RESUMEN
The dry mass and the orientation of biomolecules can be imaged without a label by measuring their permittivity tensor (PT), which describes how biomolecules affect the phase and polarization of light. Three-dimensional (3D) imaging of PT has been challenging. We present a label-free computational microscopy technique, PT imaging (PTI), for the 3D measurement of PT. PTI encodes the invisible PT into images using oblique illumination, polarization-sensitive detection and volumetric sampling. PT is decoded from the data with a vectorial imaging model and a multi-channel inverse algorithm, assuming uniaxial symmetry in each voxel. We demonstrate high-resolution imaging of PT of isotropic beads, anisotropic glass targets, mouse brain tissue, infected cells and histology slides. PTI outperforms previous label-free imaging techniques such as vector tomography, ptychography and light-field imaging in resolving the 3D orientation and symmetry of organelles, cells and tissue. We provide open-source software and modular hardware to enable the adoption of the method.
Asunto(s)
Algoritmos , Imagenología Tridimensional , Imagenología Tridimensional/métodos , Animales , Ratones , Encéfalo/diagnóstico por imagen , Microscopía/métodos , Programas Informáticos , Humanos , Procesamiento de Imagen Asistido por Computador/métodosRESUMEN
Sphingosine 1-phosphate (S1P) signaling regulates lymphocyte egress from lymphoid organs into systemic circulation. The sphingosine phosphate receptor 1 (S1P1) agonist FTY-720 (Gilenya) arrests immune trafficking and prevents multiple sclerosis (MS) relapses. However, alternative mechanisms of S1P-S1P1 signaling have been reported. Phosphoproteomic analysis of MS brain lesions revealed S1P1 phosphorylation on S351, a residue crucial for receptor internalization. Mutant mice harboring an S1pr1 gene encoding phosphorylation-deficient receptors (S1P1(S5A)) developed severe experimental autoimmune encephalomyelitis (EAE) due to autoimmunity mediated by interleukin 17 (IL-17)-producing helper T cells (TH17 cells) in the peripheral immune and nervous system. S1P1 directly activated the Jak-STAT3 signal-transduction pathway via IL-6. Impaired S1P1 phosphorylation enhances TH17 polarization and exacerbates autoimmune neuroinflammation. These mechanisms may be pathogenic in MS.
Asunto(s)
Encéfalo/metabolismo , Encefalomielitis Autoinmune Experimental/metabolismo , Interleucina-17/metabolismo , Lisofosfolípidos/metabolismo , Esclerosis Múltiple/metabolismo , Receptores de Lisoesfingolípidos/metabolismo , Transducción de Señal/inmunología , Esfingosina/análogos & derivados , Animales , Autopsia , Encéfalo/inmunología , Encéfalo/patología , Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/patología , Femenino , Regulación de la Expresión Génica , Humanos , Inflamación , Interleucina-17/genética , Interleucina-17/inmunología , Interleucina-6/genética , Interleucina-6/inmunología , Interleucina-6/metabolismo , Quinasas Janus/genética , Quinasas Janus/inmunología , Quinasas Janus/metabolismo , Lisofosfolípidos/inmunología , Ratones , Esclerosis Múltiple/genética , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/patología , Fosforilación , Receptores de Lisoesfingolípidos/genética , Receptores de Lisoesfingolípidos/inmunología , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/inmunología , Factor de Transcripción STAT3/metabolismo , Esfingosina/inmunología , Esfingosina/metabolismo , Células Th17RESUMEN
The safety and efficacy of sabatolimab, a novel immunotherapy targeting T-cell immunoglobulin domain and mucin domain-3 (TIM-3), was assessed in combination with hypomethylating agents (HMAs) in patients with HMA-naive revised International Prognostic System Score (IPSS-R) high- or very high-risk myelodysplastic syndromes (HR/vHR-MDS) or chronic myelomonocytic leukemia (CMML). Sabatolimab + HMA had a safety profile similar to that reported for HMA alone and demonstrated durable clinical responses in patients with HR/vHR-MDS. These results support the ongoing evaluation of sabatolimab-based combination therapy in MDS, CMML, and acute myeloid leukemia.
Asunto(s)
Anticuerpos Monoclonales , Leucemia Mieloide Aguda , Leucemia Mielomonocítica Crónica , Síndromes Mielodisplásicos , Humanos , Azacitidina/uso terapéutico , Decitabina/uso terapéutico , Antimetabolitos Antineoplásicos/uso terapéutico , Síndromes Mielodisplásicos/tratamiento farmacológico , Receptor 2 Celular del Virus de la Hepatitis A/uso terapéutico , Leucemia Mielomonocítica Crónica/tratamiento farmacológico , Leucemia Mieloide Aguda/tratamiento farmacológico , Anticuerpos/uso terapéutico , Resultado del TratamientoRESUMEN
Pericytes regulate the development of organ-specific characteristics of the brain vasculature such as the blood-brain barrier (BBB) and astrocytic end-feet. Whether pericytes are involved in the control of leukocyte trafficking in the adult central nervous system (CNS), a process tightly regulated by CNS vasculature, remains elusive. Using adult pericyte-deficient mice (Pdgfbret/ret ), we show that pericytes limit leukocyte infiltration into the CNS during homeostasis and autoimmune neuroinflammation. The permissiveness of the vasculature toward leukocyte trafficking in Pdgfbret/ret mice inversely correlates with vessel pericyte coverage. Upon induction of experimental autoimmune encephalomyelitis (EAE), pericyte-deficient mice die of severe atypical EAE, which can be reversed with fingolimod, indicating that the mortality is due to the massive influx of immune cells into the brain. Additionally, administration of anti-VCAM-1 and anti-ICAM-1 antibodies reduces leukocyte infiltration and diminishes the severity of atypical EAE symptoms of Pdgfbret/ret mice, indicating that the proinflammatory endothelium due to absence of pericytes facilitates exaggerated neuroinflammation. Furthermore, we show that the presence of myelin peptide-specific peripheral T cells in Pdgfbret/ret ;2D2tg mice leads to the development of spontaneous neurological symptoms paralleled by the massive influx of leukocytes into the brain. These findings indicate that intrinsic changes within brain vasculature can promote the development of a neuroinflammatory disorder.
Asunto(s)
Barrera Hematoencefálica/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Homeostasis/inmunología , Leucocitos/inmunología , Pericitos/inmunología , Animales , Barrera Hematoencefálica/patología , Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/patología , Homeostasis/genética , Molécula 1 de Adhesión Intercelular/genética , Molécula 1 de Adhesión Intercelular/inmunología , Leucocitos/patología , Ratones , Ratones Transgénicos , Pericitos/patología , Proteínas Proto-Oncogénicas c-sis/deficiencia , Proteínas Proto-Oncogénicas c-sis/inmunología , Molécula 1 de Adhesión Celular Vascular/genética , Molécula 1 de Adhesión Celular Vascular/inmunologíaRESUMEN
Multiple sclerosis (MS) is an inflammatory-demyelinating disease of the central nervous system (CNS) mediated by aberrant auto-reactive immune responses. The current immune-modulatory therapies are unable to protect and repair immune-mediated neural tissue damage. One of the therapeutic targets in MS is the sphingosine-1-phosphate (S1P) pathway which signals via sphingosine-1-phosphate receptors 1-5 (S1P1-5). S1P receptors are expressed predominantly on immune and CNS cells. Considering the potential neuroprotective properties of S1P signaling, we utilized S1P1-GFP (Green fluorescent protein) reporter mice in the cuprizone-induced demyelination model to investigate in vivo S1P - S1P1 signaling in the CNS. We observed S1P1 signaling in a subset of neural stem cells in the subventricular zone (SVZ) during demyelination. During remyelination, S1P1 signaling is expressed in oligodendrocyte progenitor cells in the SVZ and mature oligodendrocytes in the medial corpus callosum (MCC). In the cuprizone model, we did not observe S1P1 signaling in neurons and astrocytes. We also observed ß-arrestin-dependent S1P1 signaling in lymphocytes during demyelination and CNS inflammation. Our findings reveal ß-arrestin-dependent S1P1 signaling in oligodendrocyte lineage cells implying a role of S1P1 signaling in remyelination.
Asunto(s)
Esclerosis Múltiple , Remielinización , Ratones , Animales , Receptores de Esfingosina-1-Fosfato/metabolismo , Receptores de Esfingosina-1-Fosfato/uso terapéutico , Cuprizona , Receptores de Lisoesfingolípidos/metabolismo , Receptores de Lisoesfingolípidos/uso terapéutico , Sistema Nervioso Central/metabolismo , Esclerosis Múltiple/metabolismo , Oligodendroglía/metabolismo , beta-Arrestinas/metabolismo , beta-Arrestinas/uso terapéutico , Ratones Endogámicos C57BLRESUMEN
Lipid mediators influence immunity in myriad ways. For example, circulating sphingosine-1-phosphate (S1P) is a key regulator of lymphocyte egress. Although the majority of plasma S1P is bound to apolipoprotein M (ApoM) in the high-density lipoprotein (HDL) particle, the immunological functions of the ApoM-S1P complex are unknown. Here we show that ApoM-S1P is dispensable for lymphocyte trafficking yet restrains lymphopoiesis by activating the S1P1 receptor on bone marrow lymphocyte progenitors. Mice that lacked ApoM (Apom(-/-)) had increased proliferation of Lin(-) Sca-1(+) cKit(+) haematopoietic progenitor cells (LSKs) and common lymphoid progenitors (CLPs) in bone marrow. Pharmacological activation or genetic overexpression of S1P1 suppressed LSK and CLP cell proliferation in vivo. ApoM was stably associated with bone marrow CLPs, which showed active S1P1 signalling in vivo. Moreover, ApoM-bound S1P, but not albumin-bound S1P, inhibited lymphopoiesis in vitro. Upon immune stimulation, Apom(-/-) mice developed more severe experimental autoimmune encephalomyelitis, characterized by increased lymphocytes in the central nervous system and breakdown of the blood-brain barrier. Thus, the ApoM-S1P-S1P1 signalling axis restrains the lymphocyte compartment and, subsequently, adaptive immune responses. Unique biological functions imparted by specific S1P chaperones could be exploited for novel therapeutic opportunities.
Asunto(s)
Apolipoproteínas/metabolismo , Sistema Nervioso Central/patología , Lipoproteínas HDL/metabolismo , Linfocitos/citología , Linfocitos/metabolismo , Linfopoyesis , Lisofosfolípidos/metabolismo , Esfingosina/análogos & derivados , Animales , Apolipoproteínas/deficiencia , Apolipoproteínas/genética , Apolipoproteínas M , Barrera Hematoencefálica/patología , Movimiento Celular , Proliferación Celular/genética , Sistema Nervioso Central/inmunología , Sistema Nervioso Central/metabolismo , Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/metabolismo , Encefalomielitis Autoinmune Experimental/patología , Femenino , Clorhidrato de Fingolimod/farmacología , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/metabolismo , Inflamación/inmunología , Inflamación/metabolismo , Inflamación/patología , Linfocitos/inmunología , Células Progenitoras Linfoides/citología , Células Progenitoras Linfoides/metabolismo , Lisofosfolípidos/agonistas , Lisofosfolípidos/sangre , Lisofosfolípidos/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Unión Proteica , Receptores de Lisoesfingolípidos/metabolismo , Transducción de Señal , Esfingosina/agonistas , Esfingosina/sangre , Esfingosina/genética , Esfingosina/metabolismoRESUMEN
Muscarinic antagonists promote sensory neurite outgrowth in vitro and prevent and/or reverse multiple indices of peripheral neuropathy in rodent models of diabetes, chemotherapy-induced peripheral neuropathy, and HIV protein-induced neuropathy when delivered systemically. We measured plasma concentrations of the M1 receptor-selective muscarinic antagonist pirenzepine when delivered by subcutaneous injection, oral gavage, or topical application to the skin and investigated efficacy of topically delivered pirenzepine against indices of peripheral neuropathy in diabetic mice. Topical application of 2% pirenzepine to the paw resulted in plasma concentrations 6 hours postdelivery that approximated those previously shown to promote neurite outgrowth in vitro. Topical delivery of pirenzepine to the paw of mice with streptozotocin-induced diabetes dose-dependently (0.1%-10.0%) prevented tactile allodynia, thermal hypoalgesia, and loss of epidermal nerve fibers in the treated paw and attenuated large fiber motor nerve conduction slowing in the ipsilateral limb. Efficacy against some indices of neuropathy was also noted in the contralateral limb, indicating systemic effects following local treatment. Topical pirenzepine also reversed established paw heat hypoalgesia, whereas withdrawal of treatment resulted in a gradual decline in efficacy over 2-4 weeks. Efficacy of topical pirenzepine was muted when treatment was reduced from 5 to 3 or 1 day/wk. Similar local effects were noted with the nonselective muscarinic receptor antagonist atropine when applied either to the paw or to the eye. Topical delivery of muscarinic antagonists may serve as a practical therapeutic approach to treating diabetic and other peripheral neuropathies. SIGNIFICANCE STATEMENT: Muscarinic antagonist pirenzepine alleviates diabetic peripheral neuropathy when applied topically in mice.
Asunto(s)
Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Tipo 1/complicaciones , Antagonistas Muscarínicos/administración & dosificación , Antagonistas Muscarínicos/farmacología , Enfermedades del Sistema Nervioso Periférico/tratamiento farmacológico , Enfermedades del Sistema Nervioso Periférico/prevención & control , Administración Tópica , Animales , Femenino , Ratones , Ratones Endogámicos C57BL , Antagonistas Muscarínicos/uso terapéutico , Enfermedades del Sistema Nervioso Periférico/complicacionesRESUMEN
BACKGROUND: Investigating the degeneration of specific thalamic nuclei in multiple sclerosis (MS) remains challenging. METHODS: White-matter-nulled (WMn) MPRAGE, MP-FLAIR, and standard T1-weighted magnetic resonance imaging (MRI) were performed on MS patients (n = 15) and matched controls (n = 12). Thalamic lesions were counted in individual sequences and lesion contrast-to-noise ratio (CNR) was measured. Volumes of 12 thalamic nuclei were measured using an automatic segmentation pipeline specifically developed for WMn-MPRAGE. RESULTS: WMn-MPRAGE showed more thalamic MS lesions (n = 35 in 9 out of 15 patients) than MP-FLAIR (n = 25) and standard T1 (n = 23), which was associated with significant improvement of CNR (p < 0.0001). MS patients had whole thalamus atrophy (p = 0.003) with lower volumes found for the anteroventral (p < 0.001), the pulvinar (p < 0.0001), and the habenular (p = 0.004) nuclei. CONCLUSION: WMn-MPRAGE and automatic thalamic segmentation can highlight thalamic MS lesions and measure patterns of focal thalamic atrophy.
Asunto(s)
Imagen por Resonancia Magnética/métodos , Esclerosis Múltiple/diagnóstico por imagen , Neuroimagen/métodos , Núcleos Talámicos/diagnóstico por imagen , Sustancia Blanca/diagnóstico por imagen , Adulto , Atlas como Asunto , Atrofia/patología , Femenino , Humanos , Interpretación de Imagen Asistida por Computador , Procesamiento de Imagen Asistido por Computador , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/patología , Núcleos Talámicos/patología , Sustancia Blanca/patologíaRESUMEN
The small heat shock protein αB-crystallin (CRYAB) has been implicated in multiple sclerosis (MS) pathogenesis. Earlier studies have indicated that CRYAB inhibits inflammation and attenuates clinical disease when administered in the experimental autoimmune encephalomyelitis model of MS. In this study, we evaluated the role of CRYAB in primary demyelinating events. Using the cuprizone model of demyelination, a noninflammatory model that allows the analysis of glial responses in MS, we show that endogenous CRYAB expression is associated with increased severity of demyelination. Moreover, we demonstrate a strong correlation between the expression of CRYAB and the extent of reactive astrogliosis in demyelinating areas and in in vitro assays. In addition, we reveal that CRYAB is differentially phosphorylated in astrocytes in active demyelinating MS lesions, as well as in cuprizone-induced lesions, and that this phosphorylation is required for the reactive astrocyte response associated with demyelination. Furthermore, taking a proteomics approach to identify proteins that are bound by the phosphorylated forms of CRYAB in primary cultured astrocytes, we show that there is clear differential binding of protein targets due to the specific phosphorylation of CRYAB. Subsequent Ingenuity Pathway Analysis of these targets reveals implications for intracellular pathways and biological processes that could be affected by these modifications. Together, these findings demonstrate that astrocytes play a pivotal role in demyelination, making them a potential target for therapeutic intervention, and that phosphorylation of CRYAB is a key factor supporting the pathogenic response of astrocytes to oligodendrocyte injury.
Asunto(s)
Astrocitos/metabolismo , Enfermedades Desmielinizantes/metabolismo , Fosforilación/fisiología , Cadena B de alfa-Cristalina/metabolismo , Animales , Astrocitos/efectos de los fármacos , Cuprizona/farmacología , Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental/inducido químicamente , Encefalomielitis Autoinmune Experimental/metabolismo , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Esclerosis Múltiple/inducido químicamente , Esclerosis Múltiple/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Oligodendroglía/efectos de los fármacos , Oligodendroglía/metabolismo , Fosforilación/efectos de los fármacosRESUMEN
The critical role of sphingosine-1-phosphate (S1P) signaling in lymphocyte trafficking is well recognized, however, the contribution of myeloid cell-S1P signaling in neuroimmunity is less well understood. We previously reported that C57BL/6J mice harboring phosphorylation defective S1P receptor 1 (S1P1) (with mutated serines in the carboxyl terminus, leading to impaired receptor internalization) [S1P1(S5A)] developed severe, TH17-dominant experimental autoimmune encephalomyelitis. In this study, we demonstrate that S1P1-mediated TH17 polarization is not an intrinsic T cell effect, but dependent on sustained S1P1 signaling in myeloid cells. First, utilizing the S1P1(S5A) mice in the EAE model, we observed that S1P1 activated and enhanced antigen presentation function in myeloid cells. Second, sequential phosphorylation of STAT3 occurred in dendritic cells, monocytes, and macrophages/microglia during neuroinflammation. Third, we show that pro-inflammatory (CD45hiCD11b+Ly6Chi) monocytes contribute to TH17 differentiation and neuroinflammation by regulating IL-6 expression. Finally, results from experiments utilizing myeloid cell-specific S1P1 overexpression (S1pr1f/stop/f:LysMCre) mice demonstrate that myeloid cell S1P1 directly contributes to severity of neuroinflammation. These findings reveal the critical contribution of myeloid-S1P1 signaling in CNS autoimmunity.
Asunto(s)
Autoinmunidad/inmunología , Sistema Nervioso Central/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Inflamación/inmunología , Células Mieloides/inmunología , Receptores de Esfingosina-1-Fosfato/inmunología , Animales , Sistema Nervioso Central/metabolismo , Sistema Nervioso Central/patología , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Monocitos/inmunología , Monocitos/metabolismo , Células Mieloides/metabolismo , Factor de Transcripción STAT3/inmunología , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/inmunología , Receptores de Esfingosina-1-Fosfato/genética , Receptores de Esfingosina-1-Fosfato/metabolismo , Células Th17/inmunología , Células Th17/metabolismoAsunto(s)
Antígeno 2 del Estroma de la Médula Ósea/genética , Células Dendríticas/inmunología , Esclerosis Múltiple/genética , Animales , Sistema Nervioso Central/inmunología , Sistema Nervioso Central/metabolismo , Sistema Nervioso Central/patología , Células Dendríticas/metabolismo , Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/patología , Humanos , Ratones , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/metabolismo , Esclerosis Múltiple/patologíaRESUMEN
In order to gain mechanistic insights into multiple sclerosis (MS) pathogenesis, we utilized a multi-dimensional approach to test the hypothesis that mutations in myelin proteins lead to immune activation and central nervous system autoimmunity in MS. Mass spectrometry-based proteomic analysis of human MS brain lesions revealed seven unique mutations of PLP1; a key myelin protein that is known to be destroyed in MS. Surprisingly, in-depth genomic analysis of two MS patients at the genomic DNA and mRNA confirmed mutated PLP1 in RNA, but not in the genomic DNA. Quantification of wild type and mutant PLP RNA levels by qPCR further validated the presence of mutant PLP RNA in the MS patients. To seek evidence linking mutations in abundant myelin proteins and immune-mediated destruction of myelin, specific immune response against mutant PLP1 in MS patients was examined. Thus, we have designed paired, wild type and mutant peptide microarrays, and examined antibody response to multiple mutated PLP1 in sera from MS patients. Consistent with the idea of different patients exhibiting unique mutation profiles, we found that 13 out of 20 MS patients showed antibody responses against specific but not against all the mutant-PLP1 peptides. Interestingly, we found mutant PLP-directed antibody response against specific mutant peptides in the sera of pre-MS controls. The results from integrative proteomic, genomic, and immune analyses reveal a possible mechanism of mutation-driven pathogenesis in human MS. The study also highlights the need for integrative genomic and proteomic analyses for uncovering pathogenic mechanisms of human diseases.
Asunto(s)
Alergia e Inmunología , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/metabolismo , Mutación/genética , Proteína Proteolipídica de la Mielina/genética , Proteómica/métodos , Investigación Biomédica Traslacional/métodos , Secuencia de Aminoácidos , Anticuerpos/inmunología , Femenino , Humanos , Modelos Biológicos , Proteína Proteolipídica de la Mielina/químicaRESUMEN
Cellular transplantation strategies utilizing intraspinal injection of mesenchymal progenitor cells (MPCs) have been reported as beneficial for spinal cord injuries. However, intraspinal injection is not only technically challenging, but requires invasive surgical procedures for patients. Therefore, we investigated the feasibility and potential benefits of noninvasive intravenous injection of MPCs in two models of cervical spinal cord injury, unilateral C5 contusion and complete unilateral C5 hemisection. MPCs isolated from green fluorescence protein (GFP)-luciferase transgenic mice compact bone (1 × 10(6) cells), or vehicle Hank's Buffered Saline Solution (HBSS), were intravenously injected via the tail vein at D1, D3, D7, D10, or D14. Transplanted MPCs were tracked via bioluminescence imaging. Live in vivo imaging data showed that intravenously injected MPCs accumulate in the lungs, confirmed by postmortem bioluminescence signal-irrespective of the time of injection or injury model. The results showed a rapid, positive modulation of the inflammatory response providing protection to the injured spinal cord tissue. Histological processing of the lungs showed GFP(+) cells evenly distributed around the alveoli. We propose that injected cells can act as cellular target decoys to an immune system primed by injury, thereby lessening the inflammatory response at the injury site. We also propose that intravenous injected MPCs modulate the immune system via the lungs through secreted immune mediators or contact interaction with peripheral organs. In conclusion, the timing of intravenous injection of MPCs is key to the success for improving function and tissue preservation following cervical spinal cord injury. Stem Cells 2016;34:1812-1825.
Asunto(s)
Vértebras Cervicales/patología , Pulmón/patología , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas/citología , Traumatismos de la Médula Espinal/terapia , Administración Intravenosa , Animales , Axones/patología , Conducta Animal , Antígeno CD11b/metabolismo , Sulfatos de Condroitina/metabolismo , Contusiones , Femenino , Inmunohistoquímica , Mediciones Luminiscentes , Ratones , Neovascularización Fisiológica , Neuroglía/patología , Traumatismos de la Médula Espinal/patología , Distribución Tisular , Resultado del TratamientoRESUMEN
Sphingosine-1-phosphate (S1P) is a lipid second messenger that signals via five G protein-coupled receptors (S1P1-5 ). S1P receptor (S1PR) signalling is associated with a wide variety of physiological processes including lymphocyte biology, their recirculation and determination of T-cell phenotypes. The effect of FTY720 (Fingolimod, Gilenya™) to regulate lymphocyte egress and to ameliorate paralysis in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis led to the use of FTY720 as a first-line oral agent for treatment of relapsing-remitting multiple sclerosis. However, a significant body of research suggests that S1P signalling may participate in diverse immune regulatory functions other than lymphocyte trafficking. This review article discusses the current knowledge of S1P signalling in the fate and function of T regulatory, T helper type 17 and memory T cells in health and disease.
Asunto(s)
Receptores de Lisoesfingolípidos/metabolismo , Transducción de Señal , Linfocitos T/inmunología , Linfocitos T/metabolismo , Animales , Humanos , Receptores de Esfingosina-1-Fosfato , Linfocitos T/citologíaRESUMEN
Understanding the neuropathology of multiple sclerosis (MS) is essential for improved therapies. Therefore, identification of targets specific to pathological types of MS may have therapeutic benefits. Here we identify, by laser-capture microdissection and proteomics, proteins unique to three major types of MS lesions: acute plaque, chronic active plaque and chronic plaque. Comparative proteomic profiles identified tissue factor and protein C inhibitor within chronic active plaque samples, suggesting dysregulation of molecules associated with coagulation. In vivo administration of hirudin or recombinant activated protein C reduced disease severity in experimental autoimmune encephalomyelitis and suppressed Th1 and Th17 cytokines in astrocytes and immune cells. Administration of mutant forms of recombinant activated protein C showed that both its anticoagulant and its signalling functions were essential for optimal amelioration of experimental autoimmune encephalomyelitis. A proteomic approach illuminated potential therapeutic targets selective for specific pathological stages of MS and implicated participation of the coagulation cascade.
Asunto(s)
Perfilación de la Expresión Génica , Esclerosis Múltiple/metabolismo , Esclerosis Múltiple/patología , Proteómica , Adulto , Animales , Coagulación Sanguínea , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/metabolismo , Encefalomielitis Autoinmune Experimental/patología , Femenino , Humanos , Inflamación/metabolismo , Inflamación/patología , Masculino , Ratones , Persona de Mediana Edad , Esclerosis Múltiple/clasificación , Esclerosis Múltiple/tratamiento farmacológico , Proteína C/genética , Proteína C/metabolismo , Proteína C/farmacología , Células TH1/inmunología , Células Th2/inmunología , Trombina/antagonistas & inhibidores , Trombina/metabolismoRESUMEN
BACKGROUND: Antipsychotic medications (APMs) and selective serotonin reuptake inhibitors (SSRIs) are frequently utilized in patients with neuroinflammatory disorders, such as autoimmune encephalitis and multiple sclerosis (MS). This retrospective study investigates how in-hospital treatment with APMs and SSRIs in patients with these neuroinflammatory diseases are associated with differences in hospital length-of-stay (LOS) and mortality. METHODS: We evaluated all the inpatients in the Stanford University Hospital from 2008 to 2023 diagnosed with either non-infectious encephalitis or MS and subdivided them into those who did or did not receive APMs or SSRIs while hospitalized. We then analyzed whether hospital LOS and mortality differed with these medications. RESULTS: Among inpatients with non-infectious encephalitis (n = 114), those who were exposed to APMs had a significantly increased mean LOS (11.8 vs 20.9 days, p < 0.01). For inpatients with MS (n = 1095), treatment with an APM was associated with a significant increase in mean LOS (2.8 vs. 7.1, p < 0.00001). When comparing typical to atypical APMs given to subjects with MS, those who received atypical APMs showed a significant increase in LOS (4.3 vs 10.5, p < 0.01), although typical APMs showed significantly increased risk of mortality (p < 0.05). For inpatients with MS and SSRI use, there was a significant increase in mean hospital LOS (3.5 vs 5.3, p < 0.01), with a significant difference found in those who received fluoxetine or citalopram, but not sertraline or escitalopram. Finally, several healthcare disparities were found, including that Black patients were more likely to receive APMs, and those with MS were more likely to receive typical rather than atypical APMs. Conversely, Black patients with MS were less likely to receive SSRI treatment. CONCLUSIONS: There was a statistically significant increase in LOS associated with APM use in non-infectious encephalitis and MS, as well as with SSRI use in MS. These data reflect the importance of these medications in these neuroinflammatory disorders and suggest that further investigation into their risks and benefits would be warranted.
Asunto(s)
Antipsicóticos , Encefalitis , Tiempo de Internación , Esclerosis Múltiple , Humanos , Estudios Retrospectivos , Femenino , Masculino , Esclerosis Múltiple/tratamiento farmacológico , Adulto , Encefalitis/tratamiento farmacológico , Encefalitis/mortalidad , Persona de Mediana Edad , Tiempo de Internación/estadística & datos numéricos , Antipsicóticos/uso terapéutico , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Enfermedad de Hashimoto/tratamiento farmacológico , Adulto JovenRESUMEN
Few intrapericardial robotic lung resection cases have been reported in the literature because of the perceived complexity of the procedure, with most surgeons embarking on an open resection via a thoracotomy. We present the case of a right middle and lower lobe tumour involving the pericardium and the origin of the right middle lobe vein. An intrapericardial lower bilobectomy was performed, with pericardial resection, pre-pericardial fat resection and mesh reconstruction. The vascular stapler for the right middle lobe vein was fired on the atrium. The resection was completed via a retrograde and fissureless approach, dividing the bronchus intermedius first, because it was impossible to open the fissure, leaving the division of the pulmonary artery until last. The case was performed solely robotically, with no complications and excellent postoperative recovery. Robotic resection can be performed successfully when pericardial lung tumours are involved.
Asunto(s)
Atrios Cardíacos , Neoplasias Pulmonares , Pericardio , Neumonectomía , Procedimientos Quirúrgicos Robotizados , Humanos , Procedimientos Quirúrgicos Robotizados/métodos , Pericardio/cirugía , Neoplasias Pulmonares/cirugía , Neumonectomía/métodos , Atrios Cardíacos/cirugía , Masculino , Procedimientos de Cirugía Plástica/métodos , Persona de Mediana Edad , Engrapadoras Quirúrgicas , FemeninoRESUMEN
BACKGROUND AND OBJECTIVES: Neuromyelitis optica spectrum disorder (NMOSD) is a chronic CNS demyelinating autoimmune disorder targeting the astrocyte antigen aquaporin-4 (AQP4), typically presenting with optic neuritis, transverse myelitis, and brain syndromes. Cognitive dysfunction (CD) in NMOSD is under-recognized and poorly understood. The purpose of this study was to evaluate the prevalence and clinical variables associated with CD in NMOSD. METHODS: This observational retrospective study with longitudinal follow-up describes a clinical cohort seen in the Collaborative International Research in Clinical and Longitudinal Experience Study in NMOSD. Serial Montreal Cognitive Assessments (MoCAs) were performed upon enrollment and at 6-month intervals to evaluate longitudinal cognitive function relative to demographic and disease-related factors. We used 2-tailed t test, analysis of variance, the χ2 test, linear regression for univariable and adjusted analyses and simultaneous linear regression and mixed-effects model for multivariable analyses. RESULTS: Thirty-four percent (75/219) of patients met criteria for CD (MoCA <26); 29% (64/219) showed mild dysfunction (MoCA 20-26/30), and 5% (11/219) showed moderate (MoCA <20/30) dysfunction. Patients with less neurologic disability and lower pain scores had higher MoCA scores (95% CI 0.24-0.65 and 95% CI 0.09-0.42, respectively). Patients with at least high school education scored higher on the MoCA (95% CI 2.2-5). When comparing patients dichotomized for CD, patients never on rituximab scored higher than patients only treated with rituximab (p < 0.029). There was no significant association between annualized relapse rate, age, sex, disease duration, AQP4 serostatus or brain lesions, and CD. CD was more pronounced among Black than White patients (95% CI -2.7 to -0.7). Multivariable analysis of serial MoCA did not indicate change (p = 0.715). Descriptive analysis of serial MoCA showed 30% (45/150) of patients with worsening MoCA performance had impaired language and verbal recall. DISCUSSION: To our knowledge, this is the largest study of diverse cohort to investigate CD in patients with NMOSD. Our findings demonstrate 34% of patients with NMOSD experience mild-to-moderate CD, while 30% of patients demonstrated decline on serial testing. The substantial prevalence of CD in this pilot report highlights the need for improved and validated screening tools and comprehensive measures to investigate CD in NMOSD.
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Disfunción Cognitiva , Neuromielitis Óptica , Humanos , Neuromielitis Óptica/complicaciones , Neuromielitis Óptica/epidemiología , Prevalencia , Estudios Retrospectivos , Rituximab , Recurrencia Local de Neoplasia , Disfunción Cognitiva/epidemiología , Acuaporina 4RESUMEN
ABSTRACT: CD19 chimeric antigen receptor (CAR) T-cell therapy has proven highly effective for treating relapsed/refractory mantle cell lymphoma (MCL). However, immune effector cell-associated neurotoxicity syndrome (ICANS) remains a significant concern. This study aimed to evaluate the clinical, radiological, and laboratory correlatives associated with ICANS development after CD19 CAR T-cell therapy in patients with MCL. All patients (N = 26) who received standard-of-care brexucabtagene autoleucel until July 2022 at our institution were evaluated. Laboratory and radiographic correlatives including brain magnetic resonance imaging (MRI) and electroencephalogram (EEG) were evaluated to determine the clinical impact of ICANS. Seventeen (65%) patients experienced ICANS after treatment, with a median onset on day 6. Ten (38%) patients experienced severe (grade ≥3) ICANS. All patients with ICANS had antecedent cytokine release syndrome (CRS), but no correlation was observed between ICANS severity and CRS grade. Overall, 92% of EEGs revealed interictal changes; no patients experienced frank seizures because of ICANS. In total, 86% of patients with severe ICANS with postinfusion brain MRIs demonstrated acute neuroimaging findings not seen on pretreatment MRI. Severe ICANS was also associated with higher rates of cytopenia, coagulopathy, increased cumulative steroid exposure, and prolonged hospitalization. However, severe ICANS did not affect treatment outcomes of patients with MCL. Severe ICANS is frequently associated with a range of postinfusion brain MRI changes and abnormal EEG findings. Longer hospitalization was observed in patients with severe ICANS, especially those with abnormal acute MRI or EEG findings, but there was no discernible impact on overall treatment response and survival.
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Linfoma de Células del Manto , Síndromes de Neurotoxicidad , Humanos , Adulto , Linfoma de Células del Manto/terapia , Inmunoterapia Adoptiva/efectos adversos , Proteínas Adaptadoras Transductoras de Señales , Antígenos CD19 , Encéfalo , Síndrome de Liberación de CitoquinasRESUMEN
Four questions were posed about multiple sclerosis (MS) at the 2011 Charcot Lecture, Oct. 22, 2011. 1. The Male/Female Disparity: Why are women developing MS so much more frequently than men? 2. Neuronal and Glial Protection: Are there guardian molecules that protect the nervous system in MS? 3. Predictive Medicine: With all the approved drugs, how can we rationally decide which one to use? 4. The Precise Scalpel vs. the Big Hammer for Therapy: Is antigen-specific therapy for demyelinating disease possible? To emphasize how our views on the pathogenesis and treatment of MS are evolving, and given the location of the talk in Amsterdam, Piet Mondrian's progressive interpretations of trees serve as a heuristic.