RESUMEN
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
OBJECTIVE: Identify autoantibodies in anti-Ro/SS-A negative primary Sjögren's syndrome (SS). METHODS: This is a proof-of-concept, case-control study of SS, healthy (HC) and other disease (OD) controls. A discovery dataset of plasma samples (n=30 SS, n=15 HC) was tested on human proteome arrays containing 19 500 proteins. A validation dataset of plasma and stimulated parotid saliva from additional SS cases (n=46 anti-Ro+, n=50 anti-Ro-), HC (n=42) and OD (n=54) was tested on custom arrays containing 74 proteins. For each protein, the mean+3 SD of the HC value defined the positivity threshold. Differences from HC were determined by Fisher's exact test and random forest machine learning using 2/3 of the validation dataset for training and 1/3 for testing. Applicability of the results was explored in an independent rheumatology practice cohort (n=38 Ro+, n=36 Ro-, n=10 HC). Relationships among antigens were explored using Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) interactome analysis. RESULTS: Ro+ SS parotid saliva contained autoantibodies binding to Ro60, Ro52, La/SS-B and muscarinic receptor 5. SS plasma contained 12 novel autoantibody specificities, 11 of which were detected in both the discovery and validation datasets. Binding to ≥1 of the novel antigens identified 54% of Ro- SS and 37% of Ro+ SS cases, with 100% specificity in both groups. Machine learning identified 30 novel specificities showing receiver operating characteristic area under the curve of 0.79 (95% CI 0.64 to 0.93) for identifying Ro- SS. Sera from Ro- cases of an independent cohort bound 17 of the non-canonical antigens. Antigenic targets in both Ro+ and Ro- SS were part of leukaemia cell, ubiquitin conjugation and antiviral defence pathways. CONCLUSION: We identified antigenic targets of the autoantibody response in SS that may be useful for identifying up to half of Ro seronegative SS cases.
Asunto(s)
Autoanticuerpos , Síndrome de Sjögren , Humanos , Estudios de Casos y Controles , Autoantígenos , Curva ROC , Inmunoglobulina G , Anticuerpos AntinuclearesRESUMEN
B cells have emerged as an important immune cell type that can be targeted for therapy in multiple sclerosis (MS). Depleting B cells with anti-CD20 antibodies is effective in treating MS. Yet, atacicept treatment, which blocks B-cell Activating Factor (BAFF) and A Proliferation-Inducing Ligand (APRIL), two cytokines important for B cell development and function, paradoxically increases disease activity in MS patients. The reason behind the failure of atacicept is not well understood. The stark differences in clinical outcomes with these therapies demonstrate that B cells have both inflammatory and anti-inflammatory functions in MS. In this review, we summarize the importance of B cells in MS and discuss the different B cell subsets that perform inflammatory and anti-inflammatory functions and how therapies modulate B cell functions in MS patients. Additionally, we discuss the potential anti-inflammatory functions of BAFF and APRIL on MS disease.
Asunto(s)
Subgrupos de Linfocitos B , Esclerosis Múltiple , Humanos , Linfocitos B , Subgrupos de Linfocitos B/metabolismo , Citocinas/uso terapéutico , Factor Activador de Células B/metabolismoRESUMEN
Von Hippel-Lindau (VHL) is an E3 ubiquitin ligase that targets proteins, including HIF-1α, for proteasomal degradation. VHL and HIF regulate the balance between glycolysis and oxidative phosphorylation, which is critical in highly dynamic T cells. HIF-1α positively regulates Th17 differentiation, a complex process in which quiescent naive CD4 T cells undergo transcriptional changes to effector cells, which are commonly dysregulated in autoimmune diseases. The role of VHL in Th17 cells is not known. In this study, we hypothesized VHL negatively regulates Th17 differentiation and deletion of VHL in CD4 T cells would elevate HIF-1α and increase Th17 differentiation. Unexpectedly, we found that VHL promotes Th17 differentiation. Mice deficient in VHL in their T cells were resistant to an autoimmune disease, experimental autoimmune encephalomyelitis, often mediated by Th17 cells. In vitro Th17 differentiation was impaired in VHL-deficient T cells. In the absence of VHL, Th17 cells had decreased activation of STAT3 and SMAD2, suggesting that VHL indirectly or directly regulates these critical signaling molecules. Gene expression analysis revealed that in Th17 cells, VHL regulates many cellular pathways, including genes encoding proteins involved indirectly or directly in the glycolysis pathway. Compared with wild-type, VHL-deficient Th17 cells had elevated glycolysis and glycolytic capacity. Our finding has implications on the design of therapeutics targeting the distinct metabolic needs of T cells to combat chronic inflammatory diseases.
Asunto(s)
Diferenciación Celular/fisiología , Células Th17/metabolismo , Células Th17/fisiología , Ubiquitina-Proteína Ligasas/metabolismo , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/metabolismo , Animales , Femenino , Expresión Génica/fisiología , Glucólisis/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/fisiología , Proteína Smad2/metabolismoRESUMEN
Pertussis toxin (PTX) is a required co-adjuvant for experimental autoimmune encephalomyelitis (EAE) induced by immunization with myelin antigen. However, PTX's effects on EAE induced by the transfer of myelin-specific T helper cells is not known. Therefore, we investigated how PTX affects the Th17 transfer EAE model (Th17-EAE). We found that PTX significantly reduced Th17-EAE by inhibiting chemokine-receptor-dependent trafficking of Th17 cells. Strikingly, PTX also promoted the accumulation of B cells in the CNS, suggesting that PTX alters the disease toward a B-cell-dependent pathology. To determine the role of B cells, we compared the effects of PTX on Th17-EAE in wild-type (WT) and B-cell-deficient (µMT) mice. Without PTX treatment, disease severity was equivalent between WT and µMT mice. In contrast, with PTX treatment, the µMT mice had significantly less disease and a reduction in pathogenic Th17 cells in the CNS compared to the WT mice. In conclusion, this study shows that PTX inhibits the migration of pathogenic Th17 cells, while promoting the accumulation of pathogenic B cells in the CNS during Th17-EAE. These data provide useful methodological information for adoptive-transfer Th17-EAE and, furthermore, describe another important experimental system to study the pathogenic mechanisms of B cells in multiple sclerosis.
Asunto(s)
Linfocitos B/patología , Encefalomielitis Autoinmune Experimental/patología , Toxina del Pertussis/administración & dosificación , Células Th17/patología , Traslado Adoptivo/métodos , Animales , Linfocitos B/inmunología , Movimiento Celular/inmunología , Encefalomielitis Autoinmune Experimental/inducido químicamente , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/mortalidad , Femenino , Humanos , Estimación de Kaplan-Meier , Ratones , Ratones Endogámicos C57BL , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/patología , Glicoproteína Mielina-Oligodendrócito/administración & dosificación , Índice de Severidad de la Enfermedad , Células Th17/inmunología , Células Th17/trasplanteRESUMEN
Multiple sclerosis (MS) is an autoimmune demyelinating disease with progressive neurodegeneration and complex etiology likely involving genetic and environmental factors. MS has been associated with Epstein Barr virus (EBV) infection, with patients often showing enhanced responses to EBV antigens. To determine whether abnormal EBV nuclear antigen-1 (EBNA-1) humoral immunity can serve as an initiator of autoimmune responses in MS, we investigated the fine specificities of the humoral immune response against EBNA-1 in MS patients using solid phase epitope mapping. Antibodies from MS patients recognized an EBNA-1 epitope spanning amino acids 411-426, previously unknown to be recognized specifically by untreated MS patients. Antibodies against this epitope cross-reacted to myelin basic protein (MBP). Furthermore, animals immunized with this EBNA-1 polypeptide mounted a response against MBP and developed signs of experimental autoimmune encephalitis (EAE). These data support a link between MS and EBV through antibodies that cross-react between EBV proteins and the MBP autoantigen.
Asunto(s)
Infecciones por Virus de Epstein-Barr/inmunología , Antígenos Nucleares del Virus de Epstein-Barr/inmunología , Herpesvirus Humano 4/inmunología , Esclerosis Múltiple/inmunología , Péptidos/inmunología , Adulto , Animales , Anticuerpos Antivirales/inmunología , Autoantígenos/inmunología , Reacciones Cruzadas/inmunología , Modelos Animales de Enfermedad , Epítopos/inmunología , Femenino , Humanos , Inmunidad Humoral/inmunología , Ratones , Ratones Endogámicos BALB C , Esclerosis Múltiple/virologíaRESUMEN
Multiple sclerosis (MS) is an autoimmune disorder where both T cells and B cells are implicated in pathology. However, it remains unclear how these two distinct populations cooperate to drive disease. There is ample evidence from studies in both MS patients and mouse models that Th17, B cells, and follicular T helper (TFH) cells contribute to disease. This review article describes the literature that identifies mechanisms by which Th17, TFH, and B cells cooperatively drive disease activity in MS and experimental autoimmune encephalomyelitis (EAE). The curation of this literature has identified that central nervous system (CNS) infiltrating TFH cells act with TH17 cell to contribute to an inflammatory B cell response in neuroinflammation. This demonstrates that TFH cells and their products are promising targets for therapies in MS.
Asunto(s)
Encefalomielitis Autoinmune Experimental/inmunología , Tejido Linfoide/citología , Esclerosis Múltiple/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Animales , HumanosRESUMEN
Although interferon-beta is the most popular treatment for multiple sclerosis, its mechanism of action remains enigmatic. In this issue of Immunity, Prinz et al. (2008) elucidate an intriguing portrait of the pleiotropic effects of type 1 interferons in taming brain inflammation.
Asunto(s)
Encéfalo/inmunología , Citocinas/metabolismo , Encefalomielitis Autoinmune Experimental/inmunología , Interferón beta/metabolismo , Receptor de Interferón alfa y beta/metabolismo , Traslado Adoptivo , Animales , Autoinmunidad , Linfocitos B/inmunología , Linfocitos B/metabolismo , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Citocinas/inmunología , Encefalomielitis Autoinmune Experimental/metabolismo , Antígenos de Histocompatibilidad Clase II/metabolismo , Humanos , Interferón beta/inmunología , Ratones , Microglía/inmunología , Microglía/metabolismo , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/metabolismo , Vaina de Mielina/inmunología , Células Mieloides/inmunología , Células Mieloides/metabolismo , Fagocitosis , Receptor de Interferón alfa y beta/inmunología , Transducción de Señal , Regulación hacia ArribaRESUMEN
IFN-ß remains the most widely prescribed treatment for relapsing remitting multiple sclerosis. Despite widespread use of IFN-ß, the therapeutic mechanism is still partially understood. Particularly, the clinical relevance of increased B cell activity during IFN-ß treatment is unclear. In this article, we show that IFN-ß pushes some B cells into a transitional, regulatory population that is a critical mechanism for therapy. IFN-ß treatment increases the absolute number of regulatory CD19(+)CD24(++)CD38(++) transitional B cells in peripheral blood relative to treatment-naive and Copaxone-treated patients. In addition, we found that transitional B cells from both healthy controls and IFN-ß-treated MS patients are potent producers of IL-10, and that the capability of IFN-ß to induce IL-10 is amplified when B cells are stimulated. Similar changes are seen in mice with experimental autoimmune encephalomyelitis. IFN-ß treatment increases transitional and regulatory B cell populations, as well as IL-10 secretion in the spleen. Furthermore, we found that IFN-ß increases autoantibody production, implicating humoral immune activation in B cell regulatory responses. Finally, we demonstrate that IFN-ß therapy requires immune-regulatory B cells by showing that B cell-deficient mice do not benefit clinically or histopathologically from IFN-ß treatment. These results have significant implications for the diagnosis and treatment of relapsing remitting multiple sclerosis.
Asunto(s)
Autoinmunidad/efectos de los fármacos , Subgrupos de Linfocitos B/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Interferón beta/farmacología , Esclerosis Múltiple Recurrente-Remitente/inmunología , Animales , Antígenos CD/genética , Antígenos CD/inmunología , Autoanticuerpos/biosíntesis , Subgrupos de Linfocitos B/efectos de los fármacos , Subgrupos de Linfocitos B/patología , Encéfalo/efectos de los fármacos , Encéfalo/inmunología , Encéfalo/patología , Estudios de Casos y Controles , Encefalomielitis Autoinmune Experimental/inducido químicamente , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/genética , Femenino , Regulación de la Expresión Génica , Acetato de Glatiramer , Humanos , Inmunosupresores/farmacología , Interleucina-10/biosíntesis , Depleción Linfocítica , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/genética , Esclerosis Múltiple Recurrente-Remitente/patología , Glicoproteína Mielina-Oligodendrócito , Fragmentos de Péptidos , Péptidos/farmacología , Transducción de Señal , Bazo/efectos de los fármacos , Bazo/inmunología , Bazo/patologíaRESUMEN
Understanding the consequences of tuning TCR signaling on selection, peripheral T cell function, and tolerance in the context of native TCR repertoires may provide insight into the physiological control of tolerance. In this study, we show that genetic ablation of a natural tuner of TCR signaling, mir-181a-1/b-1, in double-positive thymocytes dampened TCR and Erk signaling and increased the threshold of positive selection. Whereas mir-181a-1/b-1 deletion in mice resulted in an increase in the intrinsic reactivity of naive T cells to self-antigens, it did not cause spontaneous autoimmunity. Loss of mir-181a-1/b-1 dampened the induction of experimental autoimmune encephalomyelitis and reduced basal TCR signaling in peripheral T cells and their migration from lymph nodes to pathogenic sites. Taken together, these results demonstrate that tolerance can be modulated by microRNA gene products through the control of opposing activities in T cell selection and peripheral T cell function.
Asunto(s)
Selección Clonal Mediada por Antígenos/genética , Selección Clonal Mediada por Antígenos/inmunología , Tolerancia Inmunológica/genética , MicroARNs/genética , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Animales , Autoinmunidad , Movimiento Celular/genética , Movimiento Celular/inmunología , Modelos Animales de Enfermedad , Fosfatasa 6 de Especificidad Dual/metabolismo , Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/patología , Eliminación de Gen , Inmunización , Lisofosfolípidos/inmunología , Sistema de Señalización de MAP Quinasas , Ratones , Ratones Noqueados , Oligonucleótidos/genética , Interferencia de ARN , Receptores de Antígenos de Linfocitos T/metabolismo , Transducción de Señal , Esfingosina/análogos & derivados , Esfingosina/inmunología , Timocitos/inmunología , Timocitos/metabolismoRESUMEN
Each year, 10 million people worldwide survive the neurologic injury associated with a stroke. Importantly, stroke survivors have more than twice the risk of subsequently developing dementia compared with people who have never had a stroke. The link between stroke and the later development of dementia is not understood. There are reports of oligoclonal bands in the CSF of stroke patients, suggesting that in some people a B-lymphocyte response to stroke may occur in the CNS. Therefore, we tested the hypothesis that a B-lymphocyte response to stroke could contribute to the onset of dementia. We discovered that, in mouse models, activated B-lymphocytes infiltrate infarcted tissue in the weeks after stroke. B-lymphocytes undergo isotype switching, and IgM, IgG, and IgA antibodies are found in the neuropil adjacent to the lesion. Concurrently, mice develop delayed deficits in LTP and cognition. Genetic deficiency, and the pharmacologic ablation of B-lymphocytes using an anti-CD20 antibody, prevents the appearance of delayed cognitive deficits. Furthermore, immunostaining of human postmortem tissue revealed that a B-lymphocyte response to stroke also occurs in the brain of some people with stroke and dementia. These data suggest that some stroke patients may develop a B-lymphocyte response to stroke that contributes to dementia, and is potentially treatable with FDA-approved drugs that target B cells.
Asunto(s)
Subgrupos de Linfocitos B/inmunología , Demencia/etiología , Infarto de la Arteria Cerebral Media/inmunología , Anciano , Animales , Estudios de Casos y Controles , Demencia/inmunología , Demencia/fisiopatología , Femenino , Humanos , Inmunoglobulinas/inmunología , Infarto de la Arteria Cerebral Media/complicaciones , Infarto de la Arteria Cerebral Media/fisiopatología , Potenciación a Largo Plazo , Masculino , Aprendizaje por Laberinto , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BLAsunto(s)
Encéfalo/inmunología , Quimiotaxis de Leucocito/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Esclerosis Múltiple/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Animales , Quimiocina CCL20/inmunología , Plexo Coroideo/inmunología , Humanos , Inflamación/inmunología , Interleucina-17/inmunología , Receptores CCR6/inmunologíaRESUMEN
PURPOSE: Optic neuritis affects most patients with multiple sclerosis (MS), and current treatments are unreliable. The purpose of this study was to characterize the contribution of Th1 and Th17 cells to the development of optic neuritis. METHODS: Mice were passively transferred myelin-specific Th1 or Th17 cells to induce experimental autoimmune encephalomyelitis (EAE), a model of neuroautoimmunity. Visual acuity was assessed daily with optokinetic tracking, and 1, 2, and 3 weeks post-induction, optic nerves and retinas were harvested for immunohistochemical analyses. RESULTS: Passive transfer experimental autoimmune encephalomyelitis elicits acute episodes of asymmetric visual deficits and is exacerbated in Th17-EAE relative to Th1-EAE. The Th17-EAE optic nerves contained more inflammatory infiltrates and an increased neutrophil to macrophage ratio. Significant geographic degeneration of the retinal ganglion cells accompanied Th17-EAE but not Th1. CONCLUSIONS: Th17-induced transfer EAE recapitulates pathologies observed in MS-associated optic neuritis, namely, monocular episodes of vision loss, optic nerve inflammation, and geographic retinal ganglion cell (RGC) degeneration.
Asunto(s)
Encefalomielitis Autoinmune Experimental/inmunología , Vaina de Mielina/inmunología , Neuritis Óptica/inmunología , Células Ganglionares de la Retina/patología , Células Th17/inmunología , Animales , Apoptosis/inmunología , Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental/patología , Femenino , Inmunización Pasiva , Macrófagos/inmunología , Ratones , Ratones Endogámicos C57BL , Esclerosis Múltiple/inmunología , Neutrófilos/inmunología , Neuritis Óptica/patología , Células TH1/inmunología , Agudeza Visual/fisiologíaRESUMEN
PURPOSE: Optic neuritis, inflammation of the optic nerve, is experienced by most patients with multiple sclerosis (MS) and is typically characterized by episodes of acute, monocular vision loss. These episodes of inflammation can lead to damage or degeneration of the retinal ganglion cells (RGCs), the axons of which comprise the optic nerve. Experimental autoimmune encephalomyelitis (EAE) is a well-established model of MS in which mice are immunized to produce a neuroautoimmunity that recapitulates the cardinal hallmarks of human disease, namely, inflammation, demyelination, and neurodegeneration of the brain, spinal cord, and optic nerve. Inflammation-associated oxidative stress plays a key role in promoting spinal cord damage in EAE. However, the role of oxidative stress in optic neuritis and the associated visual deficits has not been studied. To address this gap in research, we sought to determine how a deficiency in the master antioxidant transcription factor (using nuclear factor-E2-related factor [Nrf2]-deficient mice) affects visual pathology in the EAE model. METHODS: EAE was induced in 8-week-old wild-type (WT) and Nrf2 knockout (KO) mice by immunization against the myelin oligodendrocyte glycoprotein (MOG) peptide antigen. Motor deficits were monitored daily, as was visual acuity using the established functional optokinetic tracking (OKT) assay. Mice were euthanized 21 days post-immunization for histological analyses. The optic nerves were paraffin-embedded and stained with hematoxylin and eosin (H&E) or immune cell type-specific antibodies to analyze inflammatory infiltrates. The retinas were flatmounted and stained with an RGC-specific antibody, and the RGCs were counted to assess neurodegeneration. T-helper (Th) cell-associated cytokines were measured in spleens with enzyme-linked immunosorbent assay (ELISA). Immune analyses of healthy, non-EAE mice were characterized with flow cytometry to assess the baseline immune cell profiles. RESULTS: Female Nrf2 KO mice exhibited more severe EAE-induced motor deficits compared with female WT mice. In both genders, EAE elicited more severe visual acuity deficits, inflammation of the optic nerve, and RGC degeneration in KO mice compared with their strain- and age-matched WT counterparts. Visual acuity deficits were primarily present in (and only exacerbated in) one eye of each mouse. Excess inflammatory cells within the optic nerves of the KO mice were primarily comprised of T-cells, and greater RGC degeneration in the KO mice was most prevalent in the central retina compared with the peripheral retina. Nrf2 KO spleens exhibited an increased Th1- but not Th17-associated immune response. This enhanced pathology in the KO mice was not due to global differences in immune system development between the two genotypes. CONCLUSIONS: This is the first study to report that genetic ablation of Nrf2 exacerbates visual deficits, inflammation of the optic nerve, and RGC degeneration in a murine model of MS, suggesting that Nrf2 plays a neuro- and cytoprotective role in EAE-associated optic neuritis.
Asunto(s)
Encefalomielitis Autoinmune Experimental/complicaciones , Encefalomielitis Autoinmune Experimental/patología , Factor 2 Relacionado con NF-E2/deficiencia , Neuritis Óptica/complicaciones , Neuritis Óptica/patología , Agudeza Visual , Animales , Citocinas/metabolismo , Encefalomielitis Autoinmune Experimental/fisiopatología , Femenino , Inflamación/patología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Factor 2 Relacionado con NF-E2/metabolismo , Nervio Óptico/patología , Neuritis Óptica/fisiopatología , Parálisis/patología , Células Ganglionares de la Retina/metabolismo , Células Ganglionares de la Retina/patología , Caracteres Sexuales , Bazo/patología , Células TH1/metabolismoRESUMEN
The balance between controlling infection and limiting inflammation is particularly precarious in the brain because of its unique vulnerability to the toxic effects of inflammation. Astrocytes have been implicated as key regulators of neuroinflammation in CNS infections, including infection with Toxoplasma gondii, a protozoan parasite that naturally establishes a chronic CNS infection in mice and humans. In CNS toxoplasmosis, astrocytes are critical to controlling parasite growth. They secrete proinflammatory cytokines and physically encircle parasites. However, the molecular mechanisms used by astrocytes to limit neuroinflammation during toxoplasmic encephalitis have not yet been identified. TGF-ß signaling in astrocytes is of particular interest because TGF-ß is universally upregulated during CNS infection and serves master regulatory and primarily anti-inflammatory functions. We report in this study that TGF-ß signaling is activated in astrocytes during toxoplasmic encephalitis and that inhibition of astrocytic TGF-ß signaling increases immune cell infiltration, uncouples proinflammatory cytokine and chemokine production from CNS parasite burden, and increases neuronal injury. Remarkably, we show that the effects of inhibiting astrocytic TGF-ß signaling are independent of parasite burden and the ability of GFAP(+) astrocytes to physically encircle parasites.
Asunto(s)
Astrocitos/inmunología , Neuronas/inmunología , Transducción de Señal/inmunología , Toxoplasma/inmunología , Toxoplasmosis Cerebral/inmunología , Factor de Crecimiento Transformador beta/inmunología , Animales , Astrocitos/parasitología , Astrocitos/patología , Quimiocinas/genética , Quimiocinas/inmunología , Proteína Ácida Fibrilar de la Glía , Humanos , Ratones , Ratones Transgénicos , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/inmunología , Neuronas/parasitología , Neuronas/patología , Transducción de Señal/genética , Toxoplasma/genética , Toxoplasmosis Cerebral/genética , Toxoplasmosis Cerebral/patología , Factor de Crecimiento Transformador beta/genética , Regulación hacia Arriba/genética , Regulación hacia Arriba/inmunologíaRESUMEN
In multiple sclerosis, type I interferon (IFN) is considered immune-modulatory, and recombinant forms of IFN-ß are the most prescribed treatment for this disease. This is in contrast to most other autoimmune disorders, because type I IFN contributes to the pathologies. Even within the relapsing-remitting multiple sclerosis (RRMS) population, 30-50% of MS patients are non-responsive to this treatment, and it consistently worsens neuromyelitis optica, a disease similar to RRMS. In this article, we discuss the recent advances in the field of autoimmunity and introduce the theory explain how type I IFNs can be pro-inflammatory in disease that is predominantly driven by a Th17 response and are therapeutic when disease is predominantly Th1.
Asunto(s)
Enfermedades Autoinmunes/tratamiento farmacológico , Interferón Tipo I/uso terapéutico , Animales , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/metabolismo , Modelos Animales de Enfermedad , Encefalomielitis/tratamiento farmacológico , Encefalomielitis/inmunología , Encefalomielitis/metabolismo , Humanos , Interferón Tipo I/efectos adversos , Interferón Tipo I/metabolismo , Interferón beta/efectos adversos , Interferón beta/metabolismo , Interferón beta/uso terapéutico , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Células TH1/inmunología , Células TH1/metabolismo , Células Th17/inmunología , Células Th17/metabolismoRESUMEN
Type I IFNs (IFN-α and IFN-ß) and type II IFN (IFN-γ) mediate both regulation and inflammation in multiple sclerosis, neuromyelitis optica, and in experimental autoimmune encephalomyelitis (EAE). However, the underlying mechanism for these Janus-like activities of type I and II IFNs in neuroinflammation remains unclear. Although endogenous type I IFN signaling provides a protective response in neuroinflammation, we find that when IFN-γ signaling is ablated, type I IFNs drive inflammation, resulting in exacerbated EAE. IFN-γ has a disease stage-specific opposing function in EAE. Treatment of mice with IFN-γ during the initiation phase of EAE leads to enhanced severity of disease. In contrast, IFN-γ treatment during the effector phase attenuated disease. This immunosuppressive activity of IFN-γ required functional type I IFN signaling. In IFN-α/ß receptor-deficient mice, IFN-γ treatment during effector phase of EAE exacerbated disease. Using an adoptive transfer EAE model, we found that T cell-intrinsic type I and II IFN signals are simultaneously required to establish chronic EAE by encephalitogenic Th1 cells. However, in Th17 cells loss of either IFN signals leads to the development of a severe chronic disease. The data imply that type I and II IFN signals have independent but nonredundant roles in restraining encephalitogenic Th17 cells in vivo. Collectively, our data show that type I and II IFNs function in an integrated manner to regulate pathogenesis in EAE.
Asunto(s)
Encefalomielitis Autoinmune Experimental/inmunología , Interferón Tipo I/inmunología , Interferón gamma/inmunología , Traslado Adoptivo , Animales , Encefalomielitis Autoinmune Experimental/metabolismo , Inmunohistoquímica , Interferón Tipo I/metabolismo , Interferón gamma/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Transducción de Señal/inmunología , Células Th17/inmunologíaRESUMEN
In chronically inflamed tissues, such as those affected by autoimmune disease, activated Th cells often colocalize with monocytes. We investigate in this study how murine Th cells influence the phenotype and function of monocytes. The data demonstrate that Th1, Th2, and Th17 subsets promote the differentiation of autologous monocytes into MHC class II(+), CD11b(+), CD11c(+) DC that we call DCTh. Although all Th subsets induce the formation of DCTh, activated Th17 cells uniquely promote the formation of IL-12/IL-23-producing DCTh (DCTh17) that can polarize both naive and Th17 cells to a Th1 phenotype. In the inflamed CNS of mice with Th17-mediated experimental autoimmune encephalomyelitis, Th cells colocalize with DC, as well as monocytes, and the Th cells obtained from these lesions drive the formation of DCTh that are phenotypically indistinguishable from DCTh17 and polarize naive T cells toward a Th1 phenotype. These results suggest that DCTh17 are critical in the interplay of Th17- and Th1-mediated responses and may explain the previous finding that IL-17-secreting Th cells become IFN-γ-secreting Th1 cells in experimental autoimmune encephalomyelitis and other autoimmune disorders.
Asunto(s)
Autoinmunidad/inmunología , Células Dendríticas/inmunología , Inflamación/inmunología , Células TH1/inmunología , Células Th17/inmunología , Animales , Antígeno CD11b/metabolismo , Antígeno CD11c/metabolismo , Diferenciación Celular , Movimiento Celular , Polaridad Celular , Células Cultivadas , Sistema Nervioso Central/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Femenino , Antígenos de Histocompatibilidad Clase II/metabolismo , Interferón gamma/metabolismo , Interleucina-12/biosíntesis , Interleucina-17/metabolismo , Interleucina-23/biosíntesis , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Monocitos/inmunologíaRESUMEN
Interferon (IFN)-ß is the treatment most often prescribed for relapsing-remitting multiple sclerosis (RRMS). 30-50% of MS patients, however, do not respond to IFN-ß. In some cases, IFN-ß exacerbates MS, and it consistently worsens neuromyelitis optica (NMO). To eliminate unnecessary treatment for patients who are non-responsive to IFN-ß, and to avoid possible harm, researchers are identifying biomarkers that predict treatment outcome before treatment is initiated. These biomarkers reveal insights into the mechanisms of disease. Recent discoveries on human samples from patients with RRMS, NMO, psoriasis, rheumatoid arthritis, systemic lupus erythematosus and ulcerative colitis, indicate that IFN-ß is ineffective and might worsen clinical status in diverse diseases when a Th17 immune response is prominent.
Asunto(s)
Interferón beta/inmunología , Células Th17/inmunología , Animales , Enfermedades Autoinmunes/inmunología , Humanos , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Interferón beta/uso terapéutico , Modelos Inmunológicos , Células Th17/efectos de los fármacosRESUMEN
CD5 activates casein kinase 2 (CK2), a serine/threonine kinase that constitutively associates with the CK2-binding domain at the end of its cytoplasmic tail. To determine the physiological significance of CD5-dependent CK2 activation in T cells, we generated a knock-in mouse that expresses a CD5 protein containing a microdeletion with selective inability to interact with CK2 (CD5ΔCK2BD). The levels of CD5 on developing and mature T cell populations from CD5ΔCK2BD mice and CD5 wild-type (WT) mice were similar. The thymus of CD5ΔCK2BD mice contained fewer double-positive thymocytes than did that of both CD5WT and CD5 knockout (KO) mice, although the numbers of all other immature and mature T cell populations were unaltered. CD5ΔCK2BD T cells hypoproliferated and exhibited enhanced activation-induced cell death when stimulated with anti-CD3 or cognate peptide in comparison with CD5WT T cells. We also found that functional CD5-dependent CK2 signaling was necessary for efficient differentiation of naive CD4+ T cells into Th2 and Th17 cells, but not Th1 cells. We previously showed that experimental autoimmune encephalomyelitis (EAE) in CD5KO mice was less severe and delayed in onset than in CD5WT mice. Remarkably, CD5ΔCK2BD mice recapitulated both EAE severity and disease onset of CD5KO mice. Increasing the immunization dose of myelin oligodendrocyte glycoprotein 35-55 peptide, a model that mimics high-dose tolerance, led to decreased severity of EAE in CD5WT mice but not in CD5KO or CD5ΔCK2BD mice. This property was recapitulated in in vitro restimulation assays. These results demonstrate that CD5-CK2 signaling sets the threshold for T cell responsiveness and is necessary for efficient generation of Th2 and Th17 cells.