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1.
Immunity ; 54(2): 308-323.e6, 2021 02 09.
Artículo en Inglés | MEDLINE | ID: mdl-33421362

RESUMEN

Th17 cells are known to exert pathogenic and non-pathogenic functions. Although the cytokine transforming growth factor ß1 (TGF-ß1) is instrumental for Th17 cell differentiation, it is dispensable for generation of pathogenic Th17 cells. Here, we examined the T cell-intrinsic role of Activin-A, a TGF-ß superfamily member closely related to TGF-ß1, in pathogenic Th17 cell differentiation. Activin-A expression was increased in individuals with relapsing-remitting multiple sclerosis and in mice with experimental autoimmune encephalomyelitis. Stimulation with interleukin-6 and Activin-A induced a molecular program that mirrored that of pathogenic Th17 cells and was inhibited by blocking Activin-A signaling. Genetic disruption of Activin-A and its receptor ALK4 in T cells impaired pathogenic Th17 cell differentiation in vitro and in vivo. Mechanistically, extracellular-signal-regulated kinase (ERK) phosphorylation, which was essential for pathogenic Th17 cell differentiation, was suppressed by TGF-ß1-ALK5 but not Activin-A-ALK4 signaling. Thus, Activin-A drives pathogenic Th17 cell differentiation, implicating the Activin-A-ALK4-ERK axis as a therapeutic target for Th17 cell-related diseases.


Asunto(s)
Activinas/metabolismo , Encefalomielitis Autoinmune Experimental/inmunología , Esclerosis Múltiple/inmunología , Inflamación Neurogénica/inmunología , Células Th17/inmunología , Factor de Crecimiento Transformador beta/metabolismo , Receptores de Activinas Tipo I/genética , Receptores de Activinas Tipo I/metabolismo , Activinas/genética , Animales , Diferenciación Celular , Células Cultivadas , Humanos , Ratones , Ratones Noqueados , Terapia Molecular Dirigida , Transducción de Señal
2.
Proc Natl Acad Sci U S A ; 120(26): e2221007120, 2023 06 27.
Artículo en Inglés | MEDLINE | ID: mdl-37339207

RESUMEN

The objective of this study is to examine IL-11-induced mechanisms of inflammatory cell migration to the central nervous system (CNS). We report that IL-11 is produced at highest frequency by myeloid cells among the peripheral blood mononuclear cell (PBMC) subsets. Patients with relapsing-remitting multiple sclerosis (RRMS) have an increased frequency of IL-11+ monocytes, IL-11+ and IL-11R+ CD4+ lymphocytes, and IL-11R+ neutrophils in comparison to matched healthy controls. IL-11+ and granulocyte-macrophage colony-stimulating factor (GM-CSF)+ monocytes, CD4+ lymphocytes, and neutrophils accumulate in the cerebrospinal fluid (CSF). The effect of IL-11 in-vitro stimulation, examined using single-cell RNA sequencing, revealed the highest number of differentially expressed genes in classical monocytes, including up-regulated NFKB1, NLRP3, and IL1B. All CD4+ cell subsets had increased expression of S100A8/9 alarmin genes involved in NLRP3 inflammasome activation. In IL-11R+-sorted cells from the CSF, classical and intermediate monocytes significantly up-regulated the expression of multiple NLRP3 inflammasome-related genes, including complement, IL18, and migratory genes (VEGFA/B) in comparison to blood-derived cells. Therapeutic targeting of this pathway with αIL-11 mAb in mice with RR experimental autoimmune encephalomyelitis (EAE) decreased clinical scores, CNS inflammatory infiltrates, and demyelination. αIL-11 mAb treatment decreased the numbers of NFκBp65+, NLRP3+, and IL-1ß+ monocytes in the CNS of mice with EAE. The results suggest that IL-11/IL-11R signaling in monocytes represents a therapeutic target in RRMS.


Asunto(s)
Encefalomielitis Autoinmune Experimental , Inflamasomas , Animales , Ratones , Inflamasomas/metabolismo , Monocitos/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Leucocitos Mononucleares/metabolismo , Interleucina-11/genética , Interleucina-11/metabolismo , Sistema Nervioso Central/metabolismo , Movimiento Celular
3.
J Immunol ; 209(1): 49-56, 2022 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-35750335

RESUMEN

The objective of this study is to determine the mechanism of action of anti-CD52 mAb treatment in patients with relapsing-remitting multiple sclerosis (RRMS). Experimental autoimmune encephalomyelitis (EAE), an animal model of the disease, was used to address the role of T regulatory cells (Tregs) in the anti-CD52 mAb-induced suppression of the disease. In vitro studies on PBMCs from RRMS patients and matched healthy controls determined the effect of IL-7 on the expansion of CD4+CD25+CD127- Tregs and induction of their suppressive phenotype. This study using EAE animal models of MS has shown that mouse anti-CD52 mAb suppression of clinical disease was augmented by coadministration of IL-7 and partially reversed by anti-IL-7 mAb. In vitro human studies showed that IL-7 induced expansion of CD4+CD25+CD127- Tregs and increased their FOXP3, GITIR, CD46, CTLA-4, granzyme B, and perforin expression. Anti-CD52 mAb treatment of mice with relapsing-remitting EAE induced expansion of Foxp3+CD4+ Tregs and the suppression of IL-17A+CD4+ and IFN-γ+CD4+ cells in peripheral immune organs and CNS infiltrates. The effect was detected immediately after the treatment and maintained over long-term follow-up. Foxp3+CD4+ Treg-mediated suppression of IL-17A+CD4+ and IFN-γ+CD4+ cells in the spinal cord infiltrates was reversed after inducible Foxp3 depletion. Our results demonstrated that the therapeutic effect of U.S. Food and Drug Administration-approved anti-CD52 mAb is dependent on the presence of Tregs.


Asunto(s)
Encefalomielitis Autoinmune Experimental , Esclerosis Múltiple Recurrente-Remitente , Esclerosis Múltiple , Alemtuzumab/uso terapéutico , Animales , Factores de Transcripción Forkhead/metabolismo , Interleucina-17/metabolismo , Ratones , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Linfocitos T Reguladores
4.
J Immunol ; 206(9): 2015-2028, 2021 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-33820855

RESUMEN

The cGAS-cyclic GMP-AMP (cGAMP)-stimulator of IFN genes (STING) pathway induces a powerful type I IFN (IFN-I) response and is a prime candidate for augmenting immunity in cancer immunotherapy and vaccines. IFN-I also has immune-regulatory functions manifested in several autoimmune diseases and is a first-line therapy for relapsing-remitting multiple sclerosis. However, it is only moderately effective and can induce adverse effects and neutralizing Abs in recipients. Targeting cGAMP in autoimmunity is unexplored and represents a challenge because of the intracellular location of its receptor, STING. We used microparticle (MP)-encapsulated cGAMP to increase cellular delivery, achieve dose sparing, and reduce potential toxicity. In the C57BL/6 experimental allergic encephalomyelitis (EAE) model, cGAMP encapsulated in MPs (cGAMP MPs) administered therapeutically protected mice from EAE in a STING-dependent fashion, whereas soluble cGAMP was ineffective. Protection was also observed in a relapsing-remitting model. Importantly, cGAMP MPs protected against EAE at the peak of disease and were more effective than rIFN-ß. Mechanistically, cGAMP MPs showed both IFN-I-dependent and -independent immunosuppressive effects. Furthermore, it induced the immunosuppressive cytokine IL-27 without requiring IFN-I. This augmented IL-10 expression through activated ERK and CREB. IL-27 and subsequent IL-10 were the most important cytokines to mitigate autoreactivity. Critically, cGAMP MPs promoted IFN-I as well as the immunoregulatory cytokines IL-27 and IL-10 in PBMCs from relapsing-remitting multiple sclerosis patients. Collectively, this study reveals a previously unappreciated immune-regulatory effect of cGAMP that can be harnessed to restrain T cell autoreactivity.


Asunto(s)
Micropartículas Derivadas de Células/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Interferón Tipo I/inmunología , Proteínas de la Membrana/inmunología , Nucleótidos Cíclicos/inmunología , Transducción de Señal/inmunología , Animales , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Micropartículas Derivadas de Células/metabolismo , Células Cultivadas , Citocinas/inmunología , Citocinas/metabolismo , Encefalomielitis Autoinmune Experimental/metabolismo , Encefalomielitis Autoinmune Experimental/prevención & control , Femenino , Humanos , Interferón Tipo I/metabolismo , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Proteínas de la Membrana/agonistas , Proteínas de la Membrana/metabolismo , Ratones Endogámicos C57BL , Ratones Endogámicos , Ratones Noqueados , Nucleótidos Cíclicos/administración & dosificación , Nucleótidos Cíclicos/metabolismo , Transducción de Señal/efectos de los fármacos
5.
J Immunol ; 203(5): 1142-1150, 2019 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-31341075

RESUMEN

IL-11+CD4+ cells accumulate in the cerebrospinal fluid of patients with early relapsing-remitting multiple sclerosis (MS) and in active brain MS lesions. Mouse studies have confirmed a causal role of IL-11 in the exacerbation of relapsing-remitting experimental autoimmune encephalomyelitis (RREAE). Administration of IL-11 at the time of clinical onset of RREAE induced an acute exacerbation and increased clinical scores, which persisted during the entire course of the disease. IL-11 increased the numbers of spinal cord inflammatory foci, as well as the numbers of peripheral and CNS-infiltrating IL-17+CD4+ cells and IL-17A serum levels. Ag recall assays revealed that IL-11 induces IL-17A+, GM-CSF+, and IL-21+CD4+ myelin Ag-reactive cells. Passive transfer of these encephalitogenic CD4+ T cells induced severe RREAE with IL-17A+CCR6+ CD4+ and B cell accumulation within the CNS. Furthermore, passive transfer of nonmanipulated CNS-derived mononuclear cells from mice with RREAE after a single dose of IL-11 induced severe RREAE with increased accumulation of IL-17A+ and CCR6+ CD4+ cells within the CNS. These results suggest that IL-11 might serve as a biomarker of early autoimmune response and a selective therapeutic target for patients with early relapsing-remitting MS.


Asunto(s)
Encefalomielitis Autoinmune Experimental/inmunología , Interleucina-11/farmacología , Esclerosis Múltiple Recurrente-Remitente/inmunología , Células Th17/fisiología , Adulto , Anciano , Animales , Linfocitos T CD4-Positivos/inmunología , Encefalomielitis Autoinmune Experimental/etiología , Femenino , Humanos , Interleucina-17/análisis , Ratones , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/etiología , Receptores CCR6/análisis , Médula Espinal/inmunología , Médula Espinal/patología
6.
Clin Immunol ; 197: 45-53, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30149119

RESUMEN

IL-11 induced differentiation and expansion of Th17 cells in patients with early relapsing-remitting multiple sclerosis (RRMS). In mice with relapsing-remitting experimental autoimmune encephalomyelitis (RREAE), IL-11 exacerbated disease, induced demyelination in the central nervous system (CNS), increased the percentage of IL-17A+CD4+ Th17 cells in the CNS in the early acute phase, and up-regulated serum IL-17A levels and the percentage of IL-17A+CD4+ Th17 cells in lymph nodes, and IFN-γ+CD4+ T cells in spinal cord in the RR phase. IL-11 antagonist suppressed RREAE disease activities, inhibited IL-17A+CD4+ cell infiltration and demyelination in the CNS, and decreased the percentage of IL-17A+CD4+ T cells in peripheral blood mononuclear cells and ICAM1+CD4+ T cells in brain and SC. Diffusion Tensor Imaging indicated that IL-11 antagonist inhibited demyelination in several brain regions. We conclude that by suppressing Th17 cell-mediated neuroinflammation and demyelination, IL-11 antagonist can be further studied as a potential selective and early therapy for RRMS.


Asunto(s)
Encéfalo/diagnóstico por imagen , Encefalomielitis Autoinmune Experimental/inmunología , Interleucina-11/antagonistas & inhibidores , Médula Espinal/diagnóstico por imagen , Células Th17/inmunología , Animales , Encéfalo/inmunología , Imagen de Difusión Tensora , Inflamación , Interleucina-11/inmunología , Subunidad alfa del Receptor de Interleucina-11 , Leucocitos Mononucleares , Ratones , Esclerosis Múltiple Recurrente-Remitente , Proteínas Recombinantes de Fusión , Médula Espinal/inmunología
8.
J Immunol ; 194(11): 5139-49, 2015 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-25895532

RESUMEN

Clinically isolated syndrome (CIS) suggestive of multiple sclerosis (MS) is the earliest clinically evident phase of the disease, which may provide valuable insight into the molecular mechanisms of the initiation of the autoimmune response in MS. Our results introduce IL-11 as a new cytokine that plays a role in the autoimmune response in the early phase of the disease. IL-11 is the highest upregulated cytokine in the sera and cerebrospinal fluid from CIS patients, which is also increased in patients with clinically definitive relapsing-remitting MS in comparison with healthy control subjects. Serum IL-11 levels are significantly increased during clinical exacerbations in comparison with remissions in the same patients. CD4(+) cells represent a predominant cell source of IL-11 in the peripheral circulation, and the percentage of IL-11(+)CD4(+) cells is significantly increased in CIS patients in comparison with healthy control subjects. Furthermore, we have identified IL-11 as a new Th17-promoting cytokine, because it induces a differentiation of naive CD4(+) T cells into Th17 cells, as well as expansion of Th17 memory cells. Because the Th17 cytokines IL-17F, IL-21 and TNF-α, and TGF-ß induce differentiation of naive cells in the IL-11-secreting CD4(+) cells, we propose that cross-talk between IL-11(+)CD4(+) and Th17 cells may play a role in the inflammatory response in relapsing-remitting MS.


Asunto(s)
Interleucina-11/inmunología , Esclerosis Múltiple Recurrente-Remitente/inmunología , Células Th17/citología , Células Th17/inmunología , Adulto , Autoinmunidad/inmunología , Comunicación Celular/inmunología , Diferenciación Celular/inmunología , Femenino , Humanos , Memoria Inmunológica/inmunología , Inflamación/inmunología , Interleucina-11/sangre , Interleucina-11/líquido cefalorraquídeo , Interleucina-17/biosíntesis , Interleucinas/biosíntesis , Masculino , Factor de Crecimiento Transformador beta/biosíntesis , Factor de Necrosis Tumoral alfa/biosíntesis
9.
J Immunol ; 192(12): 5610-7, 2014 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-24850724

RESUMEN

IFN-ß has been used as a first-line therapy for relapsing-remitting multiple sclerosis (RRMS). Because only a few studies have addressed the role of endogenous IFN-ß in the pathogenesis of the disease, our objective was to characterize its role in the transcriptional regulation of pathogenic Th17 cytokines in patients with RRMS. In vitro studies have demonstrated that IFN-ß inhibits IL-17A, IL-17F, IL-21, IL-22, and IFN-γ secretion in CD4(+) lymphocytes through the induction of suppressor of cytokine secretion 1 and suppressor of cytokine secretion 3. We found that patients with RRMS have increased serum and cerebrospinal fluid Th17 (IL-17A and IL-17F) cytokine levels in comparison with the control subjects, suggesting that deficient endogenous IFN-ß secretion or signaling can contribute to the dysregulation of those pathogenic cytokines in CD4(+) cells. We identified that the endogenous IFN-ß from serum of RRMS patients induced a significantly lower IFN-inducible gene expression in comparison with healthy controls. In addition, in vitro studies have revealed deficient endogenous and exogenous IFN-ß signaling in the CD4(+) cells derived from patients with MS. Interestingly, upon inhibition of the endogenous IFN-ß signaling by silencing IFN regulatory factor (IRF) 7 gene expression, the resting CD4(+) T cells secreted significantly higher level of IL-17A, IL-17F, IL-21, IL-22, and IL-9, suggesting that endogenous IFN-ß suppresses the secretion of these pathogenic cytokines. In vivo recombinant IFN-ß-1a treatment induced IFNAR1 and its downstream signaling molecules' gene expression, suggesting that treatment reconstitutes a deficient endogenous IFN-ß regulation of the CD4(+) T cells' pathogenic cytokine production in patients with MS.


Asunto(s)
Adyuvantes Inmunológicos/farmacología , Interferón beta/farmacología , Esclerosis Múltiple/inmunología , Transducción de Señal/inmunología , Células Th17/inmunología , Adolescente , Adulto , Citocinas/inmunología , Femenino , Humanos , Interferón beta-1a , Interferón beta/inmunología , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/patología , Receptor de Interferón alfa y beta/inmunología , Recurrencia , Transducción de Señal/efectos de los fármacos , Células Th17/patología
10.
Clin Immunol ; 157(2): 121-32, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25596452

RESUMEN

Fractalkine (CX3CL1) levels are increased in the cerebrospinal fluid (CSF) of patients with clinically isolated syndrome (CIS), as well as in the CSF and serum samples from patients with relapsing-remitting multiple sclerosis (RRMS). A higher percentage of circulating CD4(+) T-cells expressed its surface receptor (CX3CR1) and intracellular adhesion molecule (ICAM-1) in RRMS patients in comparison to healthy controls (HCs). The CX3CR1(+)ICAM-1(+)CD4(+) T-cells are enriched in the CSF of the RRMS patients. In vitro migration studies revealed that CD4(+) T-cells, which migrated toward a CX3CL1 gradient, expressed higher levels of ICAM-1 than non-migrating cells. CX3CL1 significantly increased IFN-γ and TNF-α gene expression and IFN-γ secretion by CD4(+) T-cells derived from the RRMS patients. CX3CL1 upregulated ICAM-1 expression on the surface of RRMS patient-derived but not HC-derived CD4(+) T-cells. Thus, CX3CL1 induces recruitment of CX3CR1(+)ICAM-1(+)CD4(+) T-cells into the central nervous system (CNS) during the early inflammatory response in MS.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Movimiento Celular/inmunología , Sistema Nervioso Central/inmunología , Quimiocina CX3CL1/inmunología , Molécula 1 de Adhesión Intercelular/metabolismo , Esclerosis Múltiple Recurrente-Remitente/inmunología , ARN Mensajero/metabolismo , Receptores de Quimiocina/inmunología , Adulto , Linfocitos T CD4-Positivos/metabolismo , Receptor 1 de Quimiocinas CX3C , Estudios de Casos y Controles , Sistema Nervioso Central/metabolismo , Quimiocina CX3CL1/líquido cefalorraquídeo , Enfermedades Desmielinizantes/líquido cefalorraquídeo , Enfermedades Desmielinizantes/inmunología , Enfermedades Desmielinizantes/metabolismo , Femenino , Humanos , Molécula 1 de Adhesión Intercelular/líquido cefalorraquídeo , Interferón gamma/genética , Interferón gamma/metabolismo , Masculino , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/líquido cefalorraquídeo , Esclerosis Múltiple Recurrente-Remitente/metabolismo , Receptores de Quimiocina/metabolismo , Factor de Necrosis Tumoral alfa/genética
11.
BMC Neurol ; 15: 232, 2015 Nov 11.
Artículo en Inglés | MEDLINE | ID: mdl-26559139

RESUMEN

BACKGROUND: Brain volume atrophy is observed in relapsing-remitting multiple sclerosis (RRMS). METHODS: Brain volume changes were evaluated in 23 patients with RRMS treated with interferon ß-1a 44 µg given subcutaneously (SC) three times a week (tiw) and 15 healthy controls. Percentages of whole brain and tissue-specific volume change were measured from baseline (0 months) to 3 months, from 3 to 6 months, and from baseline to 6 months using SIENAX Multi Time Point (SX-MTP) algorithms. Immunological status of patients was also determined and correlations between subsets of T cells and changes in brain volume were assessed. RESULTS: Interferon ß-1a 44 µg SC tiw in 23 patients with RRMS resulted in significant reductions in whole brain and gray matter tissue volume early in the treatment course (baseline to 3 months; mean change; -0.95%; P = 0.030, -1.52%; P = 0.004, respectively), suggesting a short-term treatment-induced pseudoatrophy effect. From baseline to 6 months, there were significant correlations observed between decreased T- cell expression of IL-17 F and decreased whole brain and brain tissue-specific volume. CONCLUSIONS: These findings are consistent with the interpretation of the pseudoatrophy effect as resolution of inflammation following treatment initiation with interferon ß-1a 44 µg SC tiw, rather than disease-related tissue loss. TRIAL REGISTRATION: ClinicalTrials.gov; NCT01085318.


Asunto(s)
Encéfalo/efectos de los fármacos , Interferón beta-1a/uso terapéutico , Interferón beta/administración & dosificación , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/inmunología , Adulto , Anciano , Algoritmos , Atrofia/patología , Encéfalo/patología , Femenino , Humanos , Inflamación , Inyecciones Subcutáneas , Interleucina-17/metabolismo , Masculino , Persona de Mediana Edad , Tamaño de los Órganos/efectos de los fármacos , Proyectos Piloto , Recurrencia , Resultado del Tratamiento
12.
J Immunol ; 191(12): 5867-74, 2013 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-24198283

RESUMEN

Alemtuzumab (anti-CD52 mAb) provides long-lasting disease activity suppression in relapsing-remitting multiple sclerosis (RRMS). The objective of this study was to characterize the immunological reconstitution of T cell subsets and its contribution to the prolonged RRMS suppression following alemtuzumab-induced lymphocyte depletion. The study was performed on blood samples from RRMS patients enrolled in the CARE-MS II clinical trial, which was recently completed and led to the submission of alemtuzumab for U.S. Food and Drug Administration approval as a treatment for RRMS. Alemtuzumab-treated patients exhibited a nearly complete depletion of circulating CD4(+) lymphocytes at day 7. During the immunological reconstitution, CD4(+)CD25(+)CD127(low) regulatory T cells preferentially expanded within the CD4(+) lymphocytes, reaching their peak expansion at month 1. The increase in the percentage of TGF-ß1-, IL-10-, and IL-4-producing CD4(+) cells reached a maximum at month 3, whereas a significant decrease in the percentages of Th1 and Th17 cells was detected at months 12 and 24 in comparison with the baseline. A gradual increase in serum IL-7 and IL-4 and a decrease in IL-17A, IL-17F, IL-21, IL-22, and IFN-γ levels were detected following treatment. In vitro studies have demonstrated that IL-7 induced an expansion of CD4(+)CD25(+)CD127(low) regulatory T cells and a decrease in the percentages of Th17 and Th1 cells. In conclusion, our results indicate that differential reconstitution of T cell subsets and selectively delayed CD4(+) T cell repopulation following alemtuzumab-induced lymphopenia may contribute to its long-lasting suppression of disease activity.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Antígenos CD/inmunología , Antígenos de Neoplasias/inmunología , Glicoproteínas/inmunología , Inmunosupresores/uso terapéutico , Depleción Linfocítica/métodos , Linfopenia/inmunología , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Subgrupos de Linfocitos T/patología , Alemtuzumab , Anticuerpos Monoclonales Humanizados/farmacología , Antígenos de Diferenciación de Linfocitos T/análisis , Antígeno CD52 , Células Cultivadas , Ensayos Clínicos Fase III como Asunto , Humanos , Memoria Inmunológica/efectos de los fármacos , Inmunosupresores/farmacología , Interferón beta-1a , Interferón beta/farmacología , Interferón beta/uso terapéutico , Interleucina-7/farmacología , Linfocinas/sangre , Linfocinas/metabolismo , Linfopenia/sangre , Linfopenia/inducido químicamente , Esclerosis Múltiple Recurrente-Remitente/inmunología , Ensayos Clínicos Controlados Aleatorios como Asunto , Subgrupos de Linfocitos T/química , Subgrupos de Linfocitos T/metabolismo , Células TH1/patología , Células Th17/patología , Factores de Tiempo
13.
Eur J Immunol ; 43(1): 281-9, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23076801

RESUMEN

Statins, widely used cholesterol-lowering agents, have also been demonstrated to have antiinflammatory effects. Here, we characterize the capacity of simvastatin to target DCs and modulate T-cell priming and Th17-cell differentiation, in a cohort of patients with relapsing remitting multiple sclerosis (RRMS). We report that simvastatin inhibits IL-1ß, IL-23, TGF-ß, IL-21, IL-12p70, and induces IL-27 secretion from DCs in RRMS patients, providing an inhibitory cytokine milieu for Th17 and Th1-cell differentiation. The effect on DCs is mediated via induction of SOCS1, SOCS3, and SOCS7 gene expression, which are associated with the inhibition of STAT1, STAT3, and ERK1/2 phosphorylation. A geranylgeranyl transferase inhibitor replicated simvastatin's effects on DC cytokine secretion, implicating that simvastatin-induced depletion of isoprenoids mediates this effect. Simvastatin inhibited antigen presentation by DCs via suppression of the MHC class I expression, costimulatory molecules CD80 and CD40, and by inducing a dramatic loss of dendritic processes. The changes in DC morphology were also mediated via inhibition of geranylgeranylation. The therapeutic use of geranylgeranylation inhibitors may provide selective inhibition of key pathogenic cytokines that drive the autoimmune response in MS; their use represents a promising therapeutic approach that requires further clinical testing.


Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Citocinas/inmunología , Células Dendríticas/efectos de los fármacos , Monocitos/efectos de los fármacos , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Simvastatina/farmacología , Células Th17/inmunología , Adolescente , Adulto , Antiinflamatorios no Esteroideos/uso terapéutico , Presentación de Antígeno/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Células Dendríticas/inmunología , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/inmunología , Humanos , Inmunomodulación , Activación de Linfocitos/efectos de los fármacos , Masculino , Persona de Mediana Edad , Monocitos/inmunología , Esclerosis Múltiple Recurrente-Remitente/inmunología , Simvastatina/uso terapéutico , Células TH1/inmunología , Balance Th1 - Th2/efectos de los fármacos , Adulto Joven
14.
bioRxiv ; 2024 Jan 06.
Artículo en Inglés | MEDLINE | ID: mdl-38260401

RESUMEN

Unresolved and uncontrolled inflammation is considered a hallmark of pathogenesis in chronic inflammatory diseases like multiple sclerosis (MS), suggesting a defective resolution process. Inflammatory resolution is an active process partially mediated by endogenous metabolites of dietary polyunsaturated fatty acids (PUFA), collectively termed specialized pro-resolving lipid mediators (SPMs). Altered levels of resolution mediators have been reported in several inflammatory diseases and may partly explain impaired inflammatory resolution. Performing LC-MS/MS-based targeted lipid mediator profiling, we observed distinct changes in fatty acid metabolites in serum from 30 relapsing-remitting MS (RRMS) patients relative to 30 matched healthy subjects (HS). Robust linear regression revealed 12 altered lipid mediators after adjusting for confounders (p <0.05). Of these, 15d-PGJ2, PGE3, and LTB5 were increased in MS while PGF2a, 8,9-DiHETrE, 5,6-DiHETrE, 20-HETE, 15-HETE, 12-HETE, 12-HEPE, 14-HDoHE, and DHEA were decreased in MS compared to HS. In addition, 12,13-DiHOME and 12,13-DiHODE were positively correlated with expanded disability status scale values (EDSS). Using Partial Least Squares, we identified several lipid mediators with high VIP scores (VIP > 1: 32% - 52%) of which POEA, PGE3, DHEA, LTB5, and 12-HETE were top predictors for distinguishing between RRMS and HS (AUC =0.75) based on the XGBoost Classifier algorithm. Collectively, these findings suggest an imbalance between inflammation and resolution. Altogether, lipid mediators appear to have potential as diagnostic and prognostic biomarkers for RRMS.

15.
Neurol Ther ; 13(2): 283-322, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38206453

RESUMEN

Multiple sclerosis (MS) is a chronic, progressive, inflammatory disorder of the central nervous system. Relapsing-remitting MS (RRMS), the most common form of the disease, is characterized by transient neurological dysfunction with concurrent accumulation of disability. Over the past three decades, disease-modifying therapies (DMTs) capable of reducing the frequency of relapses and slowing disability worsening have been studied and approved for use in patients with RRMS. The first DMTs were interferon-betas (IFN-ßs), which were approved in the 1990s. Among them was IFN-ß-1a for subcutaneous (sc) injection (Rebif®), which was approved for the treatment of MS in Europe and Canada in 1998 and in the USA in 2002. Twenty years of clinical data and experience have supported the efficacy and safety of IFN-ß-1a sc in the treatment of RRMS, including pivotal trials, real-world data, and extension studies lasting up to 15 years past initial treatment. Today, IFN-ß-1a sc remains an important therapeutic option in clinical use, especially around pregnancy planning and lactation, and may also be considered for aging patients, in which MS activity declines and long-term immunosuppression associated with some alternative therapies is a concern. In addition, IFN-ß-1a sc is used as a comparator in many clinical studies and provides a framework for research into the mechanisms by which MS begins and progresses.

16.
Hum Brain Mapp ; 34(12): 3376-91, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-22987661

RESUMEN

Although it is inarguable that conventional MRI (cMRI) has greatly contributed to the diagnosis and assessment of multiple sclerosis (MS), cMRI does not show close correlation with clinical findings or pathologic features, and is unable to predict prognosis or stratify disease severity. To this end, diffusion tensor imaging (DTI) with tractography and neuroconnectivity analysis may assist disease assessment in MS. We, therefore, attempted this pilot study for initial assessment of early relapsing-remitting MS (RRMS). Neuroconnectivity analysis was used for evaluation of 24 early RRMS patients within 2 years of presentation, and compared to the network measures of a group of 30 age-and-gender-matched normal control subjects. To account for the situation that the connections between two adjacent regions may be disrupted by an MS lesion, a new metric, network communicability, was adopted to measure both direct and indirect connections. For each anatomical area, the brain network communicability and average path length were computed and compared to characterize the network changes in efficiencies. Statistically significant (P < 0.05) loss of communicability was revealed in our RRMS cohort, particularly in the frontal and hippocampal/parahippocampal regions as well as the motor strip and occipital lobes. Correlation with the 25-foot Walk test with communicability measures in the left superior frontal (r = -0.71) as well as the left superior temporal gyrus (r = -0.43) and left postcentral gyrus (r = -0.41) were identified. Additionally identified were increased communicability between the deep gray matter structures (left thalamus and putamen) with the major interhemispheric and intrahemispheric white matter tracts, the corpus callosum, and cingulum, respectively. These foci of increased communicability are thought to represent compensatory changes. The proposed DTI-based neuroconnectivity analysis demonstrated quantifiable, structurally relevant alterations of fiber tract connections in early RRMS and paves the way for longitudinal studies in larger patient groups.


Asunto(s)
Mapeo Encefálico , Encéfalo/patología , Esclerosis Múltiple Recurrente-Remitente/patología , Esclerosis Múltiple Recurrente-Remitente/fisiopatología , Fibras Nerviosas Mielínicas/patología , Adulto , Estudios de Casos y Controles , Imagen de Difusión por Resonancia Magnética , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Persona de Mediana Edad , Probabilidad , Caminata/fisiología
17.
Ann Neurol ; 72(3): 385-94, 2012 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23034911

RESUMEN

OBJECTIVE: Neuromyelitis optica (NMO) and multiple sclerosis (MS) are considered inflammatory demyelinating diseases with distinguishing pathological characteristics. NMO pathology shows perivascular immunoglobulin G and complement deposition, as well as an astrocytopathy with aquaporin-4 (AQP4) loss. MS lesions reveal a profound, interindividual heterogeneity in immunopathological patterns of active demyelination, which has been challenged by the description of stage-dependent sequences of pathological features. The aim of our study was to compare the histological characteristics of early active demyelinating NMO and MS brain lesions. METHODS: Thirteen cases with supraspinal active demyelinating NMO lesions were analyzed using immunohistochemistry. Results were compared with the published characteristics of MS lesions. RESULTS: A subset of supraspinal lesions from AQP4-IgG-seropositive NMO patients revealed both (1) complement activation products within macrophages at sites of active demyelination and (2) oligodendrocyte apoptosis and a preferential loss of myelin-associated glycoprotein. These characteristics resemble features previously associated with MS lesion patterns II and III, and were present in addition to characteristic histopathological NMO features, namely loss of AQP4 and astrocytes. INTERPRETATION: Early active demyelinating NMO lesions may show complement within macrophages and oligodendrocyte apoptosis associated with a selective loss of minor myelin proteins, in addition to typical NMO features. We hypothesize these findings occur simultaneously only in a subset of active demyelinating NMO lesions. These observations plausibly explain the findings of Barnett and Prineas and further support the concept of interindividual heterogeneity in MS.


Asunto(s)
Astrocitos/metabolismo , Esclerosis Múltiple/metabolismo , Esclerosis Múltiple/patología , Neuromielitis Óptica/metabolismo , Neuromielitis Óptica/patología , Adolescente , Adulto , Anciano , Precursor de Proteína beta-Amiloide/metabolismo , Apoptosis/fisiología , Acuaporina 4/inmunología , Acuaporina 4/metabolismo , Astrocitos/patología , Activación de Complemento/fisiología , Femenino , Proteína Ácida Fibrilar de la Glía/metabolismo , Humanos , Inmunoglobulina G/metabolismo , Etiquetado Corte-Fin in Situ , Macrófagos/patología , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/inmunología , Neuromielitis Óptica/inmunología
18.
J Immunol ; 187(6): 3431-7, 2011 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-21856936

RESUMEN

Subsequent to the clinical trial of simvastatin in patients with relapsing remitting multiple sclerosis (RR MS), which demonstrated the ability of simvastatin to inhibit new inflammatory CNS lesion formation, the current in vitro study has characterized the mechanisms through which simvastatin inhibits Th17 cell differentiation. The anti-inflammatory effects of statins are mediated by the inhibition of isoprenylation, which ensures proper membrane insertion and function of proteins. Small GTPases, involved in multiple signal transduction pathways, are the key targets for isoprenylation. We report that simvastatin, one of the most hydrophobic statins with good CNS penetration, inhibited Th17 cell differentiation and IL-17A, IL-17F, IL-21, and IL-22 secretion in in vitro-differentiated naive CD4(+) T cells from RR MS patients. Simvastatin exerted a less prominent effect on the cells from healthy controls, as it inhibited only IL-17F secretion. The inhibition of Th17 cell differentiation was mediated via inhibition of IFN regulatory factor 4 (IRF4) expression, which was identified as a key transcription factor for human Th17 cell differentiation using both IRF4 gene knockdown and overexpression experiments. In studies addressing which isoprenylation pathway--geranylgeranylation or farnesylation--is inhibited by simvastatin, we demonstrated that the geranylgeranyl transferase inhibitor replicated the effect of simvastatin. Selective inhibition of geranylgeranylated RhoA-associated kinase replicated the effect of simvastatin on the inhibition of IRF4 expression and IL-17A, IL-17F, IL-21, and IL-22 secretion, presenting a promising new therapeutic approach for this disabling disease.


Asunto(s)
Diferenciación Celular/efectos de los fármacos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Factores Reguladores del Interferón/biosíntesis , Esclerosis Múltiple Recurrente-Remitente/inmunología , Simvastatina/farmacología , Células Th17/efectos de los fármacos , Adolescente , Adulto , Western Blotting , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/metabolismo , Separación Celular , Técnicas de Cocultivo , Células Dendríticas/efectos de los fármacos , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Técnicas de Silenciamiento del Gen , Humanos , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células Th17/citología , Células Th17/metabolismo , Adulto Joven
19.
J Immunol ; 186(7): 4518-26, 2011 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-21368231

RESUMEN

IFN-ß-1b is a first-line immunomodulatory therapy for relapsing-remitting multiple sclerosis (RR MS). However, its effects on B cells have not been characterized. In vitro studies of B cells derived from RR MS patients revealed that IFN-ß-1b decreases B cells' stimulatory capacity, as detected by inhibition of the Ag-specific T cell proliferative response upon Ag presentation by IFN-ß-1b-treated B cells. Our study has identified that IFN-ß-1b inhibited B cells' stimulatory capacity in RR MS patients and healthy controls through the suppression of CD40 and CD80 expression, whereas the MHC class I and II expression was not changed. IFN-ß-1b in vitro treatment inhibited B cell secretion of IL-1ß and IL-23 and induced IL-12 and IL-27. Supernatants transferred from IFN-ß-1b-treated B cells inhibited Th17 cell differentiation, as they suppressed gene expression of the retinoic acid-related orphan nuclear hormone receptor C and IL-17A and secretion of IL-17A. In addition, IFN-ß-1b induced B cells' IL-10 secretion, which may mediate their regulatory effect. Studies of B cells derived from RR MS patients treated with recombinant s.c. injected IFN-ß-1b revealed that they induced a significantly lower proliferative response in allogenic MLR than the B cells from untreated patients. Further confirming the IFN-ß-1b in vitro-induced changes in B cell cytokine secretion, B cells derived from the IFN-ß-1b-treated patients secreted significantly lower levels of IL-1ß and IL-23 and higher levels of IL-12 and IL-27 in comparison with the B cells derived from untreated patients. We conclude that IFN-ß-1b exerts its therapeutic effects in part by targeting B cells' functions that contribute to the autoimmune pathogenesis of RR MS.


Asunto(s)
Subgrupos de Linfocitos B/inmunología , Subgrupos de Linfocitos B/metabolismo , Interferón beta/fisiología , Esclerosis Múltiple Recurrente-Remitente/inmunología , Esclerosis Múltiple Recurrente-Remitente/terapia , Adyuvantes Inmunológicos/fisiología , Subgrupos de Linfocitos B/patología , Células Cultivadas , Técnicas de Cocultivo , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Sistemas de Liberación de Medicamentos/métodos , Humanos , Interferón beta-1a , Interleucina-1beta/antagonistas & inhibidores , Interleucina-1beta/biosíntesis , Interleucina-23/antagonistas & inhibidores , Interleucina-23/biosíntesis , Prueba de Cultivo Mixto de Linfocitos , Esclerosis Múltiple Recurrente-Remitente/metabolismo
20.
J Autoimmun ; 38(1): 10-9, 2012 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-22123179

RESUMEN

Immunosenescence, or ageing of the immune system, contributes to the increased morbidity and mortality seen in the elderly population. Premature immunosenescence is shown to occur in a subgroup of patients with autoimmune diseases. One of the main characteristics of immunosenescence is the expansion of CD4(+)CD28(-) T cells in the blood. In this study, we investigate the potential contribution of these cells to disease processes in a subgroup of multiple sclerosis (MS) and rheumatoid arthritis (RA) patients. Characterization of CD4(+)CD28(-) T cells in patients and healthy controls reveals that they have an inflammation-seeking effector-memory T cell phenotype with cytotoxic properties, as they expel cytotoxic granules in response to a polyclonal stimulus or MS-related autoantigens. We identify CX(3)CR1, the fractalkine receptor, as a selective marker to discriminate CD4(+)CD28(-) T cells from their CD4(+)CD28(+) counterparts. CX(3)CR1 expression enables CD4(+)CD28(-) T cells to migrate towards a fractalkine gradient in vitro. In addition, we find increased levels of fractalkine in the cerebrospinal fluid and inflammatory lesions of MS patients. We demonstrate for the first time that CD4(+)CD28(-) T cells accumulate in MS lesions of a subgroup of patients. Moreover, we have indications that these cells are cytotoxic in the target tissue. Overall, our findings suggest that CD4(+)CD28(-) T cells migrate in response to a chemotactic gradient of fractalkine to sites of inflammation, where they contribute to the inflammatory processes in a subgroup of patients with MS and RA.


Asunto(s)
Encéfalo/inmunología , Linfocitos T CD4-Positivos/inmunología , Esclerosis Múltiple/inmunología , Receptores de Quimiocina/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Artritis Reumatoide/inmunología , Artritis Reumatoide/metabolismo , Encéfalo/metabolismo , Encéfalo/patología , Antígenos CD28/inmunología , Antígenos CD28/metabolismo , Linfocitos T CD4-Positivos/metabolismo , Receptor 1 de Quimiocinas CX3C , Movimiento Celular/inmunología , Células Cultivadas , Quimiocina CX3CL1/líquido cefalorraquídeo , Quimiocina CX3CL1/inmunología , Quimiocina CX3CL1/metabolismo , Femenino , Citometría de Flujo , Humanos , Inmunohistoquímica , Memoria Inmunológica/inmunología , Inmunofenotipificación , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/metabolismo , Receptores de Quimiocina/metabolismo , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/metabolismo , Adulto Joven
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