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1.
Int J Mol Sci ; 22(17)2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34502105

RESUMO

The human brain and central nervous system (CNS) harbor a select sub-group of potentially pathogenic microRNAs (miRNAs), including a well-characterized NF-kB-sensitive Homo sapiens microRNA hsa-miRNA-146a-5p (miRNA-146a). miRNA-146a is significantly over-expressed in progressive and often lethal viral- and prion-mediated and related neurological syndromes associated with progressive inflammatory neurodegeneration. These include ~18 different viral-induced encephalopathies for which data are available, at least ~10 known prion diseases (PrD) of animals and humans, Alzheimer's disease (AD) and other sporadic and progressive age-related neurological disorders. Despite the apparent lack of nucleic acids in prions, both DNA- and RNA-containing viruses along with prions significantly induce miRNA-146a in the infected host, but whether this represents part of the host's adaptive immunity, innate-immune response or a mechanism to enable the invading prion or virus a successful infection is not well understood. Current findings suggest an early and highly interactive role for miRNA-146a: (i) as a major small noncoding RNA (sncRNA) regulator of innate-immune responses and inflammatory signaling in cells of the human brain and CNS; (ii) as a critical component of the complement system and immune-related neurological dysfunction; (iii) as an inducible sncRNA of the brain and CNS that lies at a critical intersection of several important neurobiological adaptive immune response processes with highly interactive associations involving complement factor H (CFH), Toll-like receptor pathways, the innate-immunity, cytokine production, apoptosis and neural cell decline; and (iv) as a potential biomarker for viral infection, TSE and AD and other neurological diseases in both animals and humans. In this report, we review the recent data supporting the idea that miRNA-146a may represent a novel and unique sncRNA-based biomarker for inflammatory neurodegeneration in multiple species. This paper further reviews the current state of knowledge regarding the nature and mechanism of miRNA-146a in viral and prion infection of the human brain and CNS with reference to AD wherever possible.


Assuntos
Encéfalo/patologia , Viroses do Sistema Nervoso Central/imunologia , Regulação da Expressão Gênica/imunologia , MicroRNAs/metabolismo , Doenças Priônicas/imunologia , Apoptose/genética , Apoptose/imunologia , Biomarcadores/análise , Biomarcadores/metabolismo , Encéfalo/imunologia , Encéfalo/virologia , Viroses do Sistema Nervoso Central/diagnóstico , Viroses do Sistema Nervoso Central/genética , Viroses do Sistema Nervoso Central/virologia , Fator H do Complemento/metabolismo , Citocinas/metabolismo , Humanos , MicroRNAs/análise , MicroRNAs/genética , NF-kappa B/metabolismo , Doenças Priônicas/diagnóstico , Doenças Priônicas/genética , Doenças Priônicas/patologia , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Receptores Toll-Like/metabolismo
2.
Int J Mol Sci ; 22(16)2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34445635

RESUMO

Currently, migraine is treated mainly by targeting calcitonin gene-related peptides, although the efficacy of this method is limited and new treatment strategies are desired. Neuroinflammation has been implicated in the pathogenesis of migraine. In patients with migraine, peripheral levels of pro-inflammatory cytokines, such as interleukin-1ß (IL-1ß) and tumor necrosis factor-α, are known to be increased. Additionally, animal models of headache have demonstrated that immunological responses associated with cytokines are involved in the pathogenesis of migraine. Furthermore, these inflammatory mediators might alter the function of tight junctions in brain vascular endothelial cells in animal models, but not in human patients. Based on clinical findings showing elevated IL-1ß, and experimental findings involving IL-1ß and both the peripheral trigeminal ganglion and central trigeminal vascular pathways, regulation of the Il-1ß/IL-1 receptor type 1 axis might lead to new treatments for migraine. However, the integrity of the blood-brain barrier is not expected to be affected during attacks in patients with migraine.


Assuntos
Barreira Hematoencefálica/patologia , Encéfalo/patologia , Permeabilidade da Membrana Celular , Inflamação/complicações , Transtornos de Enxaqueca/patologia , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo/imunologia , Humanos , Transtornos de Enxaqueca/etiologia
3.
Nat Immunol ; 22(9): 1083-1092, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34429552

RESUMO

For decades, it was commonly accepted that the brain is secluded from peripheral immune activity and is self-sufficient for its maintenance and repair. This simplistic perception was based on the presence of resident immune cells, the microglia, and barrier systems within the brain, and the assumption that the central nervous system (CNS) lacks lymphatic drainage. This view was revised with the discoveries that higher functions of the CNS, homeostasis and repair are supported by peripheral innate and adaptive immune cells. The findings of bone marrow-derived immune cells in specialized niches, and the renewed observation that a lymphatic drainage system exists within the brain, further contributed to this revised model. In this Review, we describe the immune niches within the brain, the contribution of professional immune cells to brain functions, the bidirectional relationships between the CNS and the immune system and the relevance of immune components to brain aging and neurodegenerative diseases.


Assuntos
Encéfalo/imunologia , Imunidade/fisiologia , Microglia/imunologia , Doenças Neurodegenerativas/imunologia , Envelhecimento/imunologia , Barreira Hematoencefálica/imunologia , Células da Medula Óssea/imunologia , Líquido Cefalorraquidiano/citologia , Líquido Cefalorraquidiano/imunologia , Humanos , Subpopulações de Linfócitos/imunologia , Macrófagos/imunologia
4.
Nat Microbiol ; 6(9): 1110-1117, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34341528

RESUMO

The role of the microbiota in the development and function of γδ T cells-a T cell subset characterized by a T cell receptor composed of one γ-chain and one δ-chain-has been investigated in multiple organs in mice and humans. Interactions between the microbiota and γδ T cells affect both tissue homeostasis and disease pathologies. Notably, microbiota-induced interleukin-17 (IL-17)-producing-γδ T cells can mediate a range of immunological processes, from metabolic disorders to neuroinflammation via the gut-brain axis. However, the bidirectional interactions between γδ T cells and the microbiota have not been fully determined. In this Perspective, we dissect the roles of microbiota in modulating γδ T cell development and function, and evaluate the evidence for γδ T cell selection of commensal communities. We also discuss the potential implications of these cells in health and disease and the major open questions and research avenues in the field.


Assuntos
Microbioma Gastrointestinal , Subpopulações de Linfócitos T/imunologia , Animais , Encéfalo/imunologia , Humanos , Interleucina-17/genética , Interleucina-17/imunologia , Neuroimunomodulação , Receptores de Antígenos de Linfócitos T gama-delta/genética , Receptores de Antígenos de Linfócitos T gama-delta/imunologia
5.
Int J Mol Sci ; 22(15)2021 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-34361102

RESUMO

Interactions between the intestinal microbiota, immune system and nervous system are essential for homeostasis in the gut. Inflammasomes contribute to innate immunity and brain-gut interactions, but their role in microbiota-neuro-immune interactions is not clear. Therefore, we investigated the effect of the inflammasome on visceral pain and local and systemic neuroimmune responses after antibiotic-induced changes to the microbiota. Wild-type (WT) and caspase-1/11 deficient (Casp1 KO) mice were orally treated for 2 weeks with an antibiotic cocktail (Abx, Bacitracin A and Neomycin), followed by quantification of representative fecal commensals (by qPCR), cecal short chain fatty acids (by HPLC), pathways implicated in the gut-neuro-immune axis (by RT-qPCR, immunofluorescence staining, and flow cytometry) in addition to capsaicin-induced visceral pain responses. Abx-treatment in WT-mice resulted in an increase in colonic macrophages, central neuro-immune interactions, colonic inflammasome and nociceptive receptor gene expression and a reduction in capsaicin-induced visceral pain. In contrast, these responses were attenuated in Abx-treated Casp1 KO mice. Collectively, the data indicate an important role for the inflammasome pathway in functional and inflammatory gastrointestinal conditions where pain and alterations in microbiota composition are prominent.


Assuntos
Caspase 1/fisiologia , Microbioma Gastrointestinal , Inflamassomos/imunologia , Inflamação/complicações , Neuroimunomodulação , Dor Visceral/patologia , Animais , Antibacterianos/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/imunologia , Encéfalo/microbiologia , Encéfalo/patologia , Capsaicina/toxicidade , Colo/efeitos dos fármacos , Colo/imunologia , Colo/microbiologia , Colo/patologia , Feminino , Inflamassomos/efeitos dos fármacos , Inflamação/imunologia , Inflamação/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais , Dor Visceral/etiologia , Dor Visceral/metabolismo
6.
Cells ; 10(7)2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34360004

RESUMO

Microglia are the resident immune cells of the central nervous system contributing substantially to health and disease. There is increasing evidence that inflammatory microglia may induce or accelerate brain aging, by interfering with physiological repair and remodeling processes. Many viral infections affect the brain and interfere with microglia functions, including human immune deficiency virus, flaviviruses, SARS-CoV-2, influenza, and human herpes viruses. Especially chronic viral infections causing low-grade neuroinflammation may contribute to brain aging. This review elucidates the potential role of various neurotropic viruses in microglia-driven neurocognitive deficiencies and possibly accelerated brain aging.


Assuntos
Envelhecimento , Encéfalo/fisiopatologia , Inflamação/fisiopatologia , Microglia/virologia , Viroses/fisiopatologia , Animais , Encéfalo/imunologia , Encéfalo/virologia , COVID-19/imunologia , COVID-19/fisiopatologia , COVID-19/virologia , Humanos , Inflamação/imunologia , Inflamação/virologia , Microglia/imunologia , Microglia/patologia , SARS-CoV-2/fisiologia , Viroses/imunologia , Viroses/virologia
7.
Front Immunol ; 12: 618193, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34262556

RESUMO

Corpora amylacea (CA) in the human brain are polyglucosan bodies that accumulate residual substances originated from aging and both neurodegenerative and infectious processes. These structures, which act as waste containers, are released from the brain to the cerebrospinal fluid, reach the cervical lymph nodes via the meningeal lymphatic system and may be phagocytosed by macrophages. Recent studies indicate that CA present certain neoepitopes (NEs) that can be recognized by natural antibodies of the IgM class, and although evidence of different kinds suggests that these NEs may be formed by carbohydrate structures, their precise nature is unknown. Here, we adapted standard techniques to examine this question. We observed that the preadsorption of IgMs with specific carbohydrates has inhibitory effects on the interaction between IgMs and CA, and found that the digestion of CA proteins had no effect on this interaction. These findings point to the carbohydrate nature of the NEs located in CA. Moreover, the present study indicates that, in vitro, the binding between certain natural IgMs and certain epitopes may be disrupted by certain monosaccharides. We wonder, therefore, whether these inhibitions may also occur in vivo. Further studies should now be carried out to assess the possible in vivo effect of glycemia on the reactivity of natural IgMs and, by extension, on natural immunity.


Assuntos
Envelhecimento , Carboidratos/imunologia , Epitopos/imunologia , Hipocampo/imunologia , Corpos de Inclusão/imunologia , Idoso , Idoso de 80 Anos ou mais , Astrócitos/imunologia , Encéfalo/imunologia , Encéfalo/patologia , Epitopos/metabolismo , Feminino , Humanos , Masculino
8.
J Immunol ; 207(4): 1065-1077, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34321229

RESUMO

CNS tuberculosis (CNSTB) is the most severe manifestation of extrapulmonary tuberculosis infection, but the mechanism of how mycobacteria cross the blood-brain barrier (BBB) is not well understood. In this study, we report a novel murine in vitro BBB model combining primary brain endothelial cells, Mycobacterium bovis bacillus Calmette-Guérin-infected dendritic cells (DCs), PBMCs, and bacterial Ag-specific CD4+ T cells. We show that mycobacterial infection limits DC mobility and also induces cellular cluster formation that has a similar composition to pulmonary mycobacterial granulomas. Within the clusters, infection from DCs disseminates to the recruited monocytes, promoting bacterial expansion. Mycobacterium-induced in vitro granulomas have been described previously, but this report shows that they can form on brain endothelial cell monolayers. Cellular cluster formation leads to cluster-associated damage of the endothelial cell monolayer defined by mitochondrial stress, disorganization of the tight junction proteins ZO-1 and claudin-5, upregulation of the adhesion molecules VCAM-1 and ICAM-1, and increased transmigration of bacteria-infected cells across the BBB. TNF-α inhibition reduces cluster formation on brain endothelial cells and mitigates cluster-associated damage. These data describe a model of bacterial dissemination across the BBB shedding light on a mechanism that might contribute to CNS tuberculosis infection and facilitate treatments.


Assuntos
Barreira Hematoencefálica/imunologia , Células Dendríticas/imunologia , Mycobacterium bovis/imunologia , Tuberculose/imunologia , Fator de Necrose Tumoral alfa/imunologia , Animais , Encéfalo/imunologia , Linfócitos T CD4-Positivos/imunologia , Células Endoteliais/imunologia , Granuloma/imunologia , Molécula 1 de Adesão Intercelular/imunologia , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Molécula 1 de Adesão de Célula Vascular/imunologia
9.
Inflammopharmacology ; 29(4): 1049-1059, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34241783

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can enter the central nervous system and cause several neurological manifestations. Data from cerebrospinal fluid analyses and postmortem samples have been shown that SARS-CoV-2 has neuroinvasive properties. Therefore, ongoing studies have focused on mechanisms involved in neurotropism and neural injuries of SARS-CoV-2. The inflammasome is a part of the innate immune system that is responsible for the secretion and activation of several pro-inflammatory cytokines, such as interleukin-1ß, interleukin-6, and interleukin-18. Since cytokine storm has been known as a major mechanism followed by SARS-CoV-2, inflammasome may trigger an inflammatory form of lytic programmed cell death (pyroptosis) following SARS-CoV-2 infection and contribute to associated neurological complications. We reviewed and discussed the possible role of inflammasome and its consequence pyroptosis following coronavirus infections as potential mechanisms of neurotropism by SARS-CoV-2. Further studies, particularly postmortem analysis of brain samples obtained from COVID-19 patients, can shed light on the possible role of the inflammasome in neurotropism of SARS-CoV-2.


Assuntos
COVID-19/metabolismo , Sistema Nervoso Central/metabolismo , Inflamassomos/metabolismo , Piroptose/fisiologia , SARS-CoV-2/metabolismo , Encéfalo/imunologia , Encéfalo/metabolismo , COVID-19/imunologia , Sistema Nervoso Central/imunologia , Humanos , Inflamassomos/imunologia , SARS-CoV-2/imunologia
11.
J Neuroimmunol ; 358: 577658, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34304141

RESUMO

Several neurological symptoms and complications have been described in association with COVID-19, such as anosmia, ageusia, encephalitis and Guillain-Barré syndrome. Here, we review the literature describing SARS-CoV-2-induced neurological manifestations and provide a comprehensive discussion of proposed mechanisms underlying the neurological pathophysiology. First, we analyse the neuroinvasiveness potential of the coronavirus family based on previous SARS-CoV-1 studies. Then, we describe the current evidence on COVID-19-induced nervous tissue damage, including processes behind brain vasculopathy and cytokine storm. We also discuss in detail anosmia and Guillain-Barré syndrome. Finally, we provide a summarised timeline of the main findings in the field. Future perspectives are presented, and suggestions of further investigations to clarify how SARS-COV-2 can affect the CNS.


Assuntos
Encéfalo/imunologia , COVID-19/complicações , COVID-19/imunologia , Doenças do Sistema Nervoso/etiologia , Doenças do Sistema Nervoso/imunologia , SARS-CoV-2/imunologia , Animais , Encéfalo/patologia , COVID-19/diagnóstico , Humanos , Doenças do Sistema Nervoso/diagnóstico
12.
Front Immunol ; 12: 617032, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34194419

RESUMO

Stroke is a multiphasic process, and the initial ischemic phase of neuronal damage is followed by secondary innate and adaptive responses that unfold over days after stroke, offer a longer time frame of intervention, and represent a novel therapeutic target. Therefore, revealing the distinct functions of immune cells in both brain and periphery is important for identification of immunotherapeutic targets for stroke to extend the treatment time window. In this paper an examination of the cellular dynamics of the immune response in the central nervous system (CNS) and periphery provoked by cerebral ischemia is provided. New data is presented for the number of immune cells in brain and spleen of mice during the 7 days following middle cerebral artery occlusion (MCAO). A novel analysis of the correlation among various cell types in the brain and spleen following stroke is presented. It is found that the infiltrated macrophages in the ischemic hemisphere positively correlate with neutrophils which implies their synergic effect in migrating into the brain after stroke onset. It is noted that during infiltration of adaptive immune cells, the number of neutrophils correlate positively with T cells, which suggests neutrophils contribute to T cell infiltration in the stroked brain. Furthermore, the correlation among neurological deficit and various immune cells suggests that microglia and splenic adaptive immune cells (T and B cells) are protective while infiltrating peripheral myeloid cells (macrophage and neutrophils) worsen stroke outcome. Comprehension of such immune responses post cerebral ischemia is crucial for differentiating the drivers of outcomes and also predicting the stroke outcome.


Assuntos
Isquemia Encefálica/imunologia , Encéfalo/imunologia , Infarto da Artéria Cerebral Média/imunologia , Macrófagos/imunologia , Neutrófilos/imunologia , Baço/imunologia , Linfócitos T/imunologia , Animais , Encéfalo/patologia , Movimento Celular , Modelos Animais de Doenças , Humanos , Imunidade Celular , Camundongos , Camundongos Endogâmicos C57BL , Neuroimunomodulação , Baço/patologia
13.
Fish Shellfish Immunol ; 116: 91-97, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34224855

RESUMO

The objective of this study was to analyze the efficiency of the killed vaccine against nervous necrosis virus on Acipenser stellutus. Heat inactivated VNN vaccine was administrated in 7 g juveniles of Acipenser stellutus as a laboratory model and it was included in three different adjuvants that were used as injection and immersion forms with different doses. Ten groups consisting of 30 A. stellutus fish in each group (group 1-4 with 3 replications, others with no replicate) were divided totally into 18 aquariums. Two steps of vaccination were done with a one-month interval and after that, all treatments and control groups were challenged by the virulent VNN virus. The mortality rate of immersion and injection groups were 12.9% and 19.8% respectively, compared to 100% mortality in the control group. Histopathology and immunohistochemistry findings were evaluated. According to the mortality rate one month after challenging, a low range mortality of 12.5% was seen in group 2 with no pathological lesion and negative IHC test in the brain and eye tissues, whereas 100% of the control group (unvaccinated group) died with severe vacuolation in the brain and eye tissues and also positive IHC test. The correlation assay between these results concluded that the immersion form with 75% of aquatic-specific Montanide IMS 1312 Seppic adjuvant made better immunization with no pathological sign or forming the complex of antigen-antibody in IHC assay. These findings are important because of the impossibility of injection in the larval stage and also due to the occurrence of the disease in the first stage of sturgeon life which could cause high mortality in susceptible fish in the larval stage.


Assuntos
Doenças dos Peixes/prevenção & controle , Nodaviridae/imunologia , Infecções por Vírus de RNA/prevenção & controle , Vacinas de Produtos Inativados/administração & dosagem , Vacinas Virais/administração & dosagem , Animais , Complexo Antígeno-Anticorpo , Encéfalo/imunologia , Encéfalo/patologia , Olho/imunologia , Olho/patologia , Doenças dos Peixes/imunologia , Doenças dos Peixes/patologia , Peixes/imunologia , Imuno-Histoquímica , Infecções por Vírus de RNA/imunologia , Infecções por Vírus de RNA/patologia , Infecções por Vírus de RNA/veterinária
14.
J Neuroimmunol ; 357: 577625, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34153804

RESUMO

Innate immune memory, a crucial mechanism of epigenetically mediated myeloid cell plasticity, alters subsequent immune responses majorly by two types of immunological imprinting, training, and tolerance. Recent pioneer studies provided proof-of-principle for generation of both types of innate immune memory in brain macrophage, microglial cells. This novel study was designed to investigate whether the pattern of immune response generation, induced by peripheral administration of recombinant alarmin HMGB1, alone and in combination with other recombinant cytokines, is affected by prior exposure. The experimental outcomes revealed that full length recombinant HMGB1 exposure for seven consecutive days exhibit inflammatory response as evidenced by enhanced expression of inflammatory biomarkers and neurodegeneration. In contrary, combined doses of HMGB1 and IL-1ß, for three and seven consecutive days, exhibited lower inflammatory state compared to its alone HMGB1 counterpart. The immune tolerance state was evident by microglial polarization towards non-reactive M2 state, lower astrocyte activation, epigenetic reprogramming, and decreased neurodegeneration. This is the first demonstration that HMGB1 and IL-1ß priming can differentially affect inflammation in the brain when a host is confronted with a second, third stimulus or so on. The findings were further validated by suppressing major regulators of epigenetic reprogramming, by intranasal delivery of specific siRNAs targeting those regulators. These results may provide new evidence for the involvement of recombinant endogenous cytokine induced generation of innate immune tolerance within microglial cells and indicated the possible potential role in mediating cognitive and behavioural alterations during inflammatory diseases.


Assuntos
Encéfalo/imunologia , Proteína HMGB1/imunologia , Imunidade Inata/imunologia , Interleucina-1beta/imunologia , Microglia/imunologia , Animais , Tolerância Imunológica/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C
15.
Science ; 373(6553)2021 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-34083447

RESUMO

The meninges are a membranous structure enveloping the central nervous system (CNS) that host a rich repertoire of immune cells mediating CNS immune surveillance. Here, we report that the mouse meninges contain a pool of monocytes and neutrophils supplied not from the blood but by adjacent skull and vertebral bone marrow. Under pathological conditions, including spinal cord injury and neuroinflammation, CNS-infiltrating myeloid cells can originate from brain borders and display transcriptional signatures distinct from their blood-derived counterparts. Thus, CNS borders are populated by myeloid cells from adjacent bone marrow niches, strategically placed to supply innate immune cells under homeostatic and pathological conditions. These findings call for a reinterpretation of immune-cell infiltration into the CNS during injury and autoimmunity and may inform future therapeutic approaches that harness meningeal immune cells.


Assuntos
Células da Medula Óssea/fisiologia , Doenças do Sistema Nervoso Central/imunologia , Sistema Nervoso Central/imunologia , Meninges/imunologia , Células Mieloides/fisiologia , Crânio/anatomia & histologia , Coluna Vertebral/anatomia & histologia , Animais , Medula Óssea/fisiologia , Encéfalo/citologia , Encéfalo/imunologia , Encéfalo/fisiologia , Movimento Celular , Sistema Nervoso Central/citologia , Doenças do Sistema Nervoso Central/patologia , Dura-Máter/citologia , Dura-Máter/imunologia , Dura-Máter/fisiologia , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Homeostase , Meninges/citologia , Meninges/fisiologia , Camundongos , Monócitos/fisiologia , Neutrófilos/fisiologia , Medula Espinal/citologia , Medula Espinal/imunologia , Medula Espinal/fisiologia , Traumatismos da Medula Espinal/imunologia , Traumatismos da Medula Espinal/patologia
16.
Immunity ; 54(7): 1594-1610.e11, 2021 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-34174183

RESUMO

COVID-19 can cause severe neurological symptoms, but the underlying pathophysiological mechanisms are unclear. Here, we interrogated the brain stems and olfactory bulbs in postmortem patients who had COVID-19 using imaging mass cytometry to understand the local immune response at a spatially resolved, high-dimensional, single-cell level and compared their immune map to non-COVID respiratory failure, multiple sclerosis, and control patients. We observed substantial immune activation in the central nervous system with pronounced neuropathology (astrocytosis, axonal damage, and blood-brain-barrier leakage) and detected viral antigen in ACE2-receptor-positive cells enriched in the vascular compartment. Microglial nodules and the perivascular compartment represented COVID-19-specific, microanatomic-immune niches with context-specific cellular interactions enriched for activated CD8+ T cells. Altered brain T-cell-microglial interactions were linked to clinical measures of systemic inflammation and disturbed hemostasis. This study identifies profound neuroinflammation with activation of innate and adaptive immune cells as correlates of COVID-19 neuropathology, with implications for potential therapeutic strategies.


Assuntos
Encéfalo/imunologia , Linfócitos T CD8-Positivos/imunologia , COVID-19/imunologia , Microglia/imunologia , Barreira Hematoencefálica/imunologia , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Linfócitos T CD8-Positivos/metabolismo , COVID-19/patologia , Comunicação Celular , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/patologia , Humanos , Proteínas de Checkpoint Imunológico/metabolismo , Inflamação , Ativação Linfocitária , Esclerose Múltipla/imunologia , Esclerose Múltipla/patologia , Bulbo Olfatório/imunologia , Bulbo Olfatório/metabolismo , Bulbo Olfatório/patologia , Insuficiência Respiratória/imunologia , Insuficiência Respiratória/patologia , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
17.
Int J Mol Sci ; 22(9)2021 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-34066560

RESUMO

In recent decades, researchers around the world have been studying intensively how micro-organisms that are present inside living organisms could affect the main processes of life, namely health and pathological conditions of mind or body. They discovered a relationship between the whole microbial colonization and the initiation and development of different medical disorders. Besides already known probiotics, novel products such as postbiotics and paraprobiotics have been developed in recent years to create new non-viable micro-organisms or bacterial-free extracts, which can provide benefits to the host with additional bioactivity to probiotics, but without the risk of side effects. The best alternatives in the use of probiotics and postbiotics to maintain the health of the intestinal microbiota and to prevent the attachment of pathogens to children and adults are highlighted and discussed as controversies and challenges. Updated knowledge of the molecular and cellular mechanisms involved in the balance between microbiota and immune system for the introspection on the gut-lung-brain axis could reveal the latest benefits and perspectives of applied photobiomics for health. Multiple interconditioning between photobiomodulation (PBM), probiotics, and the human microbiota, their effects on the human body, and their implications for the management of viral infectious diseases is essential. Coupled complex PBM and probiotic interventions can control the microbiome, improve the activity of the immune system, and save the lives of people with immune imbalances. There is an urgent need to seek and develop innovative treatments to successfully interact with the microbiota and the human immune system in the coronavirus crisis. In the near future, photobiomics and metabolomics should be applied innovatively in the SARS-CoV-2 crisis (to study and design new therapies for COVID-19 immediately), to discover how bacteria can help us through adequate energy biostimulation to combat this pandemic, so that we can find the key to the hidden code of communication between RNA viruses, bacteria, and our body.


Assuntos
COVID-19/imunologia , COVID-19/microbiologia , Microbioma Gastrointestinal/imunologia , Terapia com Luz de Baixa Intensidade/métodos , Probióticos/uso terapêutico , SARS-CoV-2/imunologia , Encéfalo/imunologia , Encéfalo/efeitos da radiação , COVID-19/radioterapia , COVID-19/terapia , Síndrome da Liberação de Citocina/microbiologia , Síndrome da Liberação de Citocina/radioterapia , Microbioma Gastrointestinal/efeitos da radiação , Humanos , Pulmão/imunologia , Pulmão/efeitos da radiação , Metabolômica , Fototerapia/métodos , SARS-CoV-2/efeitos da radiação
18.
Nat Immunol ; 22(7): 880-892, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099917

RESUMO

Multidimensional single-cell analyses of T cells have fueled the debate about whether there is extensive plasticity or 'mixed' priming of helper T cell subsets in vivo. Here, we developed an experimental framework to probe the idea that the site of priming in the systemic immune compartment is a determinant of helper T cell-induced immunopathology in remote organs. By site-specific in vivo labeling of antigen-specific T cells in inguinal (i) or gut draining mesenteric (m) lymph nodes, we show that i-T cells and m-T cells isolated from the inflamed central nervous system (CNS) in a model of multiple sclerosis (MS) are distinct. i-T cells were Cxcr6+, and m-T cells expressed P2rx7. Notably, m-T cells infiltrated white matter, while i-T cells were also recruited to gray matter. Therefore, we propose that the definition of helper T cell subsets by their site of priming may guide an advanced understanding of helper T cell biology in health and disease.


Assuntos
Autoimunidade , Encéfalo/imunologia , Linhagem da Célula , Encefalomielite Autoimune Experimental/imunologia , Intestinos/imunologia , Pele/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Transferência Adotiva , Animais , Autoimunidade/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Sinalização do Cálcio , Líquido Cefalorraquidiano/imunologia , Líquido Cefalorraquidiano/metabolismo , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/metabolismo , Cloridrato de Fingolimode/farmacologia , Perfilação da Expressão Gênica , Genes Codificadores dos Receptores de Linfócitos T , Células HEK293 , Humanos , Imunossupressores/farmacologia , Intestinos/efeitos dos fármacos , Microscopia Intravital , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia de Fluorescência , Esclerose Múltipla Recidivante-Remitente/genética , Esclerose Múltipla Recidivante-Remitente/imunologia , Esclerose Múltipla Recidivante-Remitente/metabolismo , Fenótipo , Estudos Prospectivos , RNA-Seq , Receptores CXCR6/genética , Receptores CXCR6/metabolismo , Receptores Purinérgicos P2X7/genética , Receptores Purinérgicos P2X7/metabolismo , Análise de Célula Única , Pele/efeitos dos fármacos , Pele/metabolismo , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Auxiliares-Indutores/metabolismo , Linfócitos T Auxiliares-Indutores/transplante , Transcriptoma
19.
Front Immunol ; 12: 624919, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33796100

RESUMO

Neuroinflammatory and neurodegenerative diseases are a major public health problem worldwide, especially with the increase of life-expectancy observed during the last decades. For many of these diseases, we still lack a full understanding of their etiology and pathophysiology. Nonetheless their association with mitochondrial dysfunction highlights this organelle as an important player during CNS homeostasis and disease. Markers of Parkinson (PD) and Alzheimer (AD) diseases are able to induce innate immune pathways induced by alterations in mitochondrial Ca2+ homeostasis leading to neuroinflammation. Additionally, exacerbated type I IFN responses triggered by mitochondrial DNA (mtDNA), failures in mitophagy, ER-mitochondria communication and mtROS production promote neurodegeneration. On the other hand, regulation of mitochondrial dynamics is essential for CNS health maintenance and leading to the induction of IL-10 and reduction of TNF-α secretion, increased cell viability and diminished cell injury in addition to reduced oxidative stress. Thus, although previously solely seen as power suppliers to organelles and molecular processes, it is now well established that mitochondria have many other important roles, including during immune responses. Here, we discuss the importance of these mitochondrial dynamics during neuroinflammation, and how they correlate either with the amelioration or worsening of CNS disease.


Assuntos
Encéfalo/metabolismo , Inflamação/metabolismo , Mitocôndrias/metabolismo , Dinâmica Mitocondrial , Doenças Neurodegenerativas/metabolismo , Neuroimunomodulação , Alarminas/metabolismo , Animais , Encéfalo/imunologia , Encéfalo/patologia , Citocinas/metabolismo , Humanos , Inflamação/imunologia , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Mitocôndrias/imunologia , Mitocôndrias/patologia , Degeneração Neural , Doenças Neurodegenerativas/imunologia , Doenças Neurodegenerativas/patologia
20.
Immunity ; 54(4): 614-616, 2021 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-33852828

RESUMO

Microbiome-induced interferon signaling through gut-derived natural killer cells is integral to minimize peripheral inflammatory responses in the brain and spinal cord. In a recent issue of Nature, Sanmarco, Wheeler, et al. define how interferon signaling induces LAMP1+TRAIL+ astrocytes, which cause death of inflammatory T cells, mitigating degeneration in a mouse model of demyealination.


Assuntos
Astrócitos/imunologia , Inflamação/imunologia , Linfócitos T/imunologia , Animais , Encéfalo/imunologia , Modelos Animais de Doenças , Interferons/imunologia , Células Matadoras Naturais/imunologia , Camundongos , Transdução de Sinais/imunologia , Medula Espinal/imunologia
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