemic. Although the efficacy of the vaccines is beyond doubt, safety still remains a concern. We report a case of a 65-year-old woman who experienced acute severe autoimmune hepatitis two weeks after receiving the first dose of Moderna-COVID-19 vaccine. Serum immunoglobulin G was elevated and antinuclear antibody was positive (1:100, speckled pattern). Liver histology showed a marked expansion of the portal tracts, severe interface hepatitis and multiple confluent foci of lobular necrosis. She started treatment with prednisolone, with a favorable clinical and analytical evolution. Some recent reports have been suggested that COVID-19 vaccination can lead to the development of autoimmune diseases. It is speculated that the vaccine can disturb self-tolerance and trigger autoimmune responses through cross-reactivity with host cells. Therefore, healthcare providers must remain vigilant during mass COVID-19 vaccination.

Untangling COVID-19 and autoimmunity: Identification of plausible targets suggests multi organ involvement.

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

Myocarditis With COVID-19 mRNA Vaccines.

Myocarditis has been recognized as a rare complication of coronavirus disease 2019 (COVID-19) mRNA vaccinations, especially in young adult and adolescent males. According to the US Centers for Disease Control and Prevention, myocarditis/pericarditis rates are ≈12.6 cases per million doses of second-dose mRNA vaccine among individuals 12 to 39 years of age. In reported cases, patients with myocarditis invariably presented with chest pain, usually 2 to 3 days after a second dose of mRNA vaccination, and had elevated cardiac troponin levels. ECG was abnormal with ST elevations in most, and cardiac MRI was suggestive of myocarditis in all tested patients. There was no evidence of acute COVID-19 or other viral infections. In 1 case, a cardiomyopathy gene panel was negative, but autoantibody levels against certain self-antigens and frequency of natural killer cells were increased. Although the mechanisms for development of myocarditis are not clear, molecular mimicry between the spike protein of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and self-antigens, trigger of preexisting dysregulated immune pathways in certain individuals, immune response to mRNA, and activation of immunologic pathways, and dysregulated cytokine expression have been proposed. The reasons for male predominance in myocarditis cases are unknown, but possible explanations relate to sex hormone differences in immune response and myocarditis, and also underdiagnosis of cardiac disease in women. Almost all patients had resolution of symptoms and signs and improvement in diagnostic markers and imaging with or without treatment. Despite rare cases of myocarditis, the benefit-risk assessment for COVID-19 vaccination shows a favorable balance for all age and sex groups; therefore, COVID-19 vaccination is recommended for everyone ≥12 years of age.

Viral Molecular Mimicry Influences the Antitumor Immune Response in Murine and Human Melanoma.

Molecular mimicry is one of the leading mechanisms by which infectious agents can induce autoimmunity. Whether a similar mechanism triggers an antitumor immune response is unexplored, and the role of antiviral T cells infiltrating the tumor has remained anecdotal. To address these questions, we first developed a bioinformatic tool to identify tumor peptides with high similarity to viral epitopes. Using peptides identified by this tool, we demonstrated that, in mice, preexisting immunity toward specific viral epitopes enhanced the efficacy of cancer immunotherapy via molecular mimicry in different settings. To understand whether this mechanism could partly explain immunotherapy responsiveness in humans, we analyzed a cohort of patients with melanoma undergoing anti-PD1 treatment who had a high IgG titer for cytomegalovirus (CMV). In this cohort of patients, we showed that high levels of CMV-specific antibodies were associated with prolonged progression-free survival and found that, in some cases, peripheral blood mononuclear cells (PBMC) could cross-react with both melanoma and CMV homologous peptides. Finally, T-cell receptor sequencing revealed expansion of the same CD8+ T-cell clones when PBMCs were expanded with tumor or homologous viral peptides. In conclusion, we have demonstrated that preexisting immunity and molecular mimicry could influence the response to immunotherapies. In addition, we have developed a free online tool that can identify tumor antigens and neoantigens highly similar to pathogen antigens to exploit molecular mimicry and cross-reactive T cells in cancer vaccine development.

Autoreactive T cells and their role in atopic dermatitis.

Atopic dermatitis (AD) is an itchy, non-contagious relapsing and chronic inflammatory skin disease that usually develops in early childhood. This pathology is associated with food allergy, allergic asthma, allergic rhinitis and anaphylaxis which may persist in adulthood. The underlying mechanisms of AD (endotypes) are just beginning to be discovered and show a complex interaction of various pathways including skin barrier function and immune deviation. Immune reactions to self-proteins (autoantigens) of the skin have been identified in patients with inflammatory skin diseases, such as chronic spontaneous urticaria, connective tissue disease, pemphigus vulgaris and bullous pemphigoid. IgE antibodies and T cells directed against epitopes of the skin were observed in adult patients with severe and chronic AD as well. This was associated with disease severity and suggests a progression from allergic inflammation to severe autoimmune processes against the skin. IgE-mediated autoimmunity and self-reactive T cells might accelerate the ongoing skin inflammation or might contribute to the relapsing course of the disease. However, to date, the exact mechanisms of IgE-mediated autoimmunity and self-reactive T cells in the pathophysiology of AD are still unclear. The aim of this review is to evaluate the development of (autoreactive) T cells and their response to (auto)antigens, as well as the role of the peripheral tolerance in autoimmunity in the pathophysiology of AD, including the unmet needs and gaps.

How signalling games explain mimicry at many levels: from viral epidemiology to human sociology.

Mimicry is exhibited in multiple scales, ranging from molecular, to organismal, and then to human society. 'Batesian'-type mimicry entails a conflict of interest between sender and receiver, reflected in a deceptive mimic signal. 'Müllerian'-type mimicry occurs when there is perfect common interest between sender and receiver in a particular type of encounter, manifested by an honest co-mimic signal. Using a signalling games approach, simulations show that invasion by Batesian mimics will make Müllerian mimicry unstable, in a coevolutionary chase. We use these results to better understand the deceptive strategies of SARS-CoV-2 and their key role in the COVID-19 pandemic. At the biomolecular level, we explain how cellularization promotes Müllerian molecular mimicry, and discourages Batesian molecular mimicry. A wide range of processes analogous to cellularization are presented; these might represent a manner of reducing oscillatory instabilities. Lastly, we identify examples of mimicry in human society that might be addressed using a signalling game approach.

Coronavirus-induced autoimmunity.

The pandemic of Coronavirus disease 2019 (COVID-19), caused by a new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spotlighted the link between viral infection and autoimmunity. In this review, we focus on coronavirus-induced autoimmunity based on evidence from experimental animal models, SARS-CoV infection with in vitro studies of molecular mimicry and COVID-19 with several clinical reports of autoimmune manifestations of this disease. Further studies will be needed to better characterize the role of SARS-CoV-2 in the development of autoimmunity.

Use of Virus-Mimicking Nanoparticles to Investigate Early Infection Events in Upper Airway 3D Models.

The current coronavirus disease-19 (COVID-19) pandemic, caused by "severe acute respiratory syndrome coronavirus 2" (SARS-CoV-2), underscores the threat posed by newly emerging viruses. The understanding of the mechanisms driving early infection events, that are crucial for the exponential spread of the disease, is mandatory and can be significantly implemented generating 3D in vitro models as experimental platforms to investigate the infection substrates and how the virus invades and ravages the tissues.We here describe a protocol for the creation of a synthetic hydrogel-based 3D culture system that mimics in vitro the complex architectures and mechanical cues distinctive of the upper airway epithelia. We then expose the in vitro generated 3D nasal and tracheal epithelia to gold nanoparticles (AuNPs) that display the typical shape and size distinctive of SARS-CoV-2 and of the majority of Coronaviridae presently known.The infection platform here described provides an efficient and highly physiological in vitro model that reproduces the host-pathogen early interactions, using virus-mimicking nanoparticles, and offers a flexible tool to study virus entry into the cell. At the same time, it reduces the risk of accidental infection/spillovers for researchers, which represents a crucial aspect when dealing with a virus that is highly contagious, virulent, and even deadly.

Exploring the Impact of Ketodeoxynonulosonic Acid in Host-Pathogen Interactions Using Uptake and Surface Display by Nontypeable Haemophilus influenzae.

Surface expression of the common vertebrate sialic acid (Sia) N-acetylneuraminic acid (Neu5Ac) by commensal and pathogenic microbes appears structurally to represent "molecular mimicry" of host sialoglycans, facilitating multiple mechanisms of host immune evasion. In contrast, ketodeoxynonulosonic acid (Kdn) is a more ancestral Sia also present in prokaryotic glycoconjugates that are structurally quite distinct from vertebrate sialoglycans. We detected human antibodies against Kdn-terminated glycans, and sialoglycan microarray studies found these anti-Kdn antibodies to be directed against Kdn-sialoglycans structurally similar to those on human cell surface Neu5Ac-sialoglycans. Anti-Kdn-glycan antibodies appear during infancy in a pattern similar to those generated following incorporation of the nonhuman Sia N-glycolylneuraminic acid (Neu5Gc) onto the surface of nontypeable Haemophilus influenzae (NTHi), a human commensal and opportunistic pathogen. NTHi grown in the presence of free Kdn took up and incorporated the Sia into its lipooligosaccharide (LOS). Surface display of the Kdn within NTHi LOS blunted several virulence attributes of the pathogen, including Neu5Ac-mediated resistance to complement and whole blood killing, complement C3 deposition, IgM binding, and engagement of Siglec-9. Upper airway administration of Kdn reduced NTHi infection in human-like Cmah null (Neu5Gc-deficient) mice that express a Neu5Ac-rich sialome. We propose a mechanism for the induction of anti-Kdn antibodies in humans, suggesting that Kdn could be a natural and/or therapeutic "Trojan horse" that impairs colonization and virulence phenotypes of free Neu5Ac-assimilating human pathogens.IMPORTANCE All cells in vertebrates are coated with a dense array of glycans often capped with sugars called sialic acids. Sialic acids have many functions, including serving as a signal for recognition of "self" cells by the immune system, thereby guiding an appropriate immune response against foreign "nonself" and/or damaged cells. Several pathogenic bacteria have evolved mechanisms to cloak themselves with sialic acids and evade immune responses. Here we explore a type of sialic acid called "Kdn" (ketodeoxynonulosonic acid) that has not received much attention in the past and compare and contrast how it interacts with the immune system. Our results show potential for the use of Kdn as a natural intervention against pathogenic bacteria that take up and coat themselves with external sialic acid from the environment.

Immune landscape, evolution, hypoxia-mediated viral mimicry pathways and therapeutic potential in molecular subtypes of pancreatic neuroendocrine tumours.

OBJECTIVE: A comprehensive analysis of the immune landscape of pancreatic neuroendocrine tumours (PanNETs) was performed according to clinicopathological parameters and previously defined molecular subtypes to identify potential therapeutic vulnerabilities in this disease. DESIGN: Differential expression analysis of 600 immune-related genes was performed on 207 PanNET samples, comprising a training cohort (n=72) and two validation cohorts (n=135) from multiple transcriptome profiling platforms. Different immune-related and subtype-related phenotypes, cell types and pathways were investigated using different in silico methods and were further validated using spatial multiplex immunofluorescence. RESULTS: The study identified an immune signature of 132 genes segregating PanNETs (n=207) according to four previously defined molecular subtypes: metastasis-like primary (MLP)-1 and MLP-2, insulinoma-like and intermediate. The MLP-1 subtype (26%-31% samples across three cohorts) was strongly associated with elevated levels of immune-related genes, poor prognosis and a cascade of tumour evolutionary events: larger hypoxic and necroptotic tumours leading to increased damage-associated molecular patterns (viral mimicry), stimulator of interferon gene pathway, T cell-inflamed genes, immune checkpoint targets, and T cell-mediated and M1 macrophage-mediated immune escape mechanisms. Multiplex spatial profiling validated significantly increased macrophages in the MLP-1 subtype. CONCLUSION: This study provides novel data on the immune microenvironment of PanNETs and identifies MLP-1 subtype as an immune-high phenotype featuring a broad and robust activation of immune-related genes. This study, with further refinement, paves the way for future precision immunotherapy studies in PanNETs to potentially select a subset of MLP-1 patients who may be more likely to respond.