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1.
Int J Mol Sci ; 25(11)2024 May 29.
Artículo en Inglés | MEDLINE | ID: mdl-38892158

RESUMEN

Neuroinflammatory conditions in the central nervous system (CNS) are implicated in the pathogenesis of several neuroimmune disorders such as acquired demyelinating syndromes, autoimmune encephalopathies, acute or chronic bacterial and viral CNS infections as well as multiple sclerosis (MS) [...].


Asunto(s)
Enfermedades Neuroinflamatorias , Humanos , Enfermedades Neuroinflamatorias/inmunología , Animales , Esclerosis Múltiple/terapia , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/metabolismo , Esclerosis Múltiple/tratamiento farmacológico , Sistema Nervioso Central/metabolismo , Sistema Nervioso Central/patología , Sistema Nervioso Central/inmunología , Inflamación
2.
Nat Commun ; 15(1): 5404, 2024 Jun 26.
Artículo en Inglés | MEDLINE | ID: mdl-38926356

RESUMEN

B cells and T cells collaborate in multiple sclerosis (MS) pathogenesis. IgH[MOG] mice possess a B cell repertoire skewed to recognize myelin oligodendrocyte glycoprotein (MOG). Here, we show that upon immunization with the T cell-obligate autoantigen, MOG[35-55], IgH[MOG] mice develop rapid and exacerbated experimental autoimmune encephalomyelitis (EAE) relative to wildtype (WT) counterparts, characterized by aggregation of T and B cells in the IgH[MOG] meninges and by CD4+ T helper 17 (Th17) cells in the CNS. Production of the Th17 maintenance factor IL-23 is observed from IgH[MOG] CNS-infiltrating and meningeal B cells, and in vivo blockade of IL-23p19 attenuates disease severity in IgH[MOG] mice. In the CNS parenchyma and dura mater of IgH[MOG] mice, we observe an increased frequency of CD4+PD-1+CXCR5- T cells that share numerous characteristics with the recently described T peripheral helper (Tph) cell subset. Further, CNS-infiltrating B and Tph cells from IgH[MOG] mice show increased reactive oxygen species (ROS) production. Meningeal inflammation, Tph-like cell accumulation in the CNS and B/Tph cell production of ROS were all reduced upon p19 blockade. Altogether, MOG-specific B cells promote autoimmune inflammation of the CNS parenchyma and meninges in an IL-23-dependent manner.


Asunto(s)
Autoinmunidad , Linfocitos B , Linfocitos T CD4-Positivos , Encefalomielitis Autoinmune Experimental , Interleucina-23 , Glicoproteína Mielina-Oligodendrócito , Animales , Encefalomielitis Autoinmune Experimental/inmunología , Linfocitos B/inmunología , Glicoproteína Mielina-Oligodendrócito/inmunología , Ratones , Autoinmunidad/inmunología , Interleucina-23/inmunología , Interleucina-23/metabolismo , Linfocitos T CD4-Positivos/inmunología , Células Th17/inmunología , Sistema Nervioso Central/inmunología , Ratones Endogámicos C57BL , Femenino , Vaina de Mielina/inmunología , Vaina de Mielina/metabolismo , Meninges/inmunología , Meninges/patología , Esclerosis Múltiple/inmunología
3.
J Integr Neurosci ; 23(6): 119, 2024 Jun 20.
Artículo en Inglés | MEDLINE | ID: mdl-38940087

RESUMEN

OBJECTIVES: The majority of neuromyelitis optica spectrum disorders (NMOSD) patients are seropositive for aquaporin-4 (AQP4)-specific antibodies [also named neuromyelitis optica immunoglobulin G antibodies (NMO-IgG)]. Although NMO-IgG can induce pathological changes in the central nervous system (CNS), the immunological changes in the CNS and peripheral tissue remain largely unknown. We investigated whether NMO-IgG binds to tissue expressing AQP4 and induces immunological changes in the peripheral tissue and CNS. METHODS: C57BL/6 female mice were assigned into an NMOSD or control group. Pathological and immunological changes in peripheral tissue and CNS were measured by immunostaining and flow cytometry, respectively. Motor impairment was measured by open-field test. RESULTS: We found that NMO-IgG did bind to astrocyte- and AQP4-expressing peripheral tissue, but induced glial fibrillary acidic protein and AQP4 loss only in the CNS. NMO-IgG induced the activation of microglia and modulated microglia polarization toward the classical (M1) phenotype, but did not affect innate or adaptive immune cells in the peripheral immune system, such as macrophages, neutrophils, Th17/Th1, or IL-10-producing B cells. In addition, NMOSD mice showed significantly less total distance traveled and higher immobility time in the open field. CONCLUSIONS: We found that injection of human NMO-IgG led to astrocytopathic lesions with microglial activation in the CNS. However, there were no significant pathological or immunological changes in the peripheral tissues.


Asunto(s)
Acuaporina 4 , Inmunoglobulina G , Ratones Endogámicos C57BL , Neuromielitis Óptica , Animales , Neuromielitis Óptica/inmunología , Neuromielitis Óptica/patología , Acuaporina 4/inmunología , Femenino , Humanos , Ratones , Modelos Animales de Enfermedad , Microglía/metabolismo , Microglía/inmunología , Microglía/efectos de los fármacos , Autoanticuerpos/inmunología , Astrocitos/inmunología , Astrocitos/metabolismo , Astrocitos/patología , Proteína Ácida Fibrilar de la Glía/metabolismo , Proteína Ácida Fibrilar de la Glía/inmunología , Sistema Nervioso Central/inmunología , Sistema Nervioso Central/metabolismo , Sistema Nervioso Central/patología
4.
Microbiome ; 12(1): 114, 2024 Jun 24.
Artículo en Inglés | MEDLINE | ID: mdl-38915127

RESUMEN

BACKGROUND: Mediterranean diet rich in polyphenolic compounds holds great promise to prevent and alleviate multiple sclerosis (MS), a central nervous system autoimmune disease associated with gut microbiome dysbiosis. Health-promoting effects of natural polyphenols with low bioavailability could be attributed to gut microbiota reconstruction. However, its underlying mechanism of action remains elusive, resulting in rare therapies have proposed for polyphenol-targeted modulation of gut microbiota for the treatment of MS. RESULTS: We found that oral ellagic acid (EA), a natural polyphenol rich in the Mediterranean diet, effectively halted the progression of experimental autoimmune encephalomyelitis (EAE), the animal model of MS, via regulating a microbiota-metabolites-immunity axis. EA remodeled the gut microbiome composition and particularly increased the relative abundances of short-chain fatty acids -producing bacteria like Alloprevotella. Propionate (C3) was most significantly up-regulated by EA, and integrative modeling revealed a strong negative correlation between Alloprevotella or C3 and the pathological symptoms of EAE. Gut microbiota depletion negated the alleviating effects of EA on EAE, whereas oral administration of Alloprevotella rava mimicked the beneficial effects of EA on EAE. Moreover, EA directly promoted Alloprevotella rava (DSM 22548) growth and C3 production in vitro. The cell-free supernatants of Alloprevotella rava co-culture with EA suppressed Th17 differentiation by modulating acetylation in cell models. C3 can alleviate EAE development, and the mechanism may be through inhibiting HDAC activity and up-regulating acetylation thereby reducing inflammatory cytokines secreted by pathogenic Th17 cells. CONCLUSIONS: Our study identifies EA as a novel and potentially effective prebiotic for improving MS and other autoimmune diseases via the microbiota-metabolites-immunity axis. Video Abstract.


Asunto(s)
Ácido Elágico , Encefalomielitis Autoinmune Experimental , Microbioma Gastrointestinal , Esclerosis Múltiple , Propionatos , Ácido Elágico/farmacología , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/microbiología , Propionatos/metabolismo , Ratones , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/microbiología , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Femenino , Autoinmunidad/efectos de los fármacos , Disbiosis/microbiología , Sistema Nervioso Central/efectos de los fármacos , Sistema Nervioso Central/inmunología , Humanos , Administración Oral
5.
Insect Biochem Mol Biol ; 171: 104149, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38871133

RESUMEN

The central nervous system (CNS) plays a critical role in signal integration in animals and allows the orchestration of life processes to maintain homeostasis. Current research clearly shows that inflammatory processes can also be modulated by the CNS via the neuroendocrine system. One of the neuropeptide families that participate in vertebrates in this process is orexins (OXs). Interestingly, our previous results suggested that a similar dependency may also exist between neuropeptides and immune system activity in insects. Due to the structural homology of orexin and allatotropin receptors and the functional similarity between these two neuropeptide families, the main aim of this research was to perform a complex analysis of the relationships between allatotropin (AT) and the insect immune response. Our results revealed functional similarities between vertebrate OXs and insect ATs. Similar effects were observed in the profile of the expression level of the gene encoding the AT precursor in the Tenebrio molitor nervous system and in the general action of Tenmo-AT on selected immune parameters of the tested beetles. Moreover, for the first time in insects, we confirmed the role of cytokines in the modulation of neuroendocrine system by determining the effect of Spätzle-like protein injection on the expression of genes encoding AT precursor and receptor. All these results are important for understanding the evolutionary basis of hormonal regulation of the immune response.


Asunto(s)
Hormonas de Insectos , Neuropéptidos , Animales , Neuropéptidos/metabolismo , Neuropéptidos/genética , Hormonas de Insectos/metabolismo , Orexinas/metabolismo , Tenebrio/inmunología , Tenebrio/genética , Tenebrio/metabolismo , Proteínas de Insectos/metabolismo , Proteínas de Insectos/genética , Factores Inmunológicos/metabolismo , Sistema Nervioso Central/inmunología , Sistema Nervioso Central/metabolismo
6.
Int J Mol Sci ; 25(9)2024 Apr 29.
Artículo en Inglés | MEDLINE | ID: mdl-38732082

RESUMEN

Although the CNS has been considered for a long time an immune-privileged organ, it is now well known that both the parenchyma and non-parenchymal tissue (meninges, perivascular space, and choroid plexus) are richly populated in resident immune cells. The advent of more powerful tools for multiplex immunophenotyping, such as single-cell RNA sequencing technique and upscale multiparametric flow and mass spectrometry, helped in discriminating between resident and infiltrating cells and, above all, the different spectrum of phenotypes distinguishing border-associated macrophages. Here, we focus our attention on resident innate immune players and their primary role in both CNS homeostasis and pathological neuroinflammation and neurodegeneration, two key interconnected aspects of the immunopathology of multiple sclerosis.


Asunto(s)
Sistema Nervioso Central , Homeostasis , Inmunidad Innata , Humanos , Animales , Sistema Nervioso Central/inmunología , Sistema Nervioso Central/metabolismo , Sistema Nervioso Central/patología , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/patología , Macrófagos/inmunología , Macrófagos/metabolismo , Microglía/inmunología , Microglía/metabolismo
7.
Cancer Cell ; 42(6): 985-1002.e18, 2024 Jun 10.
Artículo en Inglés | MEDLINE | ID: mdl-38821061

RESUMEN

Tumors employ various strategies to evade immune surveillance. Central nervous system (CNS) has multiple features to restrain immune response. Whether tumors and CNS share similar programs of immunosuppression is elusive. Here, we analyze multi-omics data of tumors from HER2+ breast cancer patients receiving trastuzumab and anti-PD-L1 antibody and find that CNS-enriched N-acetyltransferase 8-like (NAT8L) and its metabolite N-acetylaspartate (NAA) are overexpressed in resistant tumors. In CNS, NAA is released during brain inflammation. NAT8L attenuates brain inflammation and impairs anti-tumor immunity by inhibiting cytotoxicity of natural killer (NK) cells and CD8+ T cells via NAA. NAA disrupts the formation of immunological synapse by promoting PCAF-induced acetylation of lamin A-K542, which inhibits the integration between lamin A and SUN2 and impairs polarization of lytic granules. We uncover that tumor cells mimic the anti-inflammatory mechanism of CNS to evade anti-tumor immunity and NAT8L is a potential target to enhance efficacy of anti-cancer agents.


Asunto(s)
Sinapsis Inmunológicas , Humanos , Sinapsis Inmunológicas/metabolismo , Animales , Ratones , Sistema Nervioso Central/metabolismo , Sistema Nervioso Central/inmunología , Femenino , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/efectos de los fármacos , Línea Celular Tumoral , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/patología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/tratamiento farmacológico
8.
Immunol Cell Biol ; 102(6): 452-455, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38714317

RESUMEN

In this article for the Highlights of 2023 Series, we consider the growing understanding of mast cell heterogeneity and interactions that has developed from single cell RNA sequencing studies. We also discuss novel concepts concerning mast cell interactions with the central nervous system and evidence for their role in host defense against SARS-CoV-2 infection.


Asunto(s)
COVID-19 , Mastocitos , SARS-CoV-2 , Mastocitos/inmunología , Humanos , COVID-19/inmunología , COVID-19/virología , SARS-CoV-2/inmunología , Animales , Análisis de la Célula Individual , Sistema Nervioso Central/inmunología
9.
Int Immunopharmacol ; 134: 112246, 2024 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-38759372

RESUMEN

BACKGROUND: A wide array of histone deacetylase (HDAC) inhibitors and aryl hydrocarbon receptor (AHR) agonists commonly arrest experimental autoimmune encephalomyelitis (EAE). However, it is not known whether HDAC inhibition is linked to the AHR signaling pathway in EAE. METHODS: We investigated how the pan-HDAC inhibitor SB939 (pracinostat) exerted immunoregulatory action in the myelin oligodendrocyte glycoprotein 35-55 (MOG35-55)-induced EAE mouse model by evaluating changes in of signal transducer and activator of transcription 3 (STAT3) acetylation and the expression of indoleamine 2,3-dioxygenase 1 (IDO1) and AHR in inflamed spinal cords during EAE evolution. We proved the involvement of IDO1 and the AHR in SB939-mediated immunosuppression using Ido1-/- and Ahr-/- mice. RESULTS: Administration with SB939 halted EAE progression, which depended upon IDO1 expression in neurons of the central nervous system (CNS). Our in vitro and in vivo studies demonstrated that SB939 sustained the interleukin-6-induced acetylation of STAT3, resulting in the stable transcriptional activation of Ido1. The therapeutic effect of SB939 also required the AHR, which is expressed mainly in CD4+ T cells and macrophages in CNS disease lesions. Finally, SB939 was shown to markedly reduce the proliferation of CD4+ T cells in inflamed neuronal tissues but not in the spleen or draining lymph nodes. CONCLUSIONS: Overall, our results suggest that IDO1 tryptophan metabolites produced by neuronal cells may act on AHR in pathogenic CD4+ T cells in a paracrine fashion in the CNS and that the specific induction of IDO1 expression in neurons at disease-afflicted sites can be considered a therapeutic approach to block the progression of multiple sclerosis without affecting systemic immunity.


Asunto(s)
Encefalomielitis Autoinmune Experimental , Inhibidores de Histona Desacetilasas , Indolamina-Pirrol 2,3,-Dioxigenasa , Ratones Endogámicos C57BL , Ratones Noqueados , Neuronas , Factor de Transcripción STAT3 , Animales , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/inmunología , Indolamina-Pirrol 2,3,-Dioxigenasa/genética , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/uso terapéutico , Factor de Transcripción STAT3/metabolismo , Neuronas/efectos de los fármacos , Neuronas/patología , Neuronas/metabolismo , Ratones , Receptores de Hidrocarburo de Aril/metabolismo , Receptores de Hidrocarburo de Aril/genética , Femenino , Médula Espinal/patología , Médula Espinal/metabolismo , Médula Espinal/inmunología , Médula Espinal/efectos de los fármacos , Glicoproteína Mielina-Oligodendrócito/inmunología , Sistema Nervioso Central/inmunología , Sistema Nervioso Central/efectos de los fármacos , Sistema Nervioso Central/metabolismo , Sistema Nervioso Central/patología , Ácidos Hidroxámicos/farmacología , Ácidos Hidroxámicos/uso terapéutico , Progresión de la Enfermedad , Histona Desacetilasas/metabolismo , Histona Desacetilasas/genética , Fragmentos de Péptidos/farmacología , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Interleucina-6/metabolismo , Interleucina-6/genética
10.
Viruses ; 16(5)2024 04 24.
Artículo en Inglés | MEDLINE | ID: mdl-38793545

RESUMEN

Initially reported as pneumonia of unknown origin, COVID-19 is increasingly being recognized for its impact on the nervous system, despite nervous system invasions being extremely rare. As a result, numerous studies have been conducted to elucidate the mechanisms of nervous system damage and propose appropriate coping strategies. This review summarizes the mechanisms by which SARS-CoV-2 invades and damages the central nervous system, with a specific focus on aspects apart from the immune response and inflammatory storm. The latest research findings on these mechanisms are presented, providing new insights for further in-depth research.


Asunto(s)
COVID-19 , Sistema Nervioso Central , Síndrome de Liberación de Citoquinas , SARS-CoV-2 , Animales , Humanos , Sistema Nervioso Central/virología , Sistema Nervioso Central/inmunología , COVID-19/inmunología , COVID-19/virología , Síndrome de Liberación de Citoquinas/inmunología , Inflamación/inmunología , Inflamación/virología , SARS-CoV-2/inmunología , SARS-CoV-2/patogenicidad
11.
Sci Immunol ; 9(95): eadj9730, 2024 05 10.
Artículo en Inglés | MEDLINE | ID: mdl-38728414

RESUMEN

Chimeric antigen receptor (CAR) T cell immunotherapy for the treatment of neurological autoimmune diseases is promising, but CAR T cell kinetics and immune alterations after treatment are poorly understood. Here, we performed single-cell multi-omics sequencing of paired cerebrospinal fluid (CSF) and blood samples from patients with neuromyelitis optica spectrum disorder (NMOSD) treated with anti-B cell maturation antigen (BCMA) CAR T cells. Proliferating cytotoxic-like CD8+ CAR T cell clones were identified as the main effectors in autoimmunity. Anti-BCMA CAR T cells with enhanced features of chemotaxis efficiently crossed the blood-CSF barrier, eliminated plasmablasts and plasma cells in the CSF, and suppressed neuroinflammation. The CD44-expressing early memory phenotype in infusion products was potentially associated with CAR T cell persistence in autoimmunity. Moreover, CAR T cells from patients with NMOSD displayed distinctive features of suppressed cytotoxicity compared with those from hematological malignancies. Thus, we provide mechanistic insights into CAR T cell function in patients with neurological autoimmune disease.


Asunto(s)
Autoinmunidad , Inmunoterapia Adoptiva , Receptores Quiméricos de Antígenos , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Autoinmunidad/inmunología , Sistema Nervioso Central/inmunología , Neuromielitis Óptica/inmunología , Neuromielitis Óptica/terapia , Receptores Quiméricos de Antígenos/inmunología , Análisis de la Célula Individual
12.
Cells ; 13(8)2024 Apr 13.
Artículo en Inglés | MEDLINE | ID: mdl-38667291

RESUMEN

Both Hedgehog and androgen signaling pathways are known to promote myelin regeneration in the central nervous system. Remarkably, the combined administration of agonists of each pathway revealed their functional cooperation towards higher regeneration in demyelination models in males. Since multiple sclerosis, the most common demyelinating disease, predominates in women, and androgen effects were reported to diverge according to sex, it seemed essential to assess the existence of such cooperation in females. Here, we developed an intranasal formulation containing the Hedgehog signaling agonist SAG, either alone or in combination with testosterone. We show that SAG promotes myelin regeneration and presumably a pro-regenerative phenotype of microglia, thus mimicking the effects previously observed in males. However, unlike in males, the combined molecules failed to cooperate in the demyelinated females, as shown by the level of functional improvement observed. Consistent with this observation, SAG administered in the absence of testosterone amplified peripheral inflammation by presumably activating NK cells and thus counteracting a testosterone-induced reduction in Th17 cells when the molecules were combined. Altogether, the data uncover a sex-dependent effect of the Hedgehog signaling agonist SAG on the peripheral innate immune system that conditions its ability to cooperate or not with androgens in the context of demyelination.


Asunto(s)
Enfermedades Desmielinizantes , Testosterona , Animales , Femenino , Masculino , Enfermedades Desmielinizantes/inmunología , Enfermedades Desmielinizantes/patología , Enfermedades Desmielinizantes/tratamiento farmacológico , Ratones , Testosterona/farmacología , Proteínas Hedgehog/metabolismo , Proteínas Hedgehog/agonistas , Ratones Endogámicos C57BL , Sistema Nervioso Central/efectos de los fármacos , Sistema Nervioso Central/inmunología , Sistema Nervioso Central/patología , Sistema Nervioso Central/metabolismo , Receptor Smoothened/metabolismo , Receptor Smoothened/agonistas , Vaina de Mielina/metabolismo , Modelos Animales de Enfermedad , Transducción de Señal/efectos de los fármacos , Sistema Inmunológico/efectos de los fármacos , Microglía/efectos de los fármacos , Microglía/metabolismo , Microglía/inmunología , Caracteres Sexuales
13.
Eur J Immunol ; 54(6): e2350548, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38634287

RESUMEN

Transforming growth factor beta (TGF-ß) signaling is essential for a balanced immune response by mediating the development and function of regulatory T cells (Tregs) and suppressing autoreactive T cells. Disruption of this balance can result in autoimmune diseases, including multiple sclerosis (MS). MicroRNAs (miRNAs) targeting TGF-ß signaling have been shown to be upregulated in naïve CD4 T cells in MS patients, resulting in a limited in vitro generation of human Tregs. Utilizing the murine model experimental autoimmune encephalomyelitis, we show that perinatal administration of miRNAs, which target the TGF-ß signaling pathway, enhanced susceptibility to central nervous system (CNS) autoimmunity. Neonatal mice administered with these miRNAs further exhibited reduced Treg frequencies with a loss in T cell receptor repertoire diversity following the induction of experimental autoimmune encephalomyelitis in adulthood. Exacerbated CNS autoimmunity as a result of miRNA overexpression in CD4 T cells was accompanied by enhanced Th1 and Th17 cell frequencies. These findings demonstrate that increased levels of TGF-ß-associated miRNAs impede the development of a diverse Treg population, leading to enhanced effector cell activity, and contributing to an increased susceptibility to CNS autoimmunity. Thus, TGF-ß-targeting miRNAs could be a risk factor for MS, and recovering optimal TGF-ß signaling may restore immune homeostasis in MS patients.


Asunto(s)
Autoinmunidad , Sistema Nervioso Central , Encefalomielitis Autoinmune Experimental , MicroARNs , Esclerosis Múltiple , Transducción de Señal , Linfocitos T Reguladores , Células Th17 , Factor de Crecimiento Transformador beta , MicroARNs/genética , MicroARNs/inmunología , Animales , Linfocitos T Reguladores/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/genética , Factor de Crecimiento Transformador beta/metabolismo , Ratones , Transducción de Señal/inmunología , Autoinmunidad/inmunología , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/genética , Humanos , Sistema Nervioso Central/inmunología , Células Th17/inmunología , Ratones Endogámicos C57BL , Células TH1/inmunología , Diferenciación Celular/inmunología , Femenino
14.
Trends Immunol ; 45(5): 329-337, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38600001

RESUMEN

Neurodegenerative disorders present major challenges to global health, exacerbated by an aging population and the absence of therapies. Despite diverse pathological manifestations, they share a common hallmark, loosely termed 'neuroinflammation'. The prevailing dogma is that the immune system is an active contributor to neurodegeneration; however, recent evidence challenges this. By analogy with road construction, which causes temporary closures and disruptions, the immune system's actions in the central nervous system (CNS) might initially appear destructive, and might even cause harm, while aiming to combat neurodegeneration. We propose that the application of cellular immunotherapies to coordinate the immune response towards remodeling might pave the way for new modes of tackling the roadblocks of neurodegenerative diseases.


Asunto(s)
Inmunoterapia , Enfermedades Neurodegenerativas , Animales , Humanos , Sistema Nervioso Central/inmunología , Inmunoterapia/métodos , Enfermedades Neurodegenerativas/terapia , Enfermedades Neurodegenerativas/inmunología
15.
Clin Chim Acta ; 559: 119681, 2024 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-38643816

RESUMEN

OBJECTIVES: Demyelination and immunocyte-infiltrated lesions have been found in neuro-Behçet's disease (NBD) pathology. Lacking satisfying laboratory biomarkers in NBD impedes standard clinical diagnostics. We aim to explore the ancillary indicators for NBD diagnosis unveiling its potential etiology. METHODS: 28 NBD with defined diagnosis, 29 patients with neuropsychiatric lupus erythematosus, 30 central nervous system idiopathic inflammatory demyelination diseases (CNS-IIDD), 30 CNS infections, 30 cerebrovascular diseases, and 30 noninflammatory neurological diseases (NIND) were retrospectively enrolled. Immunoglobulins (Ig) in serum and cerebral spinal fluid (CSF) were detected by immunonephelometry and myelin basic protein (MBP) by quantitative enzyme-linked immunosorbent assay. RESULTS: IgA index is almost twice enhanced in NBD than NIND with an accuracy of 0.8488 in differential diagnosis, the sensitivity and specificity of which were 75.00 % and 90.00 % when the cutoff was > 0.6814. The accuracy of CSF Ig and quotient of Ig all exceed 0.90 in discerning NBD with damaged and intact blood-brain barrier (BBB). Clustering analyses divided NBD into two different phenotypes: one with BBB damage has lower Ig synthesis, the other with extra-synthesis in parenchymal sites but with intact BBB. MBP index is significantly correlated with kappa (KAP) index and lambda (LAM) index (r = 0.358, 0.575, P < 0.001), hinting the NBD pathogenesis of CNS demyelination in triggering excessive intrathecal Ig productions and humoral responses. CONCLUSIONS: IgA index acts as a potential diagnostic indicator in differentiating NBD from NIND and CNS-IIDD. Excessive immunoglobulin production induced by CNS inflammation and demyelination might be latent immunopathogenesis of NBD.


Asunto(s)
Síndrome de Behçet , Humanos , Síndrome de Behçet/líquido cefalorraquídeo , Síndrome de Behçet/diagnóstico , Síndrome de Behçet/sangre , Masculino , Femenino , Adulto , Estudios Retrospectivos , Persona de Mediana Edad , Inmunoglobulinas/sangre , Sistema Nervioso Central/patología , Sistema Nervioso Central/metabolismo , Sistema Nervioso Central/inmunología , Adulto Joven , Enfermedades del Sistema Nervioso Central/diagnóstico , Enfermedades del Sistema Nervioso Central/inmunología , Enfermedades del Sistema Nervioso Central/líquido cefalorraquídeo , Adolescente
16.
Trends Immunol ; 45(5): 320-321, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38632002

RESUMEN

Astrocytes are essential cells of the mammalian central nervous system (CNS), with key roles in development, homeostasis, and disease. Lee and colleagues recently showed that astrocytes can develop epigenetic memory, which enhances proinflammatory responses to subsequent stimulation, potentially driving sustained neurological disease pathology, such as in multiple sclerosis (MS).


Asunto(s)
Astrocitos , Enfermedades Neuroinflamatorias , Astrocitos/inmunología , Humanos , Animales , Enfermedades Neuroinflamatorias/inmunología , Esclerosis Múltiple/inmunología , Epigénesis Genética , Sistema Nervioso Central/inmunología , Inflamación/inmunología , Enfermedad Crónica
17.
Nature ; 628(8008): 612-619, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38509366

RESUMEN

There is increasing interest in how immune cells in the meninges-the membranes that surround the brain and spinal cord-contribute to homeostasis and disease in the central nervous system1,2. The outer layer of the meninges, the dura mater, has recently been described to contain both innate and adaptive immune cells, and functions as a site for B cell development3-6. Here we identify organized lymphoid structures that protect fenestrated vasculature in the dura mater. The most elaborate of these dural-associated lymphoid tissues (DALT) surrounded the rostral-rhinal confluence of the sinuses and included lymphatic vessels. We termed this structure, which interfaces with the skull bone marrow and a comparable venous plexus at the skull base, the rostral-rhinal venolymphatic hub. Immune aggregates were present in DALT during homeostasis and expanded with age or after challenge with systemic or nasal antigens. DALT contain germinal centre B cells and support the generation of somatically mutated, antibody-producing cells in response to a nasal pathogen challenge. Inhibition of lymphocyte entry into the rostral-rhinal hub at the time of nasal viral challenge abrogated the generation of germinal centre B cells and class-switched plasma cells, as did perturbation of B-T cell interactions. These data demonstrate a lymphoid structure around vasculature in the dura mater that can sample antigens and rapidly support humoral immune responses after local pathogen challenge.


Asunto(s)
Duramadre , Inmunidad Humoral , Tejido Linfoide , Venas , Administración Intranasal , Antígenos/administración & dosificación , Antígenos/inmunología , Médula Ósea/inmunología , Sistema Nervioso Central/irrigación sanguínea , Sistema Nervioso Central/inmunología , Duramadre/irrigación sanguínea , Duramadre/inmunología , Centro Germinal/citología , Centro Germinal/inmunología , Vasos Linfáticos/inmunología , Tejido Linfoide/irrigación sanguínea , Tejido Linfoide/inmunología , Células Plasmáticas/inmunología , Cráneo/irrigación sanguínea , Linfocitos T/inmunología , Venas/fisiología , Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Animales , Ratones , Anciano de 80 o más Años
18.
Clin Exp Immunol ; 216(3): 221-229, 2024 May 16.
Artículo en Inglés | MEDLINE | ID: mdl-38456795

RESUMEN

Microglia are specialized immune cells unique to the central nervous system (CNS). Microglia have a highly plastic morphology that changes rapidly in response to injury or infection. Qualitative and quantitative measurements of ever-changing microglial morphology are considered a cornerstone of many microglia-centric research studies. The distinctive morphological variations seen in microglia are a useful marker of inflammation and severity of tissue damage. Although a wide array of damage-associated microglial morphologies has been documented, the exact functions of these distinct morphologies are not fully understood. In this review, we discuss how microglia morphology is not synonymous with microglia function, however, morphological outcomes can be used to make inferences about microglial function. For a comprehensive examination of the reactive status of a microglial cell, both histological and genetic approaches should be combined. However, the importance of quality immunohistochemistry-based analyses should not be overlooked as they can succinctly answer many research questions.


Asunto(s)
Microglía , Microglía/inmunología , Humanos , Animales , Inflamación/inmunología , Inflamación/patología , Sistema Nervioso Central/inmunología , Inmunohistoquímica
19.
Nat Rev Immunol ; 24(6): 381-398, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38097777

RESUMEN

The olfactory mucosa is a component of the nasal airway that mediates the sense of smell. Recent studies point to an important role for the olfactory mucosa as a barrier to both respiratory pathogens and to neuroinvasive pathogens that hijack the olfactory nerve and invade the CNS. In particular, the COVID-19 pandemic has demonstrated that the olfactory mucosa is an integral part of a heterogeneous nasal mucosal barrier critical to upper airway immunity. However, our insufficient knowledge of olfactory mucosal immunity hinders attempts to protect this tissue from infection and other diseases. This Review summarizes the state of olfactory immunology by highlighting the unique immunologically relevant anatomy of the olfactory mucosa, describing what is known of olfactory immune cells, and considering the impact of common infectious diseases and inflammatory disorders at this site. We will offer our perspective on the future of the field and the many unresolved questions pertaining to olfactory immunity.


Asunto(s)
COVID-19 , Mucosa Olfatoria , SARS-CoV-2 , Humanos , Mucosa Olfatoria/inmunología , COVID-19/inmunología , SARS-CoV-2/inmunología , Animales , Inmunidad Mucosa/inmunología , Sistema Nervioso Central/inmunología , Olfato/inmunología , Olfato/fisiología
20.
Nature ; 620(7975): 881-889, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-37558878

RESUMEN

Dendritic cells (DCs) have a role in the development and activation of self-reactive pathogenic T cells1,2. Genetic variants that are associated with the function of DCs have been linked to autoimmune disorders3,4, and DCs are therefore attractive therapeutic targets for such diseases. However, developing DC-targeted therapies for autoimmunity requires identification of the mechanisms that regulate DC function. Here, using single-cell and bulk transcriptional and metabolic analyses in combination with cell-specific gene perturbation studies, we identify a regulatory loop of negative feedback that operates in DCs to limit immunopathology. Specifically, we find that lactate, produced by activated DCs and other immune cells, boosts the expression of NDUFA4L2 through a mechanism mediated by hypoxia-inducible factor 1α (HIF-1α). NDUFA4L2 limits the production of mitochondrial reactive oxygen species that activate XBP1-driven transcriptional modules in DCs that are involved in the control of pathogenic autoimmune T cells. We also engineer a probiotic that produces lactate and suppresses T cell autoimmunity through the activation of HIF-1α-NDUFA4L2 signalling in DCs. In summary, we identify an immunometabolic pathway that regulates DC function, and develop a synthetic probiotic for its therapeutic activation.


Asunto(s)
Enfermedades Autoinmunes , Sistema Nervioso Central , Células Dendríticas , Subunidad alfa del Factor 1 Inducible por Hipoxia , Ácido Láctico , Humanos , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/metabolismo , Enfermedades Autoinmunes/prevención & control , Autoinmunidad , Sistema Nervioso Central/citología , Sistema Nervioso Central/inmunología , Sistema Nervioso Central/patología , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/química , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Ácido Láctico/metabolismo , Probióticos/uso terapéutico , Especies Reactivas de Oxígeno/metabolismo , Linfocitos T/inmunología , Retroalimentación Fisiológica , Lactasa/genética , Lactasa/metabolismo , Análisis de la Célula Individual
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