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Background: Chronic obstructive pulmonary disease (COPD) has been linked to immune responses to lung-associated self-antigens. Exposure to cigarette smoke (CS), the main cause of COPD, causes chronic lung inflammation, resulting in pulmonary matrix (ECM) damage. This tissue breakdown exposes collagen V (Col V), an antigen typically hidden from the immune system, which could trigger an autoimmune response. Col V autoimmunity has been linked to several lung diseases, and the induction of immune tolerance can mitigate some of these diseases. Evidence suggests that autoimmunity to Col V might also occur in COPD; thus, immunotolerance to Col V could be a novel therapeutic approach. Objective: The role of autoimmunity against collagen V in COPD development was investigated by analyzing the effects of Col V-induced tolerance on the inflammatory response and lung remodeling in a murine model of CS-induced COPD. Methods: Male C57BL/6 mice were divided into three groups: one exposed to CS for four weeks, one previously tolerated for Col V and exposed to CS for four weeks, and one kept in clean air for the same period. Then, we proceeded with lung functional and structural evaluation, assessing inflammatory cells in bronchoalveolar lavage fluid (BALF) and inflammatory markers in the lung parenchyma, inflammatory cytokines in lung and spleen homogenates, and T-cell phenotyping in the spleen. Results: CS exposure altered the structure of elastic and collagen fibers and increased the pro-inflammatory immune response, indicating the presence of COPD. Col V tolerance inhibited the onset of emphysema and prevented structural changes in lung ECM fibers by promoting an immunosuppressive microenvironment in the lung and inducing Treg cell differentiation. Conclusion: Induction of nasal tolerance to Col V can prevent inflammatory responses and lung remodeling in experimental COPD, suggesting that autoimmunity to Col V plays a role in COPD development.
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Autoinmunidad , Colágeno Tipo V , Modelos Animales de Enfermedad , Tolerancia Inmunológica , Ratones Endogámicos C57BL , Enfermedad Pulmonar Obstructiva Crónica , Animales , Enfermedad Pulmonar Obstructiva Crónica/inmunología , Ratones , Colágeno Tipo V/inmunología , Masculino , Pulmón/inmunología , Pulmón/patología , Citocinas/metabolismo , Autoantígenos/inmunologíaRESUMEN
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.
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Síndrome de Guillain-Barré , Imitación Molecular , Imitación Molecular/inmunología , Síndrome de Guillain-Barré/inmunología , Humanos , Plasmodium/inmunología , Autoantígenos/inmunología , Epítopos/inmunologíaRESUMEN
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.
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Enfermedades Cardiovasculares , Imitación Molecular , Humanos , Imitación Molecular/inmunología , Antígenos Bacterianos/inmunología , Autoantígenos/inmunología , Enfermedades Autoinmunes/inmunologíaRESUMEN
BACKGROUND: Mood disorders have been associated with risk of clinical relapses in multiple sclerosis (MS), a demyelinating disease mediated by myelin-specific T cells. OBJECTIVES: We aimed to investigate the impact of major depressive disorder (MDD) and cytokine profile of T-cells in relapsing remitting MS patients. METHODS: For our study, plasma and PBMC were obtained from 60 MS patients (30 with lifetime MDD) in remission phase. The PBMC cultures were stimulated with anti-CD3/anti-CD28 beads or myelin basic protein (MBP), and effector and regulatory T cell phenotypes were determined by flow cytometry. The cytokine levels, both in the plasma or in the supernatants collected from PBMC cultures, were quantified by Luminex. In some experiments, the effect of serotonin (5-HT) was investigated. RESULTS: Here, higher Th17-related cytokine levels in response to anti-CD3/anti-CD28 and MBP were quantified in the plasma and PBMC cultures of the MS/MDD group in comparison with MS patients. Further, elevated frequency of CD4+ and CD8+ T cells capable of producing IL-17, IL-22 and GM-CSF was observed in depressed patients. Interestingly, the percentage of myelin-specific IFN-γ+IL-17+ and IFN-γ+GM-CSF+ CD4+ T cells directly correlated with neurological disabilities. In contrast, the occurrence of MDD reduced the proportion of MBP-specific CD39+Tregs subsets. Notably, the severity of both neurological disorder and depressive symptoms inversely correlated with these Tregs. Finally, the addition of 5-HT downregulated the release of Th17-related cytokines in response to anti-CD3/anti-CD28 and myelin antigen. CONCLUSIONS: In summary, our findings suggested that recurrent major depression, by favoring imbalances of effector Th17 and Treg cell subsets, contributes to MS severity.
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Apirasa , Autoantígenos , Trastorno Depresivo Mayor , Esclerosis Múltiple , Vaina de Mielina , Linfocitos T Reguladores , Células Th17 , Apirasa/inmunología , Autoantígenos/inmunología , Linfocitos T CD8-positivos/inmunología , Citocinas/inmunología , Trastorno Depresivo Mayor/sangre , Trastorno Depresivo Mayor/diagnóstico , Trastorno Depresivo Mayor/inmunología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunología , Humanos , Interleucina-17/inmunología , Leucocitos Mononucleares/inmunología , Esclerosis Múltiple/inmunología , Vaina de Mielina/inmunología , Serotonina/inmunología , Linfocitos T Reguladores/inmunología , Células Th17/inmunologíaRESUMEN
The induction of antigen (Ag)-specific tolerance and replacement of islet ß-cells are major ongoing goals for the treatment of type 1 diabetes (T1D). Our group previously showed that a hybrid insulin peptide (2.5HIP) is a critical autoantigen for diabetogenic CD4+ T cells in the NOD mouse model. In this study, we investigated whether induction of Ag-specific tolerance using 2.5HIP-coupled tolerogenic nanoparticles (NPs) could protect diabetic NOD mice from disease recurrence upon syngeneic islet transplantation. Islet graft survival was significantly prolonged in mice treated with 2.5HIP NPs, but not NPs containing the insulin B chain peptide 9-23. Protection in 2.5HIP NP-treated mice was attributed both to the simultaneous induction of anergy in 2.5HIP-specific effector T cells and the expansion of Foxp3+ regulatory T cells specific for the same Ag. Notably, our results indicate that effector function of graft-infiltrating CD4+ and CD8+ T cells specific for other ß-cell epitopes was significantly impaired, suggesting a novel mechanism of therapeutically induced linked suppression. This work establishes that tolerance induction with an HIP can delay recurrent autoimmunity in NOD mice, which could inform the development of an Ag-specific therapy for T1D.
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Diabetes Mellitus Tipo 1/terapia , Supervivencia de Injerto/efectos de los fármacos , Insulina/administración & dosificación , Trasplante de Islotes Pancreáticos/métodos , Fragmentos de Péptidos/administración & dosificación , Animales , Autoantígenos/inmunología , Autoinmunidad/inmunología , Linfocitos T CD4-Positivos/inmunología , Diabetes Mellitus Tipo 1/prevención & control , Femenino , Islotes Pancreáticos/inmunología , Ratones , Ratones Endogámicos NOD , Nanopartículas/administración & dosificación , RecurrenciaRESUMEN
Introduction: The morphological patterns in indirect immunofluorescence assay on HEp-2 cells (HEp-2 IFA) reflect the autoantibodies in the sample. The International Consensus on ANA Patterns (ICAP) classifies 30 relevant patterns (AC-0 to AC-29). AC-4 (fine speckled nuclear pattern) is associated to anti-SS-A/Ro, anti-SS-B/La, and several autoantibodies. Anti-SS-A/Ro samples may contain antibodies to Ro60 and Ro52. A variation of AC-4 (herein designated AC-4a), characterized by myriad discrete nuclear speckles, was reported to be associated with anti-SS-A/Ro. The plain fine speckled pattern (herein designated AC-4b) seldom was associated with anti-SS-A/Ro. This study reports the experience of four expert laboratories on AC-4a and AC-4b. Methods: Anti-Ro60 monoclonal antibody A7 was used to investigate the HEp-2 IFA pattern. Records containing concomitant HEp-2 IFA and SS-A/Ro tests from Durand Laboratory, Argentina (n = 383) and Fleury Laboratory, Brazil (n = 144,471) were analyzed for associations between HEp-2 IFA patterns and disease-associated autoantibodies (DAA): double-stranded DNA, Scl-70, nucleosome, SS-B/La, Sm, and U1-RNP. A total of 381 samples from Dresden Technical University (TU-Dresden), Germany, were assayed for HEp-2 IFA and DAA. Results: Monoclonal A7 recognized Ro60 in Western blot and immunoprecipitation, and yielded the AC-4a pattern on HEp-2 IFA. Analyses from Durand Laboratory and Fleury Laboratory yielded compatible results: AC-4a was less frequent (8.9% and 2.7%, respectively) than AC-4b (26.1% and 24.2%) in HEp-2 IFA-positive samples. Reactivity to SS-A/Ro occurred in 67.6% and 96.3% of AC-4a-pattern samples against 23% and 6.8% of AC-4b pattern samples. Reciprocally, AC-4a occurred in 24% and 47.1% of anti-SS-A/Ro-positive samples, and in 3.8% and 0.1% of anti-SS-A/Ro-negative samples. Data from TU-Dresden show that the AC-4a pattern occurred in 69% of 169 anti-SS-A/Ro-monospecific samples (62% of all anti-SS-A/Ro-positive samples) and in 4% of anti-SS-A/Ro-negative samples, whereas anti-SS-A/Ro occurred in 98.3% of AC-4a samples and in 47.9% of AC-4b samples. In all laboratories, coexistence of anti-SS-B/La, but not other DAA, in anti-SS-A/Ro-positive samples did not disturb the AC-4a pattern. AC-4a was predominantly associated with anti-Ro60 antibodies. Conclusions: This study confirms the association of AC-4a pattern and anti-SS-A/Ro in opposition to the AC-4b pattern. The results of four international expert laboratories support the worldwide applicability of these AC-4 pattern variants and their incorporation into ICAP classification under codes AC-4a and AC-4b, respectively. The AC-4 pattern should be maintained as an umbrella pattern for cases in which one cannot discriminate AC-4a and AC-4b patterns. The acknowledgment of the AC-4a pattern should add value to HEp-2 IFA interpretation.
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Anticuerpos Antinucleares/análisis , Autoantígenos/inmunología , Enfermedades Autoinmunes/diagnóstico , Núcleo Celular/inmunología , Técnica del Anticuerpo Fluorescente Indirecta , ARN Citoplasmático Pequeño/inmunología , Ribonucleoproteínas/inmunología , Anticuerpos Monoclonales/inmunología , Especificidad de Anticuerpos , Argentina , Enfermedades Autoinmunes/inmunología , Brasil , Línea Celular , Consenso , Florida , Alemania , Humanos , Variaciones Dependientes del Observador , Valor Predictivo de las Pruebas , Reproducibilidad de los ResultadosRESUMEN
Toxoplasma gondii infection can trigger autoreactivity by different mechanisms. In the case of ocular toxoplasmosis, disruption of the blood-retinal barrier may cause exposure of confined retinal antigens such as recoverin. Besides, cross-reactivity can be induced by molecular mimicry of parasite antigens like HSP70, which shares 76% identity with the human ortholog. Autoreactivity can be a determining factor of clinical manifestations in the eye and in the central nervous system. We performed a prospective observational study to determine the presence of autoantibodies against recoverin and HSP70 by indirect ELISA in the serum of 65 patients with ocular, neuro-ophthalmic and congenital cerebral toxoplasmosis. We found systemic autoantibodies against recoverin and HSP70 in 33.8% and 15.6% of individuals, respectively. The presence of autoantibodies in cases of OT may be related to the severity of clinical manifestations, while in cases with CNS involvement they may have a protective role. Unexpectedly, anti-recoverin antibodies were found in patients with cerebral involvement, without ocular toxoplasmosis; therefore, we analyzed and proved cross-reactivity between recoverin and a brain antigen, hippocalcin, so the immunological phenomenon occurring in one immune-privileged organ (e.g. the central nervous system) could affect the environment of another (egg. the eye).
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Autoanticuerpos/inmunología , Autoantígenos/inmunología , Interacciones Huésped-Parásitos/inmunología , Toxoplasmosis Cerebral/inmunología , Toxoplasmosis Congénita/inmunología , Toxoplasmosis Ocular/inmunología , Adolescente , Adulto , Secuencia de Aminoácidos , Antígenos de Protozoos/inmunología , Niño , Preescolar , Reacciones Cruzadas/inmunología , Femenino , Proteínas HSP70 de Choque Térmico/química , Proteínas HSP70 de Choque Térmico/inmunología , Hipocalcina/química , Hipocalcina/inmunología , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Recoverina/química , Recoverina/inmunología , Toxoplasma/inmunología , Toxoplasmosis Cerebral/diagnóstico , Toxoplasmosis Cerebral/parasitología , Toxoplasmosis Congénita/diagnóstico , Toxoplasmosis Congénita/parasitología , Toxoplasmosis Ocular/diagnóstico , Toxoplasmosis Ocular/parasitología , Adulto JovenRESUMEN
The 78 kDa glucose-regulated protein (GRP78) is an endoplasmic reticulum (ER)-resident molecular chaperone. GRP78 is a member of the 70 kDa heat shock family of proteins involved in correcting and clearing misfolded proteins in the ER. In response to cellular stress, GRP78 escapes from the ER and moves to the plasma membrane where it (a) functions as a receptor for many ligands, and (b) behaves as an autoantigen for autoantibodies that contribute to human disease and cancer. Cell surface GRP78 (csGRP78) associates with the major histocompatibility complex class I (MHC-I), and is the port of entry for several viruses, including the predictive binding of the novel SARS-CoV-2. Furthermore, csGRP78 is found in association with partners as diverse as the teratocarcinoma-derived growth factor 1 (Cripto), the melanocortin-4 receptor (MC4R) and the DnaJ-like protein MTJ-1. CsGRP78 also serves as a receptor for a large variety of ligands including activated α2 -macroglobulin (α2 M*), plasminogen kringle 5 (K5), microplasminogen, the voltage-dependent anion channel (VDAC), tissue factor (TF), and the prostate apoptosis response-4 protein (Par-4). In this review, we discuss the mechanisms involved in the translocation of GRP78 from the ER to the cell surface, and the role of secreted GRP78 and its autoantibodies in cancer and neurological disorders.
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Enfermedades Autoinmunes del Sistema Nervioso/inmunología , COVID-19/transmisión , Proteínas de Choque Térmico/fisiología , Proteínas de Neoplasias/fisiología , Proteínas del Tejido Nervioso/fisiología , Receptores de Superficie Celular/fisiología , Receptores Virales/fisiología , SARS-CoV-2/metabolismo , Glicoproteína de la Espiga del Coronavirus/metabolismo , Autoanticuerpos/inmunología , Autoantígenos/inmunología , Enfermedades Autoinmunes del Sistema Nervioso/metabolismo , Supervivencia Celular , Chaperón BiP del Retículo Endoplásmico , Estrés del Retículo Endoplásmico/fisiología , Exosomas , Proteínas Ligadas a GPI/metabolismo , Proteínas de Choque Térmico/química , Proteínas de Choque Térmico/inmunología , Humanos , Ligandos , Invasividad Neoplásica , Proteínas de Neoplasias/inmunología , Proteínas del Tejido Nervioso/inmunología , Dominios Proteicos , Transporte de Proteínas , Transducción de Señal , Microambiente Tumoral , Respuesta de Proteína Desplegada/fisiología , Internalización del VirusRESUMEN
Human antibodies against Myelin Oligodendrocyte Glycoprotein (MOG) from immunoglobulin-G subclasses (MOG-IgG) have been recently associated with a new subgroup of neurological autoimmune diseases with distinct clinical characteristics from multiple sclerosis and neuromyelitis optica spectrum disorders. The use of MOG-IgG as a biomarker is an essential tool to assist in the diagnosis and clinical prognosis. The cell-based assay (CBA) is a methodology that expresses high levels of natively folded human MOG protein in the cell membrane being the methodology most used for clinical MOG-IgG diagnosis. However, there is still no consensus about the best approach to perform CBA to improve the results. The CBA using flow cytometry (CBA-FC) is an automated technique with objective quantification, reducing the subject of human bias that occurred at CBA using immunofluorescence (CBA-IF). In this study, we compared the performance of CBA-IF and CBA-FC as an acquisition tool analysis. The sera of 104 patients diagnosed with inflammatory Central Nervous System diseases were tested in both CBA-IF and CBA-FC. We used the dilution of 1:128 for CBA-IF and three different dilutions (1:20, 1:100, and 1:640) for CBA-FC. The CBA-FC and CBA-IF results had 88.5% agreement between assays and the CBA-IF titers by endpoint-dilution correlated with the CBA-FC titers. The highest serum dilution resulted in an increased CBA-FC specificity, but there was a reduction in the CBA-FC sensitivity. Our study showed that CBA-FC can be used in clinical practice as a diagnostic technique for MOG-IgG. In addition, in some specific cases, the combination of both techniques could be used as a tool to discriminate unspecific binding and overcome single assay limitations.
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Autoanticuerpos/sangre , Enfermedades Autoinmunes del Sistema Nervioso/diagnóstico , Citometría de Flujo/métodos , Inmunoglobulina G/sangre , Microscopía Fluorescente/métodos , Glicoproteína Mielina-Oligodendrócito/inmunología , Adulto , Autoantígenos/inmunología , Enfermedades Autoinmunes del Sistema Nervioso/sangre , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Activation of self-reactive CD8+ T cells induces a peripheral tolerance mechanism that involves loss of CD8 expression. Because genetic deficiency of Fas and Fasl causes the accumulation of double-negative (DN; CD3+ TCR-αß+ CD4- CD8-) T cells that have been proposed to derive from CD8+ cells, we decided to explore the role of Fas and FasL in self-antigen-induced CD8 downregulation. To this end, we quantified Fas and FasL induction by different stimuli and analyzed the effects of Fas/FasL deficiency during a protective immune response and after exposure to self-antigens. Our data describes how Fas and FasL upregulation differs depending on the setting of CD8 T cell activation and demonstrates that Fas/FasL signaling maintains CD8 expression during repetitive antigen stimulation and following self-antigen encounter. Together, our results reveal an unexpected role of Fas/FasL signaling and offer a new insight into the role of these molecules in the regulation of immune tolerance.
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Autoantígenos/metabolismo , Antígenos CD8/metabolismo , Linfocitos T CD8-positivos/metabolismo , Proteína Ligando Fas/metabolismo , Tolerancia Inmunológica , Activación de Linfocitos , Receptor fas/metabolismo , Traslado Adoptivo , Animales , Autoantígenos/inmunología , Antígenos CD8/inmunología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/trasplante , Células Cultivadas , Regulación hacia Abajo , Proteína Ligando Fas/genética , Proteína Ligando Fas/inmunología , Cinética , Ratones Endogámicos C57BL , Ratones Transgénicos , Fenotipo , Transducción de Señal , Receptor fas/genética , Receptor fas/inmunologíaRESUMEN
INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic is a major worldwide health disorder. There is an increasing number of neurological complications recognized with COVID-19 including patients with GBS and its variants. DEVELOPMENT: A review of the clinical cases of GBS associated to COVID-19 infection published in the last months has been developed. We included 48 patients (31 men, mean age 56.4 years). The most common COVID-19 symptoms were cough (60.4%) and fever (56.3%). Mean time from COVID-19 symptoms to neurologic manifestations was 12.1 days, but in nine patients (18.8%) developed GBS within seven days. Eleven patients (22.9%) presented cranial nerve involvement in the absence of muscle weakness; 36 presented the classic sensory motor variant (75%) and one had a pure motor variant (2.1%). The electrodiagnostic pattern was considered demyelinating in 82.4% of the generalized variants. The presence of hyposmia/dysgeusia was associated with a latency shorter than seven days to GBS onset of symptoms (30% vs 15.6%), and cranial nerve involvement in the absence of weakness (30.8% vs 17.1%). Most patients (87.5%) were treated with intravenous immunoglobulin. Neurological outcome was favorable in 64.6%; 29.2% had respiratory failure and 4.2% died shortly after being admitted. CONCLUSIONS: GBS in patients with SARS-CoV-2 infection resembles clinically and electrophysiology the classical forms. Further studies are necessary to understand whether GBS frequency is actually increased due to SARS-CoV-2 infection and explore pathogenic mechanisms.
TITLE: Síndrome de Guillain-Barré asociado a infección por COVID-19: revisión de casos publicados.Introducción. La pandemia por la enfermedad por coronavirus 2019 (COVID-19) es un importante problema para la salud mundial. Hay un incremento en las complicaciones neurológicas reconocidas por la COVID-19, incluyendo el síndrome de Guillain-Barré (SGB) y sus variantes. Desarrollo. Se realizó una revisión de los casos publicados en los últimos meses de SGB asociado a infección por COVID-19. Incluimos a 48 pacientes (31 hombres; edad media: 56,4 años). Los síntomas de COVID-19 más comunes fueron tos (60,4%) y fiebre (56,3%). El tiempo promedio entre los síntomas de COVID-19 y el SGB fue de 12,1 días, pero nueve pacientes (18,8%) desarrollaron SGB en menos de siete días. Once pacientes (22,9%) presentaron afectación de los nervios craneales en ausencia de debilidad muscular, 36 presentaron la variante clásica sensitivomotora (75%) y uno tuvo una variante motora pura (2,1%). El patrón electrofisiológico se consideró desmielinizante en el 82,4% de las variantes generalizadas. La presencia de hiposmia/disgeusia estuvo asociada con una latencia menor a los siete días hasta el inicio de los síntomas del SGB (30 frente a 15,6%) y a la afectación de los nervios craneales en ausencia de debilidad (30,8 frente a 17,1%). La mayoría de los pacientes (87,5%) fueron tratados con inmunoglobulina endovenosa. La evolución neurológica fue favorable en el 64,6%, el 29,2% tuvo insuficiencia respiratoria y hubo un 4,2% de muertes. Conclusiones. El SGB en pacientes con infección por SARS-CoV-2 es similar clínica y electrofisiológicamente a las formas clásicas. Se requieren más estudios para comprender si la frecuencia del SGB realmente aumentó debido a la pandemia por COVID-19 y explorar los mecanismos patógenos involucrados.
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COVID-19/complicaciones , Síndrome de Guillain-Barré/etiología , Pandemias , SARS-CoV-2 , Adolescente , Adulto , Anciano , Anosmia/etiología , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Autoantígenos/inmunología , Enfermedades de los Nervios Craneales/etiología , Disgeusia/etiología , Femenino , Gangliósidos/inmunología , Síndrome de Guillain-Barré/líquido cefalorraquídeo , Síndrome de Guillain-Barré/inmunología , Síndrome de Guillain-Barré/terapia , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Masculino , Persona de Mediana Edad , Plasmaféresis , Insuficiencia Respiratoria/etiología , Estudios Retrospectivos , Evaluación de Síntomas , Resultado del Tratamiento , Adulto JovenRESUMEN
Acute poststreptococcal GN (APSGN) is the prototype of immune complex GN and is associated with manifestations of autoimmune reactivity that have been neglected as epiphenomena. Recently, studies have demonstrated transient antifactor B autoantibodies that activate the alternative complement pathway, bringing self-immunity to a central position in the pathogenesis of APSGN. Therefore, examining other manifestations of autoimmunity that have been reported in association with poststreptococcal GN is of interest. This article reviews the renal and extrarenal manifestations of autoimmune reactivity in APSGN and considers their potential relevance in modifying the usually benign clinical course of the disease. It also discusses related aspects of the nephritogenic antigens, complement activation, and genetic elements associated with immune reactivity and their potential relevance to the familial incidence of the disease.
Asunto(s)
Autoinmunidad , Glomerulonefritis/etiología , Glomerulonefritis/inmunología , Infecciones Estreptocócicas/complicaciones , Antígenos Bacterianos/inmunología , Autoanticuerpos/inmunología , Autoantígenos/inmunología , Autoinmunidad/genética , Vía Alternativa del Complemento , Estudios de Asociación Genética , Glomerulonefritis/microbiología , Humanos , Glomérulos Renales/inmunología , Glomérulos Renales/microbiología , Modelos Inmunológicos , Infecciones Estreptocócicas/inmunología , Infecciones Estreptocócicas/microbiología , Streptococcus/inmunología , Streptococcus/patogenicidadRESUMEN
The current paradigm of onset and progression of periodontitis includes oral dysbiosis directed by inflammophilic bacteria, leading to altered resolution of inflammation and lack of regulation of the inflammatory responses. In the construction of explanatory models of the etiopathogenesis of periodontal disease, autoimmune mechanisms were among the first to be explored and historically, for more than five decades, they have been described in an isolated manner as part of the tissue damage process observed in periodontitis, however direct participation of these mechanisms in the tissue damage is still controversial. Autoimmunity is affected by genetic and environmental factors, leading to an imbalance between the effector and regulatory responses, mostly associated with failed resolution mechanisms. However, dysbiosis/infection and chronic inflammation could trigger autoimmunity by several mechanisms including bystander activation, dysregulation of toll-like receptors, amplification of autoimmunity by cytokines, epitope spreading, autoantigens complementarity, autoantigens overproduction, microbial translocation, molecular mimicry, superantigens, and activation or inhibition of receptors related to autoimmunity by microorganisms. Even though autoreactivity in periodontitis is biologically plausible, the associated mechanisms could be related to non-pathologic responses which could even explain non-recognized physiological functions. In this review we shall discuss from a descriptive point of view, the autoimmune mechanisms related to periodontitis physio-pathogenesis and the participation of oral dysbiosis on local periodontal autoimmune responses as well as on different systemic inflammatory diseases.
Asunto(s)
Autoinmunidad , Disbiosis/inmunología , Interacciones Huésped-Patógeno/inmunología , Microbiota/inmunología , Animales , Autoanticuerpos/inmunología , Autoantígenos/inmunología , Enfermedades Autoinmunes/etiología , Enfermedades Autoinmunes/metabolismo , Biomarcadores , Citocinas/metabolismo , Susceptibilidad a Enfermedades , Epigénesis Genética , Epítopos/inmunología , Humanos , Periodontitis/etiología , Periodontitis/metabolismo , Porphyromonas gingivalis/inmunología , Receptores Inmunológicos/metabolismoRESUMEN
Unexpected anti-red blood cell (RBC) alloantibodies are routinely investigated in immunohematology and blood banking since their existence in pregnant women may induce haemolytic disease of the foetus and newborn, and their presence in donors may induce haemolytic transfusion reactions or hyperacute rejection in solid organ transplantation. Unexpected anti-RBC alloantibodies may target antigens of the most blood types excluding the expected antibodies targeting the ABO antigens. Their incidence in humans was originally linked to alloimmunization events such as blood transfusions, transplants, or pregnancies. But later, many findings revealed their existence in pathogenic processes such as malignancies, infections, and autoimmune diseases; and usually (but not always) associated to autoimmune haemolytic anaemia (AIHA). Nevertheless, unexpected anti-RBC autoantibodies are also occasionally found in healthy individuals in the absence of AIHA and with no history of alloimmunization or the associated pathologic processes. Hence, they are generally known as non-clinically significant, are excluded for typification and called "silent red blood cell autoantibodies (SRBCAA)". This review highlights evidence related to genetic predisposition, molecular mimicry, immune dysregulation, and immune tolerance loss surrounding the existence of anti-RBC antibodies, describing the presence of SRBCAA as possible early witnesses of the development of autoimmune diseases.
Asunto(s)
Anemia Hemolítica Autoinmune/sangre , Anemia Hemolítica Autoinmune/etiología , Autoanticuerpos/inmunología , Eritrocitos/inmunología , Anemia Hemolítica Autoinmune/diagnóstico , Autoanticuerpos/sangre , Autoantígenos/inmunología , Enfermedades Autoinmunes/etiología , Autoinmunidad , Susceptibilidad a Enfermedades , Humanos , Tolerancia InmunológicaRESUMEN
TITLE: Síndrome del área postrema aislado con anticuerpos anti-MOG, una asociación poco frecuente.
Asunto(s)
Área Postrema/inmunología , Autoanticuerpos/inmunología , Autoantígenos/inmunología , Enfermedades Autoinmunes Desmielinizantes SNC/inmunología , Glicoproteína Mielina-Oligodendrócito/inmunología , Especificidad de Anticuerpos , Área Postrema/diagnóstico por imagen , Autoanticuerpos/sangre , Enfermedades Autoinmunes Desmielinizantes SNC/diagnóstico por imagen , Enfermedades Autoinmunes Desmielinizantes SNC/tratamiento farmacológico , Femenino , Hipo/etiología , Humanos , Inmunosupresores/uso terapéutico , Imagen por Resonancia Magnética , Persona de Mediana Edad , Náusea/etiología , Neuritis Óptica/etiología , Prednisona/uso terapéutico , Rituximab/uso terapéutico , Síndrome , Vómitos/etiologíaRESUMEN
OBJECTIVES: To assess the presence of self-reactive immune responses to seminal and prostate antigens (PAg), biomarkers of inflammation of the male genital tract, and semen quality parameters in patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). PATIENTS, SUBJECTS AND METHODS: Peripheral blood and semen samples were collected from patients with CP/CPPS and age-matched healthy control volunteers. We analysed the lymphoproliferative responses of peripheral blood mononuclear cells (PBMC) to different seminal plasma (SP)-derived and purified PAg, serum autoantibodies specific to PAg, leucocyte subpopulations, and inflammatory cytokines in semen, sperm apoptosis/necrosis, and semen quality parameters. RESULTS: Significantly greater PBMC proliferative responses specific to PAg, with elevated secretion of interferon (IFN)γ and interleukin (IL)-17, were detected in the patients with CP/CPPS vs the controls. Moreover, the patients with CP/CPPS had significantly greater serum immunoglobulin G immune reactivity to SP proteins, such as prostate-specific antigen and prostatic acid phosphatase, than the controls. Inflammation of the male genital tract was exemplified by high levels of IFNγ, IL-17, IL-1ß and IL-8, as well as higher counts of leukocytes, mainly CD4 T lymphocytes and macrophages, in the semen. In addition, this local inflammation was associated with an overall diminished semen quality, i.e., reduced sperm concentration, motility and viability; and higher levels of sperm apoptosis/necrosis in patients with CP/CPPS vs controls. CONCLUSION: Patients with CP/CPPS show T helper type 1 (Th1) and Th17 immune responses specific to PAg associated with chronic inflammation of the male genital tract and reduced semen quality. These immune responses may underlie the induction and development of chronic pelvic pain and inflammation of the male genital tract, which in turn could alter normal prostate functioning and impair semen quality.
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Autoantígenos/inmunología , Próstata/inmunología , Prostatitis/inmunología , Prostatitis/fisiopatología , Análisis de Semen , Semen/inmunología , Células TH1/inmunología , Células Th17/inmunología , Adulto , Proliferación Celular , Humanos , Leucocitos Mononucleares/citología , Leucocitos Mononucleares/inmunología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Prostatitis/sangreRESUMEN
Miller-Fisher syndrome and Bickerstaff brainstem encephalitis, among others, constitute the anti-GQ1b syndrome, with a common immune pathophysiologic pathway characterized by the presence of anti-GQ1b antibodies, which react against the different nervous system GQ1b sites according to their different accessibility. The Miller-Fisher syndrome has a prevalence of 0.09 cases per 100 000 people-year but there are not epidemiological studies about Bickerstaff brainstem encephalitis, that it seems to be less frequent. In spite of having a good natural outcome, the immunoglobulin administration has been established as efficacious at improving it. A twelveyear- old boy suffering from Miller-Fisher-Bickerstaff syndrome after an acute Campylobacter jejuni diarrhea with positive titers of anti-GQ1b and anti-QGT1a antibodies is presented. We communicate a very uncommon pediatric disease with the aim of warning about the importance of its early suspicion and the need of specific laboratory determinations.
El síndrome anti-GQ1b reúne el síndrome de Miller-Fisher y la encefalitis del tronco cerebral de Bickerstaff, entre otras entidades. Tienen etiopatogenia común, constituida por la presencia de anticuerpos anti-GQ1b que reaccionan contra los sitios GQ1b del sistema nervioso según sea su accesibilidad. La prevalencia anual del síndrome de Miller-Fisher es de 0,09 casos por 100 000 habitantes por año y no existen estudios epidemiológicos sobre la encefalitis del tronco cerebral de Bickerstaff, que sería menos frecuente. De evolución natural hacia la mejoría, se beneficia del tratamiento con gammaglobulina endovenosa. Se presenta a un paciente de 12 años con síndrome de Miller- FisherBickerstaff tras un episodio de diarrea aguda por Campylobacter jejuni en el que los anticuerpos anti-GQ1b resultaron positivos. Es nuestro objetivo comunicar sobre un síndrome de presentación poco habitual en pediatría a fin de advertir acerca de la necesidad de su sospecha precoz y solicitud de estudios de laboratorio específicos.
Asunto(s)
Autoanticuerpos/inmunología , Autoantígenos/inmunología , Encefalitis/diagnóstico , Gangliósidos/inmunología , Síndrome de Miller Fisher/diagnóstico , Autoanticuerpos/sangre , Autoantígenos/sangre , Biomarcadores/sangre , Niño , Encefalitis/sangre , Encefalitis/inmunología , Encefalitis/fisiopatología , Humanos , Masculino , Síndrome de Miller Fisher/sangre , Síndrome de Miller Fisher/inmunología , Síndrome de Miller Fisher/fisiopatología , SíndromeRESUMEN
Fogo selvagem (FS) is a blistering skin disease caused by pathogenic IgG4 autoantibodies to desmoglein 1 (DSG1). Preclinical FS and leishmaniasis are endemic to certain regions of Brazil and exhibit nonpathogenic anti-DSG1 antibodies. Recurring bites from Lutzomyia longipalpis, the sand fly vector of leishmaniasis, immunize individuals with L. longipalpis salivary antigens LJM17 and LJM11. We measured the antibody responses to LJM17, LJM11, and DSG1 in normal settlers and patients with FS from an endemic focus of FS and nonendemic control populations. We also immunized mice with these antigens and assessed the IgG response. Healthy individuals and patients with FS from endemic areas had significantly higher values of IgG4 anti-LJM17 antibodies than nonendemic controls (P < 0.001 for both). The levels of IgG anti-DSG1 and IgG4 anti-LJM17 and anti-LJM11 antibodies correlated positively in normal settlers and patients with FS. Mice immunized with recombinant LJM17 produced IgG1 antibodies (human IgG4 homolog) that strongly cross-reacted with recombinant DSG1; these IgG1 antibodies were inhibited by LJM17, LJM11, and DSG1 in a dose-dependent manner. However, they did not bind human or mouse epidermis by indirect immunofluorescence. Lastly, we identified short-sequence homologies of surface-exposed residues within the human DSG1 ectodomain and LJM17. Inoculation by LJM17 from L. longipalpis-elicited DSG1-cross-reactive IgG4 antibodies may lead to FS in genetically predisposed individuals.
Asunto(s)
Mordeduras y Picaduras/inmunología , Desmogleína 1/inmunología , Proteínas de Insectos/inmunología , Pénfigo/inmunología , Psychodidae/inmunología , Animales , Autoanticuerpos/inmunología , Autoantígenos/inmunología , Mordeduras y Picaduras/epidemiología , Mordeduras y Picaduras/patología , Brasil/epidemiología , Reacciones Cruzadas , Modelos Animales de Enfermedad , Enfermedades Endémicas , Epidermis/inmunología , Epidermis/patología , Humanos , Insectos Vectores/inmunología , Insectos Vectores/parasitología , Leishmaniasis Cutánea/epidemiología , Leishmaniasis Cutánea/inmunología , Leishmaniasis Cutánea/parasitología , Ratones , Pénfigo/epidemiología , Pénfigo/patología , Psychodidae/parasitología , Proteínas Recombinantes/inmunología , Proteínas y Péptidos Salivales/inmunologíaRESUMEN
BACKGROUND: Human proteins such as interleukin-24 (IL24), thyroperoxidase (TPO) and thyroglobulin (Tg) are targets of IgE or IgG autoantibodies. Why these proteins are recognized by autoantibodies in some patients with chronic spontaneous urticaria (CSU) or hypothyroidism is unknown. OBJECTIVE: Through in silico analysis, identify antigen patches of TPO, Tg and IL24 and compare the sequences of these human proteins with some prevalent allergens. METHODS: The amino acids sequences of IL24, thyroperoxidase and thyroglobulin were compared between them and with 22 environmental allergens. Phylogenetic studies and multiple pairing were carried out to explore the degree of protein identity and cover. The proteins without 3D structure reported in the database, were modeled by homology with "Swiss Modeller" and compared through PYMOL. Residues conserved and accessible to the solvent (rASA> 0.25) were located in the 3D model to identify possible areas of cross-reactivity and antigen binding. RESULTS: We build a 3D model of the TPO and thyroglobulin protein base on proteins closely related. Five epitopes for TPO, six for IL24 and six for thyroglobulin were predicted. The amino acid sequences of allergens from different sources (Dermatophagoides pteronyssinus, Blomia tropicalis, Betula verrucosa, Cynodon dactylon, Aspergillus fumigatus, Canis domesticus, Felis domesticus) were compared with human TPO, Tg and IL24. The cover and alignments between allergens and human proteins were low. CONCLUSION: We identify possible linear and conformational epitopes of TPO, Tg and IL24 that could be the target of IgE or IgG binding in patients with urticaria or hypothyroidism; These epitopes do not appear to be present among common environmental allergens, suggesting that autoreactivity to these human proteins are not by cross-reactivity.
Asunto(s)
Alérgenos/inmunología , Autoantígenos/inmunología , Urticaria Crónica/inmunología , Epítopos/inmunología , Hipotiroidismo/inmunología , Interleucinas/inmunología , Yoduro Peroxidasa/inmunología , Proteínas de Unión a Hierro/inmunología , Tiroglobulina/inmunología , Animales , Aspergillus fumigatus/inmunología , Autoanticuerpos/inmunología , Autoantígenos/química , Autoantígenos/clasificación , Gatos , Reacciones Cruzadas , Perros , Mapeo Epitopo , Epítopos/química , Epítopos/clasificación , Humanos , Interleucinas/química , Interleucinas/clasificación , Yoduro Peroxidasa/química , Yoduro Peroxidasa/clasificación , Proteínas de Unión a Hierro/química , Proteínas de Unión a Hierro/clasificación , Modelos Químicos , Filogenia , Tiroglobulina/química , Tiroglobulina/clasificaciónRESUMEN
BACKGROUND: Chronic spontaneous urticaria (CSU) is a heterogeneous disease with some frequent comorbidities like autoimmune diseases, drug reactions, and inducible urticaria. IgE antibodies against thyroid peroxidase (anti-TPO IgE) could be associated with some of these clinical characteristics. OBJECTIVE: To explore the clinical characteristics of CSU patients, according to the presence of anti-TPO IgE in serum. METHODS: Anti-TPO IgE levels were measured during the clinical control period (Urticaria Activity Score, 0 point) and exacerbation period (≥3 points) in 100 CSU patients. Patients with self-reported exacerbation of skin involvement by foods, nonsteroidal anti-inflammatory drugs (NSAIDs), and physical triggers underwent controlled challenge tests. RESULTS: We identified 2 groups of patients: (1) patients with anti-TPO IgE during the clinical control period or during an exacerbation, who had a higher frequency of atopy, asthma, and positive challenge test results with NSAIDs and (2) patients without anti-TPO IgE during any period, who had a higher frequency of positive challenge test results for inducible urticaria. Among the first group (anti-TPO IgE at any point), we identified 3 subgroups: patients with anti-TPO IgE during the clinical control period (n = 12); patients with anti-TPO IgE during the clinical control period and significantly increased levels during an urticaria exacerbation (n = 18); and patients with anti-TPO IgE only during an exacerbation (n = 13). None of the patients with self-reported food reactions had a positive challenge test result. CONCLUSION: Anti-TPO IgE is a useful biomarker for differentiating between clinical phenotypes of patients with CSU. Elevation of anti-TPO IgE during exacerbation periods supports an association between this autoantibody and the pathogenesis of urticaria.