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1.
Proc Natl Acad Sci U S A ; 117(9): 4983-4993, 2020 03 03.
Artículo en Inglés | MEDLINE | ID: mdl-32051245

RESUMEN

Lymphocytes infiltrate the stroke core and penumbra and often exacerbate cellular injury. B cells, however, are lymphocytes that do not contribute to acute pathology but can support recovery. B cell adoptive transfer to mice reduced infarct volumes 3 and 7 d after transient middle cerebral artery occlusion (tMCAo), independent of changing immune populations in recipient mice. Testing a direct neurotrophic effect, B cells cocultured with mixed cortical cells protected neurons and maintained dendritic arborization after oxygen-glucose deprivation. Whole-brain volumetric serial two-photon tomography (STPT) and a custom-developed image analysis pipeline visualized and quantified poststroke B cell diapedesis throughout the brain, including remote areas supporting functional recovery. Stroke induced significant bilateral B cell diapedesis into remote brain regions regulating motor and cognitive functions and neurogenesis (e.g., dentate gyrus, hypothalamus, olfactory areas, cerebellum) in the whole-brain datasets. To confirm a mechanistic role for B cells in functional recovery, rituximab was given to human CD20+ (hCD20+) transgenic mice to continuously deplete hCD20+-expressing B cells following tMCAo. These mice experienced delayed motor recovery, impaired spatial memory, and increased anxiety through 8 wk poststroke compared to wild type (WT) littermates also receiving rituximab. B cell depletion reduced stroke-induced hippocampal neurogenesis and cell survival. Thus, B cell diapedesis occurred in areas remote to the infarct that mediated motor and cognitive recovery. Understanding the role of B cells in neuronal health and disease-based plasticity is critical for developing effective immune-based therapies for protection against diseases that involve recruitment of peripheral immune cells into the injured brain.


Asunto(s)
Encéfalo/metabolismo , Movimiento Celular/fisiología , Neurogénesis/fisiología , Recuperación de la Función/fisiología , Accidente Cerebrovascular/metabolismo , Inmunidad Adaptativa , Animales , Linfocitos B/metabolismo , Encéfalo/patología , Cognición , Giro Dentado/metabolismo , Modelos Animales de Enfermedad , Humanos , Infarto de la Arteria Cerebral Media , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Plasticidad Neuronal , Neuronas/metabolismo
2.
Crit Care Med ; 47(3): e206-e213, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30640221

RESUMEN

OBJECTIVES: Extracorporeal membrane oxygenation provides short-term cardiopulmonary life support, but is associated with peripheral innate inflammation, disruptions in cerebral autoregulation, and acquired brain injury. We tested the hypothesis that extracorporeal membrane oxygenation also induces CNS-directed adaptive immune responses which may exacerbate extracorporeal membrane oxygenation-associated brain injury. DESIGN: A single center prospective observational study. SETTING: Pediatric and cardiac ICUs at a single tertiary care, academic center. PATIENTS: Twenty pediatric extracorporeal membrane oxygenation patients (0-14 yr; 13 females, 7 males) and five nonextracorporeal membrane oxygenation Pediatric Logistic Organ Dysfunction score matched patients INTERVENTIONS:: None. MEASUREMENTS AND MAIN RESULTS: Venous blood samples were collected from the extracorporeal membrane oxygenation circuit at day 1 (10-23 hr), day 3, and day 7 of extracorporeal membrane oxygenation. Flow cytometry quantified circulating innate and adaptive immune cells, and CNS-directed autoreactivity was detected using an in vitro recall response assay. Disruption of cerebral autoregulation was determined using continuous bedside near-infrared spectroscopy and acquired brain injury confirmed by MRI. Extracorporeal membrane oxygenation patients with acquired brain injury (n = 9) presented with a 10-fold increase in interleukin-8 over extracorporeal membrane oxygenation patients without brain injury (p < 0.01). Furthermore, brain injury within extracorporeal membrane oxygenation patients potentiated an inflammatory phenotype in adaptive immune cells and selective autoreactivity to brain peptides in circulating B cell and cytotoxic T cell populations. Correlation analysis revealed a significant relationship between adaptive immune responses of extracorporeal membrane oxygenation patients with acquired brain injury and loss of cerebral autoregulation. CONCLUSIONS: We show that pediatric extracorporeal membrane oxygenation patients with acquired brain injury exhibit an induction of pro-inflammatory cell signaling, a robust activation of adaptive immune cells, and CNS-targeting adaptive immune responses. As these patients experience developmental delays for years after extracorporeal membrane oxygenation, it is critical to identify and characterize adaptive immune cell mechanisms that target the developing CNS.


Asunto(s)
Inmunidad Adaptativa/inmunología , Lesiones Encefálicas/terapia , Encéfalo/inmunología , Oxigenación por Membrana Extracorpórea , Adolescente , Linfocitos B/inmunología , Lesiones Encefálicas/inmunología , Estudios de Casos y Controles , Niño , Preescolar , Descubrimiento de Drogas , Oxigenación por Membrana Extracorpórea/efectos adversos , Femenino , Citometría de Flujo , Humanos , Lactante , Recién Nacido , Inflamación/etiología , Inflamación/inmunología , Masculino , Puntuaciones en la Disfunción de Órganos , Proyectos Piloto , Linfocitos T Citotóxicos/inmunología
3.
Exerc Immunol Rev ; 25: 34-49, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30785868

RESUMEN

Individuals with amnestic mild cognitive impairment (aMCI) experience cognitive declines in learning and memory greater than expected for normal aging, and are at a high risk of dementia. We previously reported that sedentary aMCI patients exhibited neuroinflammation that correlated with brain amyloid beta (Aß) burden, as determined by 18F-florbetapir positron emission tomography (PET). These aMCI patients enrolled in a one-year randomized control trial (AETMCI, NCT01146717) to test the beneficial effects of 12 months of moderate-to-high intensity aerobic exercise training (AET) or stretching/toning (ST) control intervention on neurocognitive function. A subset of aMCI participants had PET imaging, cognitive testing, and immunophenotyping of cerebrospinal fluid (CSF) and peripheral blood after AET or ST interventions. As adaptive immune responses were similar between AET and ST groups, we combined AET/ST into a general 'physical activity' (PA) group and compared Aß burden, cognitive function, and adaptive immune cell subsets to sedentary lifestyle before intervention. We found that PAinduced immunomodulation of CD4+ and CD8+ T cells in CSF correlated with changes in Aß burden in brain regions associated with executive function. Furthermore, after PA, cognitive scores on tests of memory, processing speed, attention, verbal fluency, and executive function were associated with increased percent representation of circulating naïve B + T cells. We review the literature on aMCI-related cognition and immune changes as they relate to exercise, and highlight how our preliminary data suggest a complex interplay between the adaptive immune system, physical activity, cognition, and Aß burden in aMCI.


Asunto(s)
Inmunidad Adaptativa , Péptidos beta-Amiloides/metabolismo , Subgrupos de Linfocitos B/citología , Disfunción Cognitiva , Ejercicio Físico , Subgrupos de Linfocitos T/citología , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto
4.
J Neuroinflammation ; 14(1): 149, 2017 07 27.
Artículo en Inglés | MEDLINE | ID: mdl-28750671

RESUMEN

BACKGROUND: We previously found that subjects with amnestic mild cognitive impairment exhibit a pro-inflammatory immune profile in the cerebrospinal fluid similar to multiple sclerosis, a central nervous system autoimmune disease. We therefore hypothesized that early neuroinflammation would reflect increases in brain amyloid burden during amnestic mild cognitive impairment. METHODS: Cerebrospinal fluid and blood samples were collected from 24 participants with amnestic mild cognitive impairment (12 men, 12 women; 66 ± 6 years; 0.5 Clinical Dementia Rating) enrolled in the AETMCI study. Analyses of cerebrospinal fluid and blood included immune profiling by multi-parameter flow cytometry, genotyping for apolipoprotein (APO)ε, and quantification of cytokine and immunoglobin levels. Amyloid (A)ß deposition was determined by 18F-florbetapir positron emission tomography. Spearman rank order correlations were performed to assess simple linear correlation for parameters including amyloid imaging, central and peripheral immune cell populations, and protein cytokine levels. RESULTS: Soluble Aß42 in the cerebrospinal fluid declined as Aß deposition increased overall and in the precuneous and posterior cingulate cortices. Lymphocyte profiling revealed a significant decline in T cell populations in the cerebrospinal fluid, specifically CD4+ T cells, as Aß deposition in the posterior cingulate cortex increased. In contrast, increased Aß burden correlated positively with increased memory B cells in the cerebrospinal fluid, which was exacerbated in APOε4 carriers. For peripheral circulating lymphocytes, only B cell populations decreased with Aß deposition in the precuneous cortex, as peripheral T cell populations did not correlate with changes in brain amyloid burden. CONCLUSIONS: Elevations in brain Aß burden associate with a shift from T cells to memory B cells in the cerebrospinal fluid of subjects with amnestic mild cognitive impairment in this exploratory cohort. These data suggest the presence of cellular adaptive immune responses during Aß accumulation, but further study needs to determine whether lymphocyte populations contribute to, or result from, Aß dysregulation during memory decline on a larger cohort collected at multiple centers. TRIAL REGISTRATION: AETMCI NCT01146717.


Asunto(s)
Inmunidad Adaptativa/fisiología , Péptidos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Disfunción Cognitiva , Citocinas/metabolismo , Linfocitos/patología , Anciano , Compuestos de Anilina/metabolismo , Apolipoproteínas E/genética , Encéfalo/diagnóstico por imagen , Disfunción Cognitiva/sangre , Disfunción Cognitiva/líquido cefalorraquídeo , Disfunción Cognitiva/patología , Glicoles de Etileno/metabolismo , Femenino , Citometría de Flujo , Humanos , Masculino , Persona de Mediana Edad , Tomografía de Emisión de Positrones
5.
J Immunol ; 191(1): 117-26, 2013 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-23733879

RESUMEN

Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the CNS, and CD8 T cells are the predominant T cell population in MS lesions. Given that transfer of CNS-specific CD8 T cells results in an attenuated clinical demyelinating disease in C57BL/6 mice with immunization-induced experimental autoimmune encephalomyelitis (EAE), we investigated the cellular targets and mechanisms of autoreactive regulatory CD8 T cells. In this study we report that myelin oligodendrocyte glycoprotein peptide (MOG35-55)-induced CD8 T cells could also attenuate adoptively transferred, CD4 T cell-mediated EAE. Whereas CD8(-/-) mice exhibited more severe EAE associated with increased autoreactivity and inflammatory cytokine production by myelin-specific CD4 T cells, this was reversed by adoptive transfer of MOG-specific CD8 T cells. These autoregulatory CD8 T cells required in vivo MHC class Ia (K(b)D(b)) presentation. Interestingly, MOG-specific CD8 T cells could also suppress adoptively induced disease using wild-type MOG35-55-specific CD4 T cells transferred into K(b)D(b-/-) recipient mice, suggesting direct targeting of encephalitogenic CD4 T cells. In vivo trafficking analysis revealed that autoregulatory CD8 T cells are dependent on neuroinflammation for CNS infiltration, and their suppression/cytotoxicity of MOG-specific CD4 T cells is observed both in the periphery and in the CNS. These studies provide important insights into the mechanism of disease suppression mediated by autoreactive CD8 T cells in EAE.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/patología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/prevención & control , Traslado Adoptivo , Secuencia de Aminoácidos , Animales , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/patología , Enfermedades Autoinmunes/prevención & control , Linfocitos T CD8-positivos/trasplante , Células Cultivadas , Citotoxicidad Inmunológica , Encefalomielitis Autoinmune Experimental/patología , Femenino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Datos de Secuencia Molecular
6.
Clin Immunol ; 152(1-2): 115-26, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24657764

RESUMEN

Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS). Although its etiology remains unknown, pathogenic T cells are thought to underlie MS immune pathology. We recently showed that MS patients harbor CNS-specific CD8+ Tregs that are deficient during disease relapse. We now demonstrate that CNS-specific CD8+ Tregs were cytolytic and could eliminate pathogenic CD4+ T cells. These CD8+ Tregs were present primarily in terminally differentiated (CD27-, CD45RO-) subset and their suppression was IFNγ, perforin and granzyme B-dependent. Interestingly, MS patients with acute relapse displayed a significant loss in terminally differentiated CD8+ T cells, with a concurrent loss in expression of perforin and granzyme B. Pre-treatment of exacerbation-derived CD8+ T cells with IL-12 significantly restored suppressive capability of these cells through upregulation of granzyme B. Our studies uncover immune-suppressive mechanisms of CNS-specific CD8+ Tregs, and may contribute to design of novel immune therapies for MS.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Esclerosis Múltiple/inmunología , Linfocitos T Reguladores/inmunología , Adulto , Anciano , Diferenciación Celular/inmunología , Progresión de la Enfermedad , Femenino , Granzimas/biosíntesis , Granzimas/inmunología , Antígenos de Histocompatibilidad Clase I/inmunología , Humanos , Interferón gamma/inmunología , Interleucina-12/farmacología , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Antígenos Comunes de Leucocito/metabolismo , Activación de Linfocitos/inmunología , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/patología , Perforina/inmunología , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/metabolismo , Regulación hacia Arriba , Adulto Joven
7.
Eur J Immunol ; 43(2): 382-93, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-23169140

RESUMEN

The autoimmune disease systemic lupus erythematosus is characterized by loss of tolerance to nuclear Ags and a heightened inflammatory environment, which together result in end organ damage. Lyn-deficient mice, a model of systemic lupus erythematosus, lack an inhibitor of B-cell and myeloid cell activation. This results in B-cell hyper-responsiveness, plasma cell accumulation, autoantibodies, and glomerulonephritis (GN). IL-21 is associated with autoimmunity in mice and humans and promotes B-cell differentiation and class switching. Here, we explore the role of IL-21 in the autoimmune phenotypes of lyn(-/-) mice. We find that IL-21 mRNA is reduced in the spleens of lyn(-/-) IL-6(-/-) and lyn(-/-) Btk(lo) mice, neither of which produce pathogenic autoantibodies or develop significant GN. While IL-21 is dispensable for plasma cell accumulation and IgM autoantibodies in lyn(-/-) mice, it is required for anti-DNA IgG antibodies and some aspects of T-cell activation. Surprisingly, GN still develops in lyn(-/-) IL-21(-/-) mice. This likely results from the presence of IgG autoantibodies against a limited set of non-DNA Ags. These studies identify a specific role for IL-21 in the class switching of anti-DNA B cells and demonstrate that neither IL-21 nor anti-DNA IgG is required for kidney damage in lyn(-/-) mice.


Asunto(s)
Anticuerpos Antinucleares/inmunología , ADN/inmunología , Inmunoglobulina G/inmunología , Interleucinas/inmunología , Riñón/inmunología , Familia-src Quinasas/genética , Agammaglobulinemia Tirosina Quinasa , Animales , Autoanticuerpos/inmunología , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/metabolismo , Linfocitos B/inmunología , Linfocitos B/metabolismo , ADN/genética , Glomerulonefritis/genética , Glomerulonefritis/inmunología , Glomerulonefritis/metabolismo , Interleucina-6/deficiencia , Interleucina-6/genética , Interleucina-6/inmunología , Interleucina-6/metabolismo , Interleucinas/genética , Interleucinas/metabolismo , Riñón/metabolismo , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/inmunología , Lupus Eritematoso Sistémico/metabolismo , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Células Mieloides/inmunología , Células Mieloides/metabolismo , Células Plasmáticas/inmunología , Células Plasmáticas/metabolismo , Proteínas Tirosina Quinasas/genética , Proteínas Tirosina Quinasas/metabolismo , Bazo/inmunología , Bazo/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo , Familia-src Quinasas/inmunología , Familia-src Quinasas/metabolismo
8.
J Neuroinflammation ; 11: 22, 2014 Jan 31.
Artículo en Inglés | MEDLINE | ID: mdl-24485041

RESUMEN

BACKGROUND: Repetitive hypoxic preconditioning (RHP) creates an anti-inflammatory phenotype that protects from stroke-induced injury for months after a 2-week treatment. The mechanisms underlying long-term tolerance are unknown, though one exposure to hypoxia significantly increased peripheral B cell representation. For this study, we sought to determine if RHP specifically recruited B cells into the protected ischemic hemisphere, and whether RHP could phenotypically alter B cells prior to stroke onset. METHODS: Adult, male SW/ND4 mice received RHP (nine exposures over 2 weeks; 8 to 11 % O2; 2 to 4 hours) or identical exposures to 21 % O2 as control. Two weeks following RHP, a 60-minute transient middle cerebral artery occlusion was induced. Standard techniques quantified CXCL13 mRNA and protein expression. Two days after stroke, leukocytes were isolated from brain tissue (70:30 discontinuous Percoll gradient) and profiled on a BD-FACS Aria flow cytometer. In a separate cohort without stroke, sorted splenic CD19+ B cells were isolated 2 weeks after RHP and analyzed on an Illumina MouseWG-6 V2 Bead Chip. Final gene pathways were determined using Ingenuity Pathway Analysis. Student's t-test or one-way analysis of variance determined significance (P < 0.05). RESULTS: CXCL13, a B cell-specific chemokine, was upregulated in post-stroke cortical vessels of both groups. In the ischemic hemisphere, RHP increased B cell representation by attenuating the diapedesis of monocyte, macrophage, neutrophil and T cells, to quantities indistinguishable from the uninjured, contralateral hemisphere. Pre-stroke splenic B cells isolated from RHP-treated mice had >1,900 genes differentially expressed by microarray analysis. Genes related to B-T cell interactions, including antigen presentation, B cell differentiation and antibody production, were profoundly downregulated. Maturation and activation were arrested in a cohort of B cells from pre-stroke RHP-treated mice while regulatory B cells, a subset implicated in neurovascular protection from stroke, were upregulated. CONCLUSIONS: Collectively, our data characterize an endogenous neuroprotective phenotype that utilizes adaptive immune mechanisms pre-stroke to protect the brain from injury post-stroke. Future studies to validate the role of B cells in minimizing injury and promoting central nervous system recovery, and to determine whether B cells mediate an adaptive immunity to systemic hypoxia that protects from subsequent stroke, are needed.


Asunto(s)
Linfocitos B/metabolismo , Terapia de Inmunosupresión , Infarto de la Arteria Cerebral Media/complicaciones , Precondicionamiento Isquémico , Animales , Antígenos CD/metabolismo , Linfocitos B/patología , Proliferación Celular , Quimiocina CXCL1/metabolismo , Modelos Animales de Enfermedad , Endotelio/metabolismo , Endotelio/patología , Citometría de Flujo , Lateralidad Funcional , Regulación de la Expresión Génica/fisiología , Masculino , Ratones , Análisis por Micromatrices , Fosfopiruvato Hidratasa/metabolismo , Factores de Tiempo
9.
Ann Clin Transl Neurol ; 10(2): 276-291, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36579400

RESUMEN

OBJECTIVE: Despite successful endovascular therapy, a proportion of stroke patients exhibit long-term functional decline, regardless of the cortical reperfusion. Our objective was to evaluate the early activation of the adaptive immune response and its impact on neurological recovery in patients with large vessel occlusion (LVO). METHODS: Nineteen (13 females, 6 males) patients with acute LVO were enrolled in a single-arm prospective cohort study. During endovascular therapy (EVT), blood samples were collected from pre and post-occlusion, distal femoral artery, and median cubital vein (controls). Cytokines, chemokines, cellular and functional profiles were evaluated with immediate and follow-up clinical and radiographic parameters, including cognitive performance and functional recovery. RESULTS: In the hyperacute phase (within hours), adaptive immune activation was observed in the post-occlusion intra-arterial environment (post). Ischemic vascular tissue had a significant increase in T-cell-related cytokines, including IFN-γ and MMP-9, while GM-CSF, IL-17, TNF-α, IL-6, MIP-1a, and MIP-1b were decreased. Cellularity analysis revealed an increase in inflammatory IL-17+ and GM-CSF+ helper T-cells, while natural killer (NK), monocytes and B-cells were decreased. A correlation was observed between hypoperfused tissue, infarct volume, inflammatory helper, and cytotoxic T-cells. Moreover, helper and cytotoxic T-cells were also significantly increased in patients with improved motor function at 3 months. INTERPRETATION: We provide evidence of the activation of the inflammatory adaptive immune response during the hyperacute phase and the association of pro-inflammatory cytokines with greater ischemic tissue and worsening recovery after successful reperfusion. Further characterization of these immune pathways is warranted to test selective immunomodulators during the early stages of stroke rehabilitation.


Asunto(s)
Isquemia Encefálica , Disfunción Cognitiva , Trastornos de la Destreza Motora , Femenino , Humanos , Masculino , Citocinas , Factor Estimulante de Colonias de Granulocitos y Macrófagos , Inmunidad , Interleucina-17 , Estudios Prospectivos , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/inmunología , Accidente Cerebrovascular/terapia , Isquemia Encefálica/complicaciones , Isquemia Encefálica/inmunología , Isquemia Encefálica/terapia , Disfunción Cognitiva/etiología , Disfunción Cognitiva/inmunología , Trastornos de la Destreza Motora/etiología , Trastornos de la Destreza Motora/inmunología , Enfermedades Neuroinflamatorias/inmunología
10.
J Autoimmun ; 36(2): 115-24, 2011 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21257291

RESUMEN

Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS). MS is thought to be T-cell-mediated, with prior research predominantly focusing on CD4+ T-cells. There is a high prevalence of CNS-specific CD8+ T-cell responses in MS patients and healthy subjects. However, the role of neuroantigen-specific CD8+ T-cells in MS is poorly understood, with the prevalent notion that these may represent pathogenic T-cells. We show here that healthy subjects and MS patients demonstrate similar magnitudes of CD8+ and CD4+ T-cell responses to various antigenic stimuli. Interestingly, CD8+ T-cells specific for CNS autoantigens, but not those specific for control foreign antigens, exhibit immune regulatory ability, suppressing proliferation of CD4+CD25- T-cells when stimulated by their cognate antigen. While CD8+ T-cell-mediated immune suppression is similar between healthy subjects and clinically quiescent treatment-naïve MS patients, it is significantly deficient during acute exacerbation of MS. Of note, the recovery of neuroantigen-specific CD8+ T-cell suppression correlates with disease recovery post-relapse. These studies reveal a novel immune suppressor function for neuroantigen-specific CD8+ T-cells that is clinically relevant in the maintenance of peripheral tolerance and the intrinsic regulation of MS immune pathology.


Asunto(s)
Autoantígenos/inmunología , Linfocitos T CD8-positivos/inmunología , Esclerosis Múltiple/inmunología , Linfocitos T Reguladores/inmunología , Adulto , Anciano , Antígenos/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/metabolismo , Línea Celular , Proliferación Celular , Sistema Nervioso Central/inmunología , Sistema Nervioso Central/metabolismo , Sistema Nervioso Central/patología , Femenino , Citometría de Flujo , Humanos , Subunidad alfa del Receptor de Interleucina-2/inmunología , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/metabolismo , Linfocitos T Reguladores/metabolismo , Adulto Joven
11.
J Autoimmun ; 35(1): 33-44, 2010 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-20172692

RESUMEN

Immune-based self-recognition and failure to modulate this response are believed to contribute to the debilitating autoimmune pathology observed in multiple sclerosis (MS). Studies from its murine model, experimental autoimmune encephalomyelitis (EAE), have shown that neuroantigen-specific CD4+T cells are capable of inducing disease, while their immune sibling, the CD8+T cells, have largely been ignored. To understand their role in autoimmune demyelination, we first confirmed that, similar to our observations in human MS, there is robust induction of neuroantigen-reactive CD8+T cells in several models, including MOG(35-55)/CFA-induced EAE. However, MOG(35-55)-specific CD8+T-cells, when purified, were unable to adoptively transfer disease into naïve mice (in contrast to CD4+T-cells). In fact, we observed that the transfer of these neuroantigen-specific CD8+T cells was able to suppress the induction of EAE and to inhibit ongoing EAE. These regulatory CD8+T cells produced IFN-gamma and perforin and were able to kill MOG loaded CD4+T-cells as well as CD4-depleted APC, suggesting a cytotoxic/suppressor mechanism. Inhibition of EAE was associated with both the modulation of APC function as well as decreased MOG-specific CD4+T cell responses. Our studies reveal a novel and unexpected immune regulatory function for neuroantigen-specific CD8+T cells and have interesting biologic and therapeutic implications.


Asunto(s)
Linfocitos T CD8-positivos/metabolismo , Sistema Nervioso Central/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Esclerosis Múltiple/inmunología , Linfocitos T Reguladores/metabolismo , Animales , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Células Cultivadas , Citotoxicidad Inmunológica , Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental/patología , Femenino , Glicoproteínas/inmunología , Humanos , Interferón gamma/metabolismo , Ratones , Ratones Endogámicos C57BL , Glicoproteína Mielina-Oligodendrócito , Fragmentos de Péptidos/inmunología , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/patología
12.
Sci Rep ; 10(1): 11809, 2020 07 16.
Artículo en Inglés | MEDLINE | ID: mdl-32678268

RESUMEN

Cerebral vasospasm (VSP) is a common phenomenon after aneurysmal subarachnoid hemorrhage (aSAH) and contributes to neurocognitive decline. The natural history of the pro-inflammatory immune response after aSAH has not been prospectively studied in human cerebrospinal fluid (CSF). In this pilot study, we aimed to identify specific immune mediators of VSP after aSAH. Peripheral blood (PB) and CSF samples from patients with aSAH were prospectively collected at different time-points after hemorrhage: days 0-1 (acute); days 2-4 (pre-VSP); days 5-9 (VSP) and days 10 + (post-VSP peak). Presence and severity of VSP was assessed with computed tomography angiography/perfusion imaging and clinical examination. Cytokine and immune mediators' levels were quantified using ELISA. Innate and adaptive immune cells were characterized by flow cytometry, and cell counts at different time-points were compared with ANOVA. Confocal immunostaining was used to determine the presence of specific immune cell populations detected in flow cytometry. Thirteen patients/aneurysms were included. Five (38.5%) patients developed VSP after a mean of 6.8 days from hemorrhage. Flow cytometry demonstrated decreased numbers of CD45+ cells during the acute phase in PB of aSAH patients compared with healthy controls. In CSF of VSP patients, NK cells (CD3-CD161 +) were increased during the acute phase and progressively declined, whereas CD8+CD161+ lymphocytes significantly increased at days 5-9. Microglia cells (CD45dimCD11b +) increased over time after SAH. This increase was particularly significant in patients with VSP. Levels of VEGF and MMP-9 were consistently higher in VSP patients, with the highest difference occurring at the acute phase. Confocal immunostaining demonstrated the presence of CD8+CD161+ lymphocytes in the arterial wall of two unruptured intracranial aneurysms. In this preliminary study, human CSF showed active presence of innate and adaptive immune cells after aSAH. CD8+CD161+ lymphocytes may have an important role in the inflammatory response after aneurysmal rupture and were identified in the aneurysmal wall of unruptured brain aneurysms. Microglia activation occurs 6 + days after aSAH.


Asunto(s)
Aneurisma Roto/complicaciones , Inmunidad , Hemorragia Subaracnoidea/etiología , Hemorragia Subaracnoidea/metabolismo , Inmunidad Adaptativa , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores , Citocinas/metabolismo , Femenino , Humanos , Inmunidad Innata , Inmunohistoquímica , Mediadores de Inflamación , Masculino , Persona de Mediana Edad , Hemorragia Subaracnoidea/patología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Subgrupos de Linfocitos T/patología , Vasoespasmo Intracraneal/etiología , Vasoespasmo Intracraneal/metabolismo
13.
J Cereb Blood Flow Metab ; 37(3): 801-813, 2017 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-27006446

RESUMEN

Repetitive hypoxic preconditioning creates long-lasting, endogenous protection in a mouse model of stroke, characterized by reductions in leukocyte-endothelial adherence, inflammation, and infarct volumes. The constitutively expressed chemokine CXCL12 can be upregulated by hypoxia and limits leukocyte entry into brain parenchyma during central nervous system inflammatory autoimmune disease. We therefore hypothesized that the sustained tolerance to stroke induced by repetitive hypoxic preconditioning is mediated, in part, by long-term CXCL12 upregulation at the blood-brain barrier (BBB). In male Swiss Webster mice, repetitive hypoxic preconditioning elevated cortical CXCL12 protein levels, and the number of cortical CXCL12+ microvessels, for at least two weeks after the last hypoxic exposure. Repetitive hypoxic preconditioning-treated mice maintained more CXCL12-positive vessels than untreated controls following transient focal stroke, despite cortical decreases in CXCL12 mRNA and protein. Continuous administration of the CXCL12 receptor (CXCR4) antagonist AMD3100 for two weeks following repetitive hypoxic preconditioning countered the increase in CXCL12-positive microvessels, both prior to and following stroke. AMD3100 blocked the protective post-stroke reductions in leukocyte diapedesis, including macrophages and NK cells, and blocked the protective effect of repetitive hypoxic preconditioning on lesion volume, but had no effect on blood-brain barrier dysfunction. These data suggest that CXCL12 upregulation prior to stroke onset, and its actions following stroke, contribute to the endogenous, anti-inflammatory phenotype induced by repetitive hypoxic preconditioning.


Asunto(s)
Quimiocina CXCL12/metabolismo , Precondicionamiento Isquémico , Leucocitos/inmunología , Accidente Cerebrovascular/patología , Animales , Barrera Hematoencefálica , Movimiento Celular/inmunología , Inflamación/patología , Inflamación/prevención & control , Masculino , Ratones , Regulación hacia Arriba
14.
J Neuroimmunol ; 180(1-2): 159-71, 2006 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-16935352

RESUMEN

We have demonstrated that GA therapy induces a differential upregulation of GA-specific, cytotoxic/suppressor CD8+ T-cell responses in MS patients. We utilized a novel combination of flow sorting and anchored PCR to analyze the evolving clonal composition of GA-specific CD4+ and CD8+ T-cells. TCRbeta chain analysis revealed the development of an oligoclonal GA-specific CD8+ repertoire with persistence of dominant clones over long periods. Interestingly, some sequences resembled published oligoclonal CD8+ TCR sequences from MS lesions. In contrast, GA-specific CD4+ responses were polyclonal and showed continual evolution of their repertoire. This clonotypic and functional analysis provides mechanistic insights into GA therapy.


Asunto(s)
Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/inmunología , Péptidos/farmacología , Adulto , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Antígenos CD8/efectos de los fármacos , Antígenos CD8/genética , Antígenos CD8/inmunología , Células Clonales/efectos de los fármacos , Células Clonales/inmunología , Femenino , Citometría de Flujo/métodos , Acetato de Glatiramer , Humanos , Factores Inmunológicos/farmacología , Factores Inmunológicos/uso terapéutico , Inmunosupresores/farmacología , Inmunosupresores/uso terapéutico , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Esclerosis Múltiple/fisiopatología , Péptidos/uso terapéutico , Reacción en Cadena de la Polimerasa/métodos , Receptores de Antígenos de Linfocitos T alfa-beta/efectos de los fármacos , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología
15.
Neurotherapeutics ; 13(4): 729-747, 2016 10.
Artículo en Inglés | MEDLINE | ID: mdl-27492770

RESUMEN

It is well established that post-stroke inflammation contributes to neurovascular injury, blood-brain barrier disruption, and poor functional recovery in both animal and clinical studies. However, recent studies also suggest that several leukocyte subsets, activated during the post-stroke immune response, can exhibit both pro-injury and pro-recovery phenotypes. In accordance with these findings, B lymphocytes, or B cells, play a heterogeneous role in the adaptive immune response to stroke. This review highlights what is currently understood about the various roles of B cells, with an emphasis on stroke risk factors, as well as post-stroke injury and repair. This includes an overview of B cell functions, such as antibody production, cytokine secretion, and contribution to the immune response as antigen presenting cells. Next, evidence for B cell-mediated mechanisms in stroke-related risk factors, including hypertension, diabetes, and atherosclerosis, is outlined, followed by studies that focus on B cells during endogenous protection from stroke. Subsequently, animal studies that investigate the role of B cells in post-stroke injury and repair are summarized, and the final section describes current B cell-related clinical trials for stroke, as well as other central nervous system diseases. This review reveals the complex role of B cells in stroke, with a focus on areas for potential clinical intervention for a disease that affects millions of people globally each year.


Asunto(s)
Linfocitos B/fisiología , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/patología , Accidente Cerebrovascular/prevención & control , Animales , Humanos , Accidente Cerebrovascular/inmunología
16.
J Leukoc Biol ; 99(1): 21-9, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26038434

RESUMEN

pCH is an important risk factor for brain injury and long-term morbidity in children, occurring during the developmental stages of neurogenesis, neuronal migration, and myelination. We show that a rodent model of pCH results in an early decrease in mature myelin. Although pCH does increase progenitor oligodendrocytes in the developing brain, BrdU labeling revealed a loss in dividing progenitor oligodendrocytes, indicating a defect in mature cell replacement and myelinogenesis. Mice continued to exhibited hypomyelination, concomitant with long-term impairment of motor function, weeks after cessation of pCH. The implication of a novel neuroimmunologic interplay, pCH also induced a significant egress of infiltrating CD4 T cells into the developing brain. This pCH-mediated neuroinflammation included oligodendrocyte-directed autoimmunity, with an increase in peripheral myelin-specific CD4 T cells. Thus, both the loss of available, mature, myelin-producing glial cells and an active increase in autoreactive, myelin-specific CD4 T cell infiltration into pCH brains may contribute to early pCH-induced hypomyelination in the developing CNS. The elucidation of potential mechanisms of hypoxia-driven autoimmunity will expand our understanding of the neuroimmune axis during perinatal CNS disease states that may contribute to long-term functional disability.


Asunto(s)
Autoinmunidad , Corteza Cerebral/inmunología , Corteza Cerebral/metabolismo , Hipoxia/inmunología , Hipoxia/metabolismo , Vaina de Mielina/inmunología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Animales , Conducta Animal , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/patología , Corteza Cerebral/patología , Modelos Animales de Enfermedad , Femenino , Inflamación , Ratones , Actividad Motora , Proteína Básica de Mielina/inmunología , Neuroglía/inmunología , Neuroglía/metabolismo , Neuroglía/patología , Embarazo , Especificidad del Receptor de Antígeno de Linfocitos T/inmunología , Subgrupos de Linfocitos T/patología
17.
Artículo en Inglés | MEDLINE | ID: mdl-26137595

RESUMEN

The immune system plays a major pathological and regulatory role in multiple sclerosis (MS) and, therefore, is a focus of extensive research. Animal models of MS have been crucial in understanding the pathological processes in MS and developing certain treatments, however, all crucial aspects of the human disease may not be appropriately modeled. With the exception of detecting oligoclonal bands and IgG synthesis in cerebrospinal fluids of MS patients, there has not been major progress in the development of immunologic tests that can be used for diagnosis of MS. Further, due to the lack of validated immune assays, routine monitoring of the immune system following therapy initiation is not a part of standard patient care in MS. This is critical since immunomodulatory therapies used for MS treatment are not benign and, more importantly, there is a considerable variation in clinical responses in MS patients initiating such therapies. Flow cytometry is a powerful tool that can be used for studying both the phenotype and function of immune cells. The studies described here will demonstrate how flow cytometry can be used to apply current knowledge about the MS immune system to develop a diagnostic laboratory test for the immunologic monitoring of this disease. Importantly, we will also show that the multiparameter flow cytometry based assay developed by us can also be implemented for the immunologic evaluation of therapeutic success in MS patients.

18.
Neurol Neuroimmunol Neuroinflamm ; 2(6): e170, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26587555

RESUMEN

OBJECTIVE: To determine the antigenic determinants and specific molecular requirements for the generation of autoregulatory neuroantigen-specific CD8(+) T cells in models of multiple sclerosis (MS). METHODS: We have previously shown that MOG35-55-specific CD8(+) T cells suppress experimental autoimmune encephalomyelitis (EAE) in the C57BL/6 model. In this study, we utilized multiple models of EAE to assess the ability to generate autoregulatory CD8(+) T cells. RESULTS: We demonstrate that alternative myelin peptides (PLP178-191) and other susceptible mouse strains (SJL) generated myelin-specific CD8(+) T cells, which were fully capable of suppressing disease. The disease-ameliorating function of these cells was dependent on the specific cognate myelin antigen. Generation of these autoregulatory CD8(+) T cells was not affected by thymic selection, but was dependent on the presence of both CD4(+) and CD8(+) T-cell epitopes in the immunizing encephalitogenic antigen. CONCLUSIONS: These studies show that the generation of autoregulatory CD8(+) T cells is a more generalized, antigen-specific phenomenon across multiple neuroantigens and mouse strains, with significant implications in understanding disease regulation.

19.
Discov Med ; 19(106): 381-92, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-26105701

RESUMEN

Stroke affects millions of people worldwide every year. Despite this prevalence, mechanisms of long-term injury and repair within the ischemic brain are still understudied. Sterile inflammation occurs in the injured brain after stroke, with damaged tissue exposing central nervous system (CNS)-derived antigen that could initiate potential autoimmune responses. We used a standard immunology-based recall response assay for murine immune cells, isolated from the cervical lymph nodes and spleen after transient stroke, to determine if stroke induces autoreactivity to CNS target antigens. Our assays included novel neuronal peptides, in addition to myelin-, nuclear-, glial-, and endothelial-derived peptides. Autoimmune responses to an antigen were considered positive based on proliferation and activation over non-stimulated conditions. Stroke induced a significant increase in autoreactive CD4+ and CD8+ T cells, as well as autoreactive CD19+ B cells, as early as 4 days after stroke onset. Mice with large infarct volumes exhibited early T and B cell autoreactivity to NR2A, an NMDA receptor subunit, in cells isolated from lymph nodes but not spleen. Mice with small infarct volumes exhibited high autoreactivity to MAP2, a dendritic cytoskeletal protein, as well as myelin-derived peptides. This autoimmunity was maintained through 10 days post-stroke in both lymph nodes and spleen for all lymphocyte subsets. Sham surgery also induced early autoreactive B cell responses to MAP2 and myelin. Based on these observations, we hypothesize that stroke induces a secondary, complex, and dynamic autoimmune response to neuronal antigens with the potential to potentiate, or perhaps even ameliorate, long-term neuroinflammation.


Asunto(s)
Inmunidad Adaptativa/inmunología , Antígenos/inmunología , Autoinmunidad/inmunología , Neuronas/metabolismo , Accidente Cerebrovascular/inmunología , Secuencia de Aminoácidos , Animales , Linfocitos B/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Humanos , Ganglios Linfáticos , Masculino , Ratones , Datos de Secuencia Molecular , Vaina de Mielina/metabolismo , Péptidos/química , Recuperación de la Función , Bazo/patología
20.
J Vis Exp ; (99): e52675, 2015 May 04.
Artículo en Inglés | MEDLINE | ID: mdl-25993394

RESUMEN

Experimental animal models of stroke are invaluable tools for understanding stroke pathology and developing more effective treatment strategies. A 2 week protocol for repetitive hypoxic preconditioning (RHP) induces long-term protection against central nervous system (CNS) injury in a mouse model of focal ischemic stroke. RHP consists of 9 stochastic exposures to hypoxia that vary in both duration (2 or 4 hr) and intensity (8% and 11% O2). RHP reduces infarct volumes, blood-brain barrier (BBB) disruption, and the post-stroke inflammatory response for weeks following the last exposure to hypoxia, suggesting a long-term induction of an endogenous CNS-protective phenotype. The methodology for the dual quantification of infarct volume and BBB disruption is effective in assessing neurovascular protection in mice with RHP or other putative neuroprotectants. Adult male Swiss Webster mice were preconditioned by RHP or duration-equivalent exposures to 21% O2 (i.e. room air). A 60 min transient middle cerebral artery occlusion (tMCAo) was induced 2 weeks following the last hypoxic exposure. Both the occlusion and reperfusion were confirmed by transcranial laser Doppler flowmetry. Twenty-two hr after reperfusion, Evans Blue (EB) was intravenously administered through a tail vein injection. 2 hr later, animals were sacrificed by isoflurane overdose and brain sections were stained with 2,3,5- triphenyltetrazolium chloride (TTC). Infarcts volumes were then quantified. Next, EB was extracted from the tissue over 48 hr to determine BBB disruption after tMCAo. In summary, RHP is a simple protocol that can be replicated, with minimal cost, to induce long-term endogenous neurovascular protection from stroke injury in mice, with the translational potential for other CNS-based and systemic pro-inflammatory disease states.


Asunto(s)
Hipoxia/patología , Infarto de la Arteria Cerebral Media/patología , Precondicionamiento Isquémico/métodos , Animales , Barrera Hematoencefálica/patología , Encéfalo/irrigación sanguínea , Encéfalo/patología , Modelos Animales de Enfermedad , Azul de Evans/administración & dosificación , Azul de Evans/química , Hipoxia/metabolismo , Infarto de la Arteria Cerebral Media/metabolismo , Flujometría por Láser-Doppler , Masculino , Ratones , Distribución Aleatoria
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