RESUMO
Central nervous system (CNS) infections including meningitis and encephalitis, resulting from the blood-borne spread of specific microorganisms, provoke nervous tissue damage due to the inflammatory process. Moreover, different pathologies such as sepsis can generate systemic inflammation. Bacterial lipopolysaccharide (LPS) induces the release of inflammatory mediators and damage molecules, which are then released into the bloodstream and can interact with structures such as the CNS, thus modifying the blood-brain barrier's (BBB´s) and blood-cerebrospinal fluid barrier´s (BCSFB´s) function and inducing aseptic neuroinflammation. During neuroinflammation, the participation of glial cells (astrocytes, microglia, and oligodendrocytes) plays an important role. They release cytokines, chemokines, reactive oxygen species, nitrogen species, peptides, and even excitatory amino acids that lead to neuronal damage. The neurons undergo morphological and functional changes that could initiate functional alterations to neurodegenerative processes. The present work aims to explain these processes and the pathophysiological interactions involved in CNS damage in the absence of microbes or inflammatory cells.
Assuntos
Encefalite , Doenças Neuroinflamatórias , Humanos , Inflamação/metabolismo , Encefalite/patologia , Microglia/metabolismo , Neurônios/metabolismoRESUMO
Tuberculosis (TB) of the central nervous system (CNS) presents high mortality due to brain damage and inflammation events. The formation and deposition of immune complexes (ICs) in the brain microvasculature during Mycobacterium tuberculosis (Mtb) infection are crucial for its pathobiology. The relevance of ICs to Mtb antigens in the pathogenesis of CNS-TB has been poorly explored. Here, we aimed to establish a murine experimental model of ICs-mediated brain vasculitis induced by cell wall antigens of Mtb. We administered a cell wall extract of the prototype pathogenic Mtb strain H37Rv to male BALB/c mice by subcutaneous and intravenous routes. Serum concentration and deposition of ICs onto blood vessels were determined by polyethylene glycol precipitation, ELISA, and immunofluorescence. Histopathological changes in the brain, lung, spleen, liver, and kidney were evaluated by hematoxylin and eosin staining. Our results evidenced that vasculitis developed in the studied tissues. High serum levels of ICs and vascular deposition were evident in the brain, lung, and kidneys early after the last cell wall antigen administration. Cell wall Mtb antigens induce strong type III hypersensitivity reactions and the development of systemic vasculitis with brain vascular changes and meningitis, supporting a role for ICs in the pathogenesis of TB.
Assuntos
Mycobacterium tuberculosis , Tuberculose , Vasculite , Masculino , Animais , Camundongos , Complexo Antígeno-Anticorpo , Modelos Animais de Doenças , Tuberculose/microbiologia , Antígenos de Bactérias , Parede CelularRESUMO
The α-synucleinopathies constitute a subset of neurodegenerative disorders, of which Parkinson's disease (PD) is the most common worldwide, characterized by the accumulation of misfolded α-synuclein in the cytoplasm of neurons, which spreads in a prion-like manner to anatomically interconnected brain areas. However, it is not clear how α-synucleinopathy triggers neurodegeneration. We recently developed a rat model through a single intranigral administration of the neurotoxic ß-sitosterol ß-D-glucoside (BSSG), which produces α-synucleinopathy. In this model, we aimed to evaluate the temporal pattern of levels in oxidative and nitrosative stress and mitochondrial complex I (CI) dysfunction and how these biochemical parameters are associated with neurodegeneration in different brain areas with α-synucleinopathy (Substantia nigra pars compacta, the striatum, in the hippocampus and the olfactory bulb, where α-syn aggregation spreads). Interestingly, an increase in oxidative stress and mitochondrial CI dysfunction accompanied neurodegeneration in those brain regions. Furthermore, in silico analysis suggests a high-affinity binding site for BSSG with peroxisome proliferator-activated receptors (PPAR) alpha (PPAR-α) and gamma (PPAR-γ). These findings will contribute to elucidating the pathophysiological mechanisms associated with α-synucleinopathies and lead to the identification of new early biomarkers and therapeutic targets.
Assuntos
Encéfalo , Complexo I de Transporte de Elétrons , Mitocôndrias , Estresse Oxidativo , Sinucleinopatias , alfa-Sinucleína , Animais , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Complexo I de Transporte de Elétrons/metabolismo , Mitocôndrias/metabolismo , Estresse Nitrosativo , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Ratos , Sinucleinopatias/metabolismo , Sinucleinopatias/fisiopatologia , alfa-Sinucleína/química , alfa-Sinucleína/metabolismoRESUMO
SARS-CoV-2 infection is causing a pandemic disease that is reflected in challenging public health problems worldwide. Human leukocyte antigen (HLA)-based epitope prediction and its association with disease outcomes provide an important base for treatment design. A bioinformatic prediction of T cell epitopes and their restricted HLA Class I and II alleles was performed to obtain immunogenic epitopes and HLA alleles from the spike protein of the severe acute respiratory syndrome coronavirus 2 virus. Also, a correlation with the predicted fatality rate of hospitalized patients in 28 states of Mexico was done. Here, we describe a set of 10 highly immunogenic epitopes, together with different HLA alleles that can efficiently present these epitopes to T cells. Most of these epitopes are located within the S1 subunit of the spike protein, suggesting that this area is highly immunogenic. A statistical negative correlation was found between the frequency of HLA-DRB1*01 and the fatality rate in hospitalized patients in Mexico.
Assuntos
Apresentação de Antígeno , COVID-19 , Cadeias HLA-DRB1/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , COVID-19/imunologia , COVID-19/mortalidade , Biologia Computacional , Epitopos de Linfócito T/imunologia , Variação Genética , Hospitalização , Humanos , México , Estrutura Terciária de Proteína , SARS-CoV-2/imunologiaRESUMO
OBJECTIVES: Expression of α4ß7 integrin can identify gut-homing immune cells. This study aimed to determine the expression of Toll-like receptor 2 (TLR2) and TLR4 in α4ß7-positive leukocytes of patients with axial SpA (axSpA). METHODS: We analysed the frequencies of α4ß7-positive T cells, Tγδ cells and monocytes in 14 patients with axSpA and 14 healthy controls, together with the expression of TLR2 and TLR4 by flow cytometry. Also, the concentration of faecal calprotectin was measured in all patients and controls. RESULTS: We found significantly higher percentages of α4ß7-positive T (P = 0.026) and Tγδ cells (P = 0.0118) in the patients with axSpA than in controls; these cells showed differential expression of TLR2 and TLR4 when compared with α4ß7-negative cells. Such differences were not correlated with disease activity or faecal calprotectin concentration. CONCLUSION: There is an increase in circulating α4ß7-positive T and Tγδ cells in patients with axSpA. These cells differentially express TLR2 and TLR4.
Assuntos
Monócitos/metabolismo , Espondiloartropatias/metabolismo , Subpopulações de Linfócitos T/metabolismo , Linfócitos T/metabolismo , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/metabolismo , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Integrinas/metabolismo , Complexo Antígeno L1 Leucocitário/metabolismo , Masculino , Receptores de Antígenos de Linfócitos T gama-delta/metabolismoRESUMO
Spondyloarthritis is an autoinflammatory rheumatic disease in which arthritis and osteoproliferation lead the patients who suffer from it to chronic disability. This disease is associated with the expression of class I MHC molecule HLA-B27, which tends to be misfolded in the endoplasmic reticulum and, therefore, expressed in aberrant forms. This phenomena lead to endoplasmic reticulum stress, which in time, evokes a whole response to cellular injury. Under these conditions, the molecules involved in restoring cell homeostasis play a key role. Such is the case of the "heat-shock proteins", which usually regulate protein folding, but also have important immunomodulatory functions, as well as some roles in tissue modeling. In this review, we attempt to summarize the involvement of cell stress and heat-shock proteins in the homeostatic disturbances and pathological conditions associated with this disease.
Assuntos
Autofagia Mediada por Chaperonas/imunologia , Estresse do Retículo Endoplasmático/imunologia , Antígeno HLA-B27/imunologia , Proteínas de Choque Térmico/imunologia , Espondiloartropatias/imunologia , Resposta a Proteínas não Dobradas/imunologia , Autofagia , Degradação Associada com o Retículo Endoplasmático , Antígeno HLA-B27/genética , Antígeno HLA-B27/metabolismo , Proteínas de Choque Térmico/metabolismo , Humanos , Espondiloartropatias/metabolismoRESUMO
The γδ T cells are lymphocytes with an innate-like phenotype that can distribute to different tissues to reside and participate in homeostatic functions such as pathogen defense, tissue modeling, and response to stress. These cells originate during fetal development and migrate to the tissues in a TCR chain-dependent manner. Their unique manner to respond to danger signals facilitates the initiation of cytokine-mediated diseases such as spondyloarthritis and psoriasis, which are immune-mediated diseases with a very strong link with mucosal disturbances, either in the skin or the gut. In spondyloarthritis, γδ T cells are one of the main sources of IL-17 and, therefore, the main drivers of inflammation and probably new bone formation. Remarkably, this population can be the bridge between gut and joint inflammation.
Assuntos
Receptores de Antígenos de Linfócitos T gama-delta , Espondilartrite , Humanos , Inflamação , Linfócitos T , BiologiaRESUMO
To analyze the effect of levofloxacin-induced intestinal microbiota modifications on intestinal, joint, and systemic inflammation in the DBA/1 mice with spontaneous arthritis. The study included two groups of mice, one of which received levofloxacin. The composition and structure of the microbiota were determined in the mice's stool using 16S rRNA sequencing; the differential taxa and metabolic pathway between mice treated with levofloxacin and control mice were also defied. The effect of levofloxacin was evaluated in the intestines, hind paws, and spines of mice through DNA microarray transcriptome and histopathological analyses; systemic inflammation was measured by flow cytometry. Levofloxacin decreased the pro-inflammatory bacteria, including Prevotellaceae, Odoribacter, and Blautia, and increased the anti-inflammatory Muribaculaceae in mice's stool. Histological analysis confirmed the intestinal inflammation in control mice, while in levofloxacin-treated mice, inflammation was reduced; in the hind paws and spines, levofloxacin also decreased the inflammation. Microarray showed the downregulation of genes and signaling pathways relevant in spondyloarthritis, including several cytokines and chemokines. Levofloxacin-treated mice showed differential transcriptomic profiles between peripheral and axial joints and intestines. Levofloxacin decreased the expression of TNF-α, IL-23a, and JAK3 in the three tissues, but IL-17 behaved differently in the intestine and the joints. Serum TNF-α was also reduced in levofloxacin-treated mice. Our results suggest that the microbiota modification aimed at reducing pro-inflammatory and increasing anti-inflammatory bacteria could potentially be a coadjuvant in treating inflammatory arthropathies.
Assuntos
Levofloxacino , Espondilartrite , Camundongos , Animais , Levofloxacino/farmacologia , Transcriptoma , Fator de Necrose Tumoral alfa/genética , Disbiose/microbiologia , RNA Ribossômico 16S/genética , Camundongos Endogâmicos DBA , Inflamação/tratamento farmacológico , Inflamação/genética , Inflamação/patologia , Camundongos Endogâmicos C57BLRESUMO
INTRODUCTION: Central nervous system (CNS) tuberculosis (TB) is the most severe form of TB due to its high mortality and functional sequelae. There are several differential diagnoses for TB; and, it can also cause secondary conditions, such as vasculitis. METHODOLOGY: 155 biopsies, corresponding to 155 different patients out of 5,386 registered biopsies from 2008-2013, met the criteria of unknown etiology vasculitis and evidence of cerebral vascular disease. These were analyzed to assess the presence of central nervous system TB. The selected cases were assessed with Suzaan Marais (SM) criteria for clinical tuberculosis. After that, Ziehl-Neelsen (ZN) staining and polymerase chain reaction (PCR) were performed to amplify a fragment of the insertion sequence IS6110 of M. tuberculosis. 21 patients met the criteria for definitive tuberculosis by ZN staining and PCR, and 2 met the criteria for possible tuberculosis. Tumor necrosis factor (TNF)-α, TNF-R1, and TNF-R2 were determined by immunohistochemistry in histological sections from formalin-fixed paraffin-embedded (FF-PE) tissues in the 23 selected patients. RESULTS: Granulomatous TB was present in almost half of the cases. TNF-R1 and TNF-R2 were expressed mainly in blood vessels, histiocytes, and macrophages. TNF-R2 expression was higher than the other markers, which suggests an anti-inflammatory response against M. tuberculosis. CONCLUSIONS: The histopathological presentation of TB is not always limited to granulomas, abscesses, or meningitis; there are also clinical presentations characterized only with chronic inflammation of nervous and vascular tissue.
Assuntos
Mycobacterium tuberculosis , Tuberculose , Vasculite , Humanos , Receptores Tipo I de Fatores de Necrose Tumoral , Receptores Tipo II do Fator de Necrose Tumoral , Tuberculose/diagnóstico , Fator de Necrose Tumoral alfa , Vasculite/complicaçõesRESUMO
Spondyloarthritis (SpA) is a group that includes a wide spectrum of clinically similar diseases manifested by oligoarticular arthritis and axial or peripheral ankylosis. Although axial SpA is predominant in Caucasians and adult-onset patients, juvenile-onset and Latin American patients are characterized by severe peripheral arthritis and particularly foot involvement. The peripheral involvement of SpA can vary from tarsal arthritis to the most severe form named ankylosing tarsitis (AT). Although the cause and etiopathogenesis of axSpA are often studied, the specific characteristics of pSpA are unknown. Several animal models of SpA develop initial tarsitis and foot ankylosis as the main signs, emphasizing the role of foot inflammation in the overall SpA spectrum. In this review, we attempt to highlight the clinical characteristics of foot involvement in SpA and update the knowledge regarding its pathogenesis, focusing on animal models and the role of mechanical forces in inflammation.