RESUMEN
Bullous pemphigoid (BP) is the most common autoimmune bullous disease: it most commonly affects individuals over 70 years old and impacts severely on their quality of life. BP represents a paradigm for an organ-specific autoimmune disease and is characterized by circulating IgG autoantibodies to hemidesmosomal components: BP180 and BP230. While the crucial role of these autoantibodies in triggering BP inflammatory cascade is fully acknowledged, many ancillary etiological mechanisms need to be elucidated yet. Cutaneous melanoma is due to a malignant transformation of skin melanocytes, that produce and distribute pigments to surrounding keratinocytes. Melanoma is the most fatal skin cancer because of its increasing incidence and its propensity to metastasize. Several data such as: i) reported cases of concomitant melanoma and BP; ii) results from association studies; iii) BP onset following immune check-point inhibitors therapy; iv) expression of BP antigens in transformed melanocytes; and vi) circulating autoantibodies to BP antigens in melanoma patients suggest an intriguing, although unproven, possible association between melanoma and BP. However, a possible causative link is still debated and the putative pathogenetic mechanism underlying this association is unclear. This review aims to describe and discuss the possible relationship between BP and melanoma and give an overview of the speculations for or against this association. Of note, if demonstrated, this association could unwrap considerations of clinical relevance that represent new research frontiers.
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Autoanticuerpos , Autoantígenos , Melanoma , Penfigoide Ampolloso , Humanos , Penfigoide Ampolloso/inmunología , Penfigoide Ampolloso/etiología , Melanoma/inmunología , Melanoma/etiología , Autoanticuerpos/inmunología , Autoanticuerpos/sangre , Autoantígenos/inmunología , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/etiología , Colágeno Tipo XVII , Colágenos no Fibrilares/inmunología , Melanocitos/inmunología , Melanocitos/patología , Animales , Relevancia ClínicaAsunto(s)
Autoanticuerpos , Enfermedades del Colágeno , Penfigoide Ampolloso , Humanos , Penfigoide Ampolloso/diagnóstico , Penfigoide Ampolloso/inmunología , Penfigoide Ampolloso/tratamiento farmacológico , Enfermedades del Colágeno/patología , Enfermedades del Colágeno/diagnóstico , Diagnóstico Diferencial , Autoanticuerpos/sangre , Femenino , Piel/patología , Piel/inmunología , Piel/efectos de los fármacos , Anciano , Biopsia , Masculino , Valor Predictivo de las Pruebas , Autoantígenos/inmunología , LamininaRESUMEN
INTRODUCTION: In rheumatoid arthritis (RA), immunosuppressive therapies may achieve symptomatic relief, but do not induce long-term, drug-free remission. Meanwhile, the lifelong use of immunosuppressive drugs confers increased risk for malignancy and infections. As such, there is an unmet need for novel treatments that selectively target the pathogenic immune response in RA by inducing tolerance to autoantigens. Autologous cell therapy using antigen-loaded tolerogenic dendritic cells (tolDCs) aims to reinstate autoantigen-specific immunological tolerance in RA and could potentially meet this need. METHODS AND ANALYSIS: We report here the design of the phase I/II, investigator-initiated, open-label, dose-escalation trial TOLERANT. In this study, we will evaluate the intranodal administration of tolDCs in patients with RA that are in remission under immunosuppressive therapy. The tolDCs in this trial are loaded with the heat shock protein 70-derived peptide mB29a, which is an effective surrogate autoantigen in animal models of arthritis. Within this study, three dose-escalation cohorts (two intranodal injections of 5×106, 10×106 and 15×106 tolDCs), each consisting of three patients, are evaluated to identify the highest safe dose (recommended dose), and an extension cohort of nine patients will be treated with the recommended dose. The (co-)primary endpoints of this study are safety and feasibility, which we assess by the number of AEs and the successful production of tolDCs. The secondary endpoints include the immunological effects of the treatment, which we assess with a variety of high-dimensional and antigen-specific immunological assays. Clinical effects are exploratory outcomes. ETHICS AND DISSEMINATION: Ethical approval for this study has been obtained from the Netherlands Central Committee on Research Involving Human Subjects. The outcomes of the trial will be disseminated through publications in open-access, peer-reviewed scientific journals, scientific conferences and to patient associations. TRIAL REGISTRATION NUMBERS: NCT05251870; 2019-003620-20 (EudraCT); NL71296.000.20 (CCMO register).
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Artritis Reumatoide , Autoantígenos , Células Dendríticas , Humanos , Artritis Reumatoide/inmunología , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/terapia , Células Dendríticas/inmunología , Autoantígenos/inmunología , Tolerancia Inmunológica , Proteínas HSP70 de Choque Térmico/inmunología , Masculino , Femenino , Ensayos Clínicos Fase I como Asunto , Adulto , Persona de Mediana Edad , Ensayos Clínicos Fase II como Asunto , Trasplante AutólogoRESUMEN
Collagen posttranslational processing is crucial for its proper assembly and function. Disruption of collagen processing leads to tissue development and structure disorders like osteogenesis imperfecta (OI). OI-related collagen processing machinery includes prolyl 3-hydroxylase 1 (P3H1), peptidyl-prolyl cis-trans isomerase B (PPIB), and cartilage-associated protein (CRTAP), with their structural organization and mechanism unclear. We determine cryo-EM structures of the P3H1/CRTAP/PPIB complex. The active sites of P3H1 and PPIB form a face-to-face bifunctional reaction center, indicating a coupled modification mechanism. The structure of the P3H1/CRTAP/PPIB/collagen peptide complex reveals multiple binding sites, suggesting a substrate interacting zone. Unexpectedly, a dual-ternary complex is observed, and the balance between ternary and dual-ternary states can be altered by mutations in the P3H1/PPIB active site and the addition of PPIB inhibitors. These findings provide insights into the structural basis of collagen processing by P3H1/CRTAP/PPIB and the molecular pathology of collagen-related disorders.
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Colágeno , Microscopía por Crioelectrón , Ciclofilinas , Proteínas de la Matriz Extracelular , Humanos , Colágeno/metabolismo , Colágeno/química , Proteínas de la Matriz Extracelular/metabolismo , Proteínas de la Matriz Extracelular/química , Proteínas de la Matriz Extracelular/genética , Ciclofilinas/metabolismo , Ciclofilinas/química , Ciclofilinas/genética , Dominio Catalítico , Isomerasa de Peptidilprolil/metabolismo , Isomerasa de Peptidilprolil/química , Isomerasa de Peptidilprolil/genética , Procesamiento Proteico-Postraduccional , Sitios de Unión , Unión Proteica , Autoantígenos/metabolismo , Autoantígenos/química , Autoantígenos/genética , Modelos Moleculares , Mutación , Osteogénesis Imperfecta/metabolismo , Osteogénesis Imperfecta/genética , Procolágeno-Prolina Dioxigenasa/metabolismo , Procolágeno-Prolina Dioxigenasa/genética , Procolágeno-Prolina Dioxigenasa/química , Glicoproteínas de Membrana , Proteoglicanos , Chaperonas Moleculares , Prolil HidroxilasasRESUMEN
Melanoma incidence is increasing globally. Although novel therapies have improved the survival of primary melanoma patients over the past decade, the overall survival rate for metastatic melanoma remains low. In addition to traditional prognostic factors such as Breslow thickness, ulceration, and mitotic rate, novel genetic and molecular markers have been investigated. In our study, we analyzed the expression of G-protein coupled estrogen receptor 1 (GPER1) and the endodomain of collagen XVII (COL17) in relation to clinicopathological factors in primary cutaneous melanomas with known lymph node status in both sexes, using immunohistochemistry. We found, that GPER1 expression correlated with favorable clinicopathological factors, including lower Breslow thickness, lower mitotic rate and absence of ulceration. In contrast, COL17 expression was associated with poor prognostic features, such as higher tumor thickness, higher mitotic rate, presence of ulceration and presence of regression. Melanomas positive for both GPER1 and COL17 had significantly lower mean Breslow thickness and mitotic rate compared to cases positive for COL17 only. Our data indicate that GPER1 and COL17 proteins may be of potential prognostic value in primary cutaneous melanomas.
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Autoantígenos , Biomarcadores de Tumor , Colágeno Tipo XVII , Melanoma , Colágenos no Fibrilares , Receptores de Estrógenos , Receptores Acoplados a Proteínas G , Neoplasias Cutáneas , Humanos , Melanoma/patología , Melanoma/metabolismo , Femenino , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Pronóstico , Masculino , Receptores de Estrógenos/metabolismo , Persona de Mediana Edad , Biomarcadores de Tumor/metabolismo , Anciano , Colágenos no Fibrilares/metabolismo , Colágenos no Fibrilares/genética , Autoantígenos/metabolismo , Adulto , Melanoma Cutáneo Maligno , Anciano de 80 o más AñosRESUMEN
Rheumatoid arthritis (RA) is a chronic autoimmune disease with a complex etiology. Neutrophil extracellular traps (NETs are NETwork protein structures activated by neutrophils to induce the cleavage and release of DNA-protein complexes). Current studies have shown the critical involvement of NETs in the progression of autoimmune diseases, Neutrophils mostly gather in the inflammatory sites of patients and participate in the pathogenesis of autoimmune diseases in various ways. NETs, as the activated state of neutrophils, have attracted much attention in immune diseases. Many molecules released in NETs are targeted autoantigens in autoimmune diseases, such as histones, citrulline peptides, and myeloperoxidase. All of these suggest that NETs have a direct causal relationship between the production of autoantigens and autoimmune diseases. For RA in particular, as a disorder of the innate and adaptive immune response, the pathogenesis of RA is inseparable from the generation of RA. In this article, we investigate the emerging role of NETs in the pathogenesis of RA and suggest that NETs may be an important target for the treatment of inflammatory autoimmune diseases.
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Artritis Reumatoide , Progresión de la Enfermedad , Trampas Extracelulares , Neutrófilos , Trampas Extracelulares/inmunología , Trampas Extracelulares/metabolismo , Humanos , Artritis Reumatoide/inmunología , Artritis Reumatoide/metabolismo , Artritis Reumatoide/etiología , Artritis Reumatoide/patología , Neutrófilos/inmunología , Neutrófilos/metabolismo , Animales , Autoantígenos/inmunologíaRESUMEN
Autoimmune diseases (ADs) showcase the intricate balance between the immune system's protective functions and its potential for self-inflicted damage. These disorders arise from the immune system's erroneous targeting of the body's tissues, resulting in damage and disease. The ability of T cells to distinguish between self and non-self-antigens is pivotal to averting autoimmune reactions. Perturbations in this process contribute to AD development. Autoreactive T cells that elude thymic elimination are activated by mimics of self-antigens or are erroneously activated by self-antigens can trigger autoimmune responses. Various mechanisms, including molecular mimicry and bystander activation, contribute to AD initiation, with specific triggers and processes varying across the different ADs. In addition, the formation of neo-epitopes could also be implicated in the emergence of autoreactivity. The specificity of T cell responses centers on the antigen recognition sequences expressed by T cell receptors (TCRs), which recognize peptide fragments displayed by major histocompatibility complex (MHC) molecules. The assortment of TCR gene combinations yields a diverse array of T cell populations, each with distinct affinities for self and non-self antigens. However, new evidence challenges the traditional notion that clonal expansion solely steers the selection of higher-affinity T cells. Lower-affinity T cells also play a substantial role, prompting the "two-hit" hypothesis. High-affinity T cells incite initial responses, while their lower-affinity counterparts perpetuate autoimmunity. Precision treatments that target antigen-specific T cells hold promise for avoiding widespread immunosuppression. Nevertheless, detection of such antigen-specific T cells remains a challenge, and multiple technologies have been developed with different sensitivities while still harboring several drawbacks. In addition, elements such as human leukocyte antigen (HLA) haplotypes and validation through animal models are pivotal for advancing these strategies. In brief, this review delves into the intricate mechanisms contributing to ADs, accentuating the pivotal role(s) of antigen-specific T cells in steering immune responses and disease progression, as well as the novel strategies for the identification of antigen-specific cells and their possible future use in humans. Grasping the mechanisms behind ADs paves the way for targeted therapeutic interventions, potentially enhancing treatment choices while minimizing the risk of systemic immunosuppression.
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Autoantígenos , Enfermedades Autoinmunes , Autoinmunidad , Receptores de Antígenos de Linfocitos T , Linfocitos T , Humanos , Autoantígenos/inmunología , Animales , Enfermedades Autoinmunes/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores de Antígenos de Linfocitos T/genética , Linfocitos T/inmunología , Activación de Linfocitos/inmunologíaRESUMEN
Autoimmune diabetes is a disease characterized by the selective destruction of insulin-secreting ß-cells of the endocrine pancreas by islet-reactive T cells. Autoimmune disease requires a complex interplay between host genetic factors and environmental triggers that promote the activation of such antigen-specific T lymphocyte responses. Given the critical involvement of self-reactive T lymphocyte in diabetes pathogenesis, understanding how these T lymphocyte populations contribute to disease is essential to develop targeted therapeutics. To this end, several key antigenic T lymphocyte epitopes have been identified and studied to understand their contributions to disease with the aim of developing effective treatment approaches for translation to the clinical setting. In this review, we discuss the role of pathogenic islet-specific T lymphocyte responses in autoimmune diabetes, the mechanisms and cell types governing autoantigen presentation, and therapeutic strategies targeting such T lymphocyte responses for the amelioration of disease.
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Autoantígenos , Diabetes Mellitus Tipo 1 , Linfocitos T , Humanos , Diabetes Mellitus Tipo 1/inmunología , Autoantígenos/inmunología , Animales , Linfocitos T/inmunología , Epítopos de Linfocito T/inmunología , Células Secretoras de Insulina/inmunología , Autoinmunidad , Activación de Linfocitos/inmunología , Presentación de Antígeno/inmunologíaRESUMEN
BACKGROUND: In addition to primary injury, secondary injuries related to BBB disruption and immune-inflammatory response also play an important role in intracerebral hemorrhage (ICH). And the Golgi apparatus play an important role in the state of ICH. METHODS: ICH model and GM130-silencing ICH model were established in SD rats. The Garcia score was used to score the neurological defects of the rats. Blood-brain barrier (BBB) integrity were assessed by amount of extravasated Evans blue, and tight junction proteins. The expression of PD-L1 and GM130were detected through Western-blot and the subtype of microglia was showing with Immunofluorescence staining. RESULTS: Compared with the ICH group, GM130-silencing ICH rats got a worsened neurological deficit and enlarged volume of the hematoma. Evan's blue extravasation aggravated as well. The expression of GM130 in peri-hematoma tissue was further decreased, and the morphology and structure of the Golgi apparatus were further damaged. Meanwhile, the GM130 deficit resulted in decreased expression of PD-L1 and more polarization of microglia to the M1 subtype. CONCLUSION: We demonstrate that GM130 could influence the integrity of BBB and plays a role in neuroinflammation via regulation of PD-L1 after ICH. The manipulation of GM130 might be a promising therapeutical target in ICH.
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Antígeno B7-H1 , Barrera Hematoencefálica , Hemorragia Cerebral , Proteínas de la Membrana , Microglía , Animales , Masculino , Ratas , Autoantígenos , Antígeno B7-H1/metabolismo , Antígeno B7-H1/genética , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/patología , Hemorragia Cerebral/metabolismo , Hemorragia Cerebral/genética , Hemorragia Cerebral/patología , Modelos Animales de Enfermedad , Regulación hacia Abajo , Aparato de Golgi/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Microglía/metabolismo , Microglía/patología , Ratas Sprague-DawleyRESUMEN
TOR (target of rapamycin), a ubiquitous protein kinase central to cellular homeostasis maintenance, fundamentally regulates ribosome biogenesis in part by its target La-related protein 1 (LARP1). Among other target transcripts, LARP1 specifically binds TOP (terminal oligopyrimidine) mRNAs encoding all 80 ribosomal proteins in a TOR-dependent manner through its C-terminal region containing the DM15 module. Though the functional implications of the LARP1 interaction with target mRNAs is controversial, it is clear that the TOP-LARP1-TOR axis is critical to cellular health in humans. Its existence and role in evolutionarily divergent animals remain less understood. We focused our work on expanding our knowledge of the first arm of the axis: the connection between LARP1-DM15 and the 5' TOP motif. We show that the overall DM15 architecture observed in humans is conserved in fruit fly and zebrafish. Both adopt familiar curved arrangements of HEAT-like repeats that bind 5' TOP mRNAs on the same conserved surface, although molecular dynamics simulations suggest that the N-terminal fold of the fruit fly DM15 is predicted to be unstable and unfold. We demonstrate that each ortholog interacts with TOP sequences with varying affinities. Importantly, we determine that the ability of the DM15 region to bind some TOP sequences but not others might amount to the context of the RNA structure, rather than the ability of the module to recognize some sequences but not others. We propose that TOP mRNAs may retain similar secondary structures to regulate LARP1 DM15 recognition.
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Autoantígenos , Evolución Molecular , Ribonucleoproteínas , Antígeno SS-B , Ribonucleoproteínas/metabolismo , Ribonucleoproteínas/genética , Ribonucleoproteínas/química , Autoantígenos/metabolismo , Autoantígenos/genética , Autoantígenos/química , Animales , Humanos , Pez Cebra/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Simulación de Dinámica Molecular , Secuencia de Aminoácidos , Unión ProteicaRESUMEN
To broadly measure the spectrum of cellular self-antigens for natural killer T cells (NKT), we developed a sensitive lipidomics system to analyze lipids trapped between CD1d and NKT T cell receptors (TCRs). We captured diverse antigen complexes formed in cells from natural endogenous lipids, with or without inducing endoplasmic reticulum (ER) stress. After separating protein complexes with no, low, or high CD1d-TCR interaction, we eluted lipids to establish the spectrum of self-lipids that facilitate this interaction. Although this unbiased approach identified fifteen molecules, they clustered into only two related groups: previously known phospholipid antigens and unexpected neutral lipid antigens. Mass spectrometry studies identified the neutral lipids as ceramides, deoxyceramides, and diacylglycerols, which can be considered headless lipids because they lack polar headgroups that usually form the TCR epitope. The crystal structure of the TCR-ceramide-CD1d complex showed how the missing headgroup allowed the TCR to predominantly contact CD1d, supporting a model of CD1d autoreactivity. Ceramide and related headless antigens mediated physiological TCR binding affinity, weak NKT cell responses, and tetramer binding to polyclonal human and mouse NKT cells. Ceramide and sphingomyelin are oppositely regulated components of the "sphingomyelin cycle" that are altered during apoptosis, transformation, and ER stress. Thus, the unique molecular link of ceramide to NKT cell response, along with the recent identification of sphingomyelin blockers of NKT cell activation, provide two mutually reinforcing links for NKT cell response to sterile cellular stress conditions.
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Antígenos CD1d , Lipidómica , Células T Asesinas Naturales , Receptores de Antígenos de Linfocitos T , Células T Asesinas Naturales/inmunología , Células T Asesinas Naturales/metabolismo , Antígenos CD1d/inmunología , Antígenos CD1d/metabolismo , Animales , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Ratones , Lipidómica/métodos , Humanos , Autoantígenos/inmunología , Autoantígenos/metabolismo , Ceramidas/metabolismo , Ceramidas/inmunología , Lípidos/química , Lípidos/inmunología , Estrés del Retículo Endoplásmico/inmunologíaRESUMEN
Posttranslational modifications can enhance immunogenicity of self-proteins. In several conditions, including hypertension, systemic lupus erythematosus, and heart failure, isolevuglandins (IsoLGs) are formed by lipid peroxidation and covalently bond with protein lysine residues. Here, we show that the murine class I major histocompatibility complex (MHC-I) variant H-2Db uniquely presents isoLG-modified peptides and developed a computational pipeline that identifies structural features for MHC-I accommodation of such peptides. We identified isoLG-adducted peptides from renal proteins, including sodium glucose transporter 2, cadherin 16, Kelch domain-containing protein 7A, and solute carrier family 23, that are recognized by CD8+ T cells in tissues of hypertensive mice, induce T cell proliferation in vitro, and prime hypertension after adoptive transfer. Finally, we find patterns of isoLG-adducted antigen restriction in class I human leukocyte antigens that are similar to those in murine analogs. Thus, we have used a combined computational and experimental approach to define likely antigenic peptides in hypertension.
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Modelos Animales de Enfermedad , Hipertensión , Procesamiento Proteico-Postraduccional , Animales , Hipertensión/inmunología , Hipertensión/metabolismo , Hipertensión/patología , Ratones , Humanos , Linfocitos T CD8-positivos/inmunología , Autoantígenos/inmunología , Autoantígenos/metabolismo , Antígenos H-2/inmunología , Antígenos H-2/genética , Antígenos H-2/metabolismo , Péptidos/inmunología , Péptidos/metabolismoRESUMEN
Autoimmune hepatitis (AIH) is a severe hepatopathy characterized by hypergammaglobulinemia, presence of serum autoantibodies and histological appearance of interface hepatitis. Liver damage in AIH is initiated by the presentation of a liver autoantigen to uncommitted Th0 lymphocytes, followed by a cascade of effector immune responses culminating with the production of inflammatory cytokines, activation of cytotoxic cells and subsequent hepatocyte injury. B cells actively participate in AIH liver damage by presenting autoantigens to uncommitted T lymphocytes. B cells also undergo maturation into plasma cells that are responsible for production of immunoglobulin G and autoantibodies, which mediate antibody dependent cell cytotoxicity. Perpetuation of effector immunity with consequent progression of liver damage is permitted by impairment in regulatory T cells (Tregs), a lymphocyte subset central to the maintenance of immune homeostasis. Treg impairment in AIH is multifactorial, deriving from numerical decrease, reduced suppressive function, poor response to IL-2 and less stable phenotype. In this review, we discuss the role of B and T lymphocytes in the pathogenesis of AIH. Immunotherapeutic strategies that could limit inflammation and halt disease progression while reconstituting tolerance to liver autoantigens are also reviewed and discussed.
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Linfocitos B , Hepatitis Autoinmune , Humanos , Hepatitis Autoinmune/inmunología , Hepatitis Autoinmune/patología , Linfocitos B/inmunología , Animales , Autoantígenos/inmunología , Linfocitos T/inmunología , Linfocitos T Reguladores/inmunología , Autoanticuerpos/inmunologíaRESUMEN
BACKGROUND: During infection with the Lyme arthritis (LA) pathogen Borrelia burgdorferi, T-cell responses to both host and pathogen are dysregulated, resulting in chronic infection and frequent development of autoimmunity. METHODS: To assess CD4+ T-cell epitopes presented during development of LA, we used an unbiased, immunopeptidomics approach to characterize the major histocompatibility complex (MHC) class II immunopeptidome in B burgdorferi-infected C57BL/6 (B6) mice, which develop mild, self-limiting LA, and infected B6 Il10-/- mice, which develop severe, persistent LA at 0, 4, and 16 weeks postinfection (22-23 mice per group). RESULTS: Peptides derived from proteins involved in adaptive T- and B-cell responses and cholesterol metabolism, including human Lyme autoantigen apolipoprotein B-100 (apoB-100), were enriched in infected Il10-/- mice; whereas peptides derived from proteins involved in neutrophil extracellular net formation were enriched in infected B6 mice. Presentation of apoB-100 peptides showed evidence of epitope expansion during infection. Of several identified B burgdorferi peptides, only 1, a methyl-accepting chemotaxis protein peptide Mcp4442-462, was immunogenic. CONCLUSIONS: ApoB-100, a human Lyme autoantigen, undergoes marked epitope expansion during LA development. The paucity of immunogenic B burgdorferi epitopes supports previous findings suggesting CD4+ T-cell responses are suppressed in murine LA.
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Apolipoproteína B-100 , Autoantígenos , Borrelia burgdorferi , Antígenos de Histocompatibilidad Clase II , Enfermedad de Lyme , Ratones Endogámicos C57BL , Animales , Borrelia burgdorferi/inmunología , Enfermedad de Lyme/inmunología , Enfermedad de Lyme/microbiología , Ratones , Antígenos de Histocompatibilidad Clase II/inmunología , Antígenos de Histocompatibilidad Clase II/metabolismo , Apolipoproteína B-100/inmunología , Autoantígenos/inmunología , Linfocitos T CD4-Positivos/inmunología , Epítopos de Linfocito T/inmunología , Interleucina-10/metabolismo , Ratones Noqueados , Modelos Animales de Enfermedad , Femenino , HumanosRESUMEN
Autoantibody binding has a central role in autoimmune diseases and has also been linked to cancer, infections, and behavioral disorders. Autoimmune neurological diseases remain misclassified also due to an incomplete understanding of the underlying disease-specific epitopes. Such epitopes are crucial for both pathology and diagnosis, but have historically been overlooked. Recent technological advancements have enabled the exploration of these epitopes, potentially opening novel clinical avenues. The precise identification of novel B and T cell epitopes and their autoreactivity has led to the discovery of autoantigen-specific biomarkers for patients at high risk of autoimmune neurological diseases. In this review, we propose utilizing newly available synthetic and cellular-surface display technologies and guide epitope-focused studies to unlock the potential of disease-specific epitopes for improving diagnosis and treatments. Additionally, we offer recommendations to guide emerging epitope-focused studies to broaden the current landscape.
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Enfermedades Autoinmunes del Sistema Nervioso , Humanos , Animales , Enfermedades Autoinmunes del Sistema Nervioso/inmunología , Epítopos/inmunología , Autoanticuerpos/inmunología , Autoantígenos/inmunología , Enfermedades Autoinmunes/inmunología , Enfermedades del Sistema Nervioso/inmunologíaRESUMEN
The most characteristic feature of membranous nephropathy (MN) is the presence of subepithelial electron dense deposits and the consequential thickening of the glomerular basement membrane. There have been great advances in the understanding of the destiny of immune complexes in MN by the benefit of experimental models represented by Heymann nephritis. Subepithelial immune complexes are formed in situ by autoantibodies targeting native autoantigens or exogenous planted antigens such as the phospholipase A2 receptor (PLA2R) and cationic BSA respectively. The nascent immune complexes would not be pathogenic until they develop into immune deposits. Podocytes are the major source of autoantigens in idiopathic membranous nephropathy. They also participate in the modulation and removal of the immune complexes to a large extent. The balance between deposition and clearance is regulated by a wide range of factors such as the composition and physicochemical properties of the immune complexes and the complement system. Complement components such as C3 and C1q have been reported to be precipitated with the deposits whereas a complement regulatory protein CR1 expressed by podocytes is involved in the phagocytosis of immune complexes by podocytes. Podocytes regulate the dynamic change of immune complexes which is disturbed in membranous nephropathy. To elucidate the precise fate of the immune complexes is essential for developing more rational and novel therapies for membranous nephropathy.
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Complejo Antígeno-Anticuerpo , Glomerulonefritis Membranosa , Podocitos , Glomerulonefritis Membranosa/inmunología , Humanos , Complejo Antígeno-Anticuerpo/inmunología , Complejo Antígeno-Anticuerpo/metabolismo , Podocitos/inmunología , Podocitos/metabolismo , Animales , Autoanticuerpos/inmunología , Autoantígenos/inmunología , Receptores de Fosfolipasa A2/inmunologíaRESUMEN
Alport syndrome is a hereditary kidney disease caused by collagen IV mutations that interfere with the formation and deposition of the α3α4α5 protomer into the glomerular basement membrane. In this issue, Yu et al. show that the chemical chaperone tauroursodeoxycholic acid prevented kidney structural changes and function decline in mice with a pathogenic missense Col4a3 mutation by increasing mutant α3α4α5 protomer glomerular basement membrane deposition and preventing podocyte apoptosis induced by endoplasmic reticulum stress.
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Autoantígenos , Colágeno Tipo IV , Membrana Basal Glomerular , Nefritis Hereditaria , Ácido Tauroquenodesoxicólico , Nefritis Hereditaria/genética , Nefritis Hereditaria/tratamiento farmacológico , Nefritis Hereditaria/patología , Nefritis Hereditaria/metabolismo , Animales , Colágeno Tipo IV/genética , Colágeno Tipo IV/metabolismo , Ácido Tauroquenodesoxicólico/farmacología , Ácido Tauroquenodesoxicólico/uso terapéutico , Ratones , Membrana Basal Glomerular/patología , Membrana Basal Glomerular/efectos de los fármacos , Humanos , Autoantígenos/genética , Autoantígenos/metabolismo , Estrés del Retículo Endoplásmico/efectos de los fármacos , Apoptosis/efectos de los fármacos , Modelos Animales de Enfermedad , Podocitos/efectos de los fármacos , Podocitos/patología , Podocitos/metabolismo , Mutación Missense , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismoRESUMEN
Human telomerase assembly is a highly dynamic process. Using biochemical approaches, we find that LARP3 and LARP7/MePCE are involved in the early stage of human telomerase RNA (hTR) and that their binding to RNA is destabilized when the mature form is produced. LARP3 plays a negative role in preventing the processing of the 3'-extended long (exL) form and the binding of LARP7 and MePCE. Interestingly, the tertiary structure of the exL form prevents LARP3 binding and facilitates hTR biogenesis. Furthermore, low levels of LARP3 promote hTR maturation, increase telomerase activity, and elongate telomeres. LARP7 and MePCE depletion inhibits the conversion of the 3'-extended short (exS) form into mature hTR and the cytoplasmic accumulation of hTR, resulting in telomere shortening. Taken together our data suggest that LARP3 and LARP7/MePCE mediate the processing of hTR precursors and regulate the production of functional telomerase.
Asunto(s)
Autoantígenos , ARN , Ribonucleoproteínas , Antígeno SS-B , Telomerasa , Humanos , Autoantígenos/metabolismo , Autoantígenos/genética , Células HeLa , Unión Proteica , Ribonucleoproteínas/metabolismo , Ribonucleoproteínas/genética , ARN/metabolismo , ARN/genética , Telomerasa/metabolismo , Telomerasa/genética , Telómero/metabolismo , Telómero/genética , Acortamiento del TelómeroRESUMEN
OBJECTIVE: Prognostic stratification of endometrial cancer involves the assessment of stage, uterine risk factors, and molecular classification. This process can be further refined through annotation of prognostic biomarkers, notably L1 cell adhesion molecule (L1CAM) and hormonal receptors. Loss of asparaginase-like protein 1 (ASRGL1) has been shown to correlate with poor outcome in endometrial cancer. Our objective was to assess prognostication of endometrial cancer by ASRGL1 in conjunction with other available methodologies. STUDY DESIGN: This was a retrospective study of patients who underwent primary treatment at a single tertiary center. Tumors were molecularly classified by the Proactive Molecular Risk Classifier for Endometrial Cancer. Expression of ASRGL1, L1CAM, estrogen receptor, and progesterone receptor was determined by immunohistochemistry. ASRGL1 expression intensity was scored into four classes. RESULTS: In a cohort of 775 patients, monitored for a median time of 81 months, ASRGL1 expression intensity was related to improved disease-specific survival in a dose-dependent manner (P < 0.001). Low expression levels were associated with stage II-IV disease and presence of uterine factors, i.e. high grade, lymphovascular space invasion, and deep myometrial invasion (P < 0.001 for all). Among the molecular subgroups, low expression was most prevalent in p53 abnormal carcinomas (P < 0.001). Low ASRGL1 was associated with positive L1CAM expression and negative estrogen and progesterone receptor expression (P < 0.001 for all). After adjustment for stage and uterine factors, strong ASRGL1 staining intensity was associated with a lower risk for cancer-related deaths (hazard ratio 0.56, 95 % confidence interval 0.32-0.97; P = 0.038). ASRGL1 was not associated with the outcome when adjusted for stage, molecular subgroups, L1CAM, and hormonal receptors. When analyzed separately within the different molecular subgroups, ASRGL1 showed an association with disease-specific survival specifically in "no specific molecular profile" subtype carcinomas (P < 0.001). However, this association became nonsignificant upon controlling for confounders. CONCLUSIONS: Low ASRGL1 expression intensity correlates with poor survival in endometrial cancer. ASRGL1 contributes to more accurate prognostication when controlled for stage and uterine factors. However, when adjusted for stage and other biomarkers, including molecular subgroups, ASRGL1 does not improve prognostic stratification.