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1.
Proc Natl Acad Sci U S A ; 120(1): e2209944120, 2023 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-36574650

RESUMO

After natalizumab (NAT) cessation, some multiple sclerosis (MS) patients experience a severe disease rebound. The rebound pathophysiology is still unclear; however, it has been linked to interleukin-17-producing T-helper (Th17) cells. We demonstrate that during NAT treatment, MCAM+CCR6+Th17 cells gradually acquire a pathogenic profile, including proinflammatory cytokine production, pathogenic transcriptional signatures, brain endothelial barrier impairment, and oligodendrocyte damage via induction of apoptotic pathways. This is accompanied by an increase in Th17 cell frequencies in the cerebrospinal fluid of NAT-treated patients. Notably, Th17 cells derived from NAT-treated patients, who later developed a disease rebound upon treatment cessation, displayed a distinct transcriptional pathogenicity profile associated with altered migratory properties. Accordingly, increased brain infiltration of patient Th17 cells was illustrated in a humanized mouse model and brain histology from a rebound patient. Therefore, peripheral blood-accumulated MCAM+CCR6+Th17 cells might be involved in rebound pathophysiology, and monitoring of changes in Th17 cell pathogenicity in patients before/during NAT treatment cessation might enable rebound risk assessment in the future.


Assuntos
Esclerose Múltipla , Células Th17 , Animais , Camundongos , Natalizumab/farmacologia , Natalizumab/uso terapêutico , Virulência , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/líquido cefalorraquidiano , Encéfalo
2.
Brain ; 2024 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-39021292

RESUMO

Epstein-Barr virus (EBV) infection has long been associated with the development of multiple sclerosis (MS). MS patients have elevated titers of EBV-specific antibodies in serum and show signs of CNS damage only after EBV infection. Regarding CD8+ T-cells, an elevated but ineffective response to EBV was suggested in MS patients, who present with a broader MHC-I-restricted EBV-specific T-cell receptor beta chain (TRB) repertoire compared to controls. It is not known whether this altered EBV response could be subject to dynamic changes, e.g., by approved MS therapies, and whether it is specific for MS. 1317 peripheral blood TRB repertoire samples of healthy donors (n=409), patients with MS (n=710) before and after treatment, patients with neuromyelitis optica spectrum disorder (n=87), myelin-oligodendrocyte-glycoprotein antibody-associated disease (n=64) and Susac's syndrome (n=47) were analyzed. Apart from MS, none of the evaluated diseases presented with a broader anti-EBV TRB repertoire. In MS patients undergoing autologous hematopoietic stem-cell transplantation, EBV reactivation coincided with elevated MHC-I-restricted EBV-specific TRB sequence matches. Therapy with ocrelizumab, teriflunomide or dimethyl fumarate reduced EBV-specific, but not CMV-specific MHC-I-restricted TRB sequence matches. Together, this data suggests that the aberrant MHC-I-restricted T-cell response directed against EBV is specific to MS with regard to NMO, MOGAD and Susac's Syndrome and that it is specifically modified by MS treatments interfering with EBV host cells or activated lymphocytes.

3.
Proc Natl Acad Sci U S A ; 118(1)2021 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-33376202

RESUMO

Multiple sclerosis (MS) disease risk is associated with reduced sun-exposure. This study assessed the relationship between measures of sun exposure (vitamin D [vitD], latitude) and MS severity in the setting of two multicenter cohort studies (nNationMS = 946, nBIONAT = 990). Additionally, effect-modification by medication and photosensitivity-associated MC1R variants was assessed. High serum vitD was associated with a reduced MS severity score (MSSS), reduced risk for relapses, and lower disability accumulation over time. Low latitude was associated with higher vitD, lower MSSS, fewer gadolinium-enhancing lesions, and lower disability accumulation. The association of latitude with disability was lacking in IFN-ß-treated patients. In carriers of MC1R:rs1805008(T), who reported increased sensitivity toward sunlight, lower latitude was associated with higher MRI activity, whereas for noncarriers there was less MRI activity at lower latitudes. In a further exploratory approach, the effect of ultraviolet (UV)-phototherapy on the transcriptome of immune cells of MS patients was assessed using samples from an earlier study. Phototherapy induced a vitD and type I IFN signature that was most apparent in monocytes but that could also be detected in B and T cells. In summary, our study suggests beneficial effects of sun exposure on established MS, as demonstrated by a correlative network between the three factors: Latitude, vitD, and disease severity. However, sun exposure might be detrimental for photosensitive patients. Furthermore, a direct induction of type I IFNs through sun exposure could be another mechanism of UV-mediated immune-modulation in MS.


Assuntos
Monócitos/efeitos da radiação , Esclerose Múltipla/sangue , Esclerose Múltipla/imunologia , Receptor Tipo 1 de Melanocortina/genética , Transcriptoma/efeitos da radiação , Vitamina D/sangue , Linfócitos B/efeitos da radiação , Estudos de Coortes , Feminino , Variação Genética , Genótipo , Humanos , Interferon beta/farmacologia , Interferon beta/uso terapêutico , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Esclerose Múltipla/patologia , Esclerose Múltipla/radioterapia , Fenótipo , Fototerapia , Recidiva , Índice de Gravidade de Doença , Luz Solar , Linfócitos T/metabolismo , Linfócitos T/efeitos da radiação , Transcriptoma/genética
4.
Brain ; 145(5): 1711-1725, 2022 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-35661859

RESUMO

Alemtuzumab is a monoclonal antibody that causes rapid depletion of CD52-expressing immune cells. It has proven to be highly efficacious in active relapsing-remitting multiple sclerosis; however, the high risk of secondary autoimmune disorders has greatly complicated its use. Thus, deeper insight into the pathophysiology of secondary autoimmunity and potential biomarkers is urgently needed. The most critical time points in the decision-making process for alemtuzumab therapy are before or at Month 12, where the ability to identify secondary autoimmunity risk would be instrumental. Therefore, we investigated components of blood and CSF of up to 106 multiple sclerosis patients before and after alemtuzumab treatment focusing on those critical time points. Consistent with previous reports, deep flow cytometric immune-cell profiling (n = 30) demonstrated major effects on adaptive rather than innate immunity, which favoured regulatory immune cell subsets within the repopulation. The longitudinally studied CSF compartment (n = 18) mainly mirrored the immunological effects observed in the periphery. Alemtuzumab-induced changes including increased numbers of naïve CD4+ T cells and B cells as well as a clonal renewal of CD4+ T- and B-cell repertoires were partly reminiscent of haematopoietic stem cell transplantation; in contrast, thymopoiesis was reduced and clonal renewal of T-cell repertoires after alemtuzumab was incomplete. Stratification for secondary autoimmunity did not show clear immununological cellular or proteomic traits or signatures associated with secondary autoimmunity. However, a restricted T-cell repertoire with hyperexpanded T-cell clones at baseline, which persisted and demonstrated further expansion at Month 12 by homeostatic proliferation, identified patients developing secondary autoimmune disorders (n = 7 without secondary autoimmunity versus n = 5 with secondary autoimmunity). Those processes were followed by an expansion of memory B-cell clones irrespective of persistence, which we detected shortly after the diagnosis of secondary autoimmune disease. In conclusion, our data demonstrate that (i) peripheral immunological alterations following alemtuzumab are mirrored by longitudinal changes in the CSF; (ii) incomplete T-cell repertoire renewal and reduced thymopoiesis contribute to a proautoimmune state after alemtuzumab; (iii) proteomics and surface immunological phenotyping do not identify patients at risk for secondary autoimmune disorders; (iv) homeostatic proliferation with disparate dynamics of clonal T- and B-cell expansions are associated with secondary autoimmunity; and (v) hyperexpanded T-cell clones at baseline and Month 12 may be used as a biomarker for the risk of alemtuzumab-induced autoimmunity.


Assuntos
Doenças Autoimunes , Autoimunidade , Alemtuzumab/efeitos adversos , Doenças Autoimunes/induzido quimicamente , Humanos , Fenótipo , Proteômica
5.
Brain ; 144(9): 2625-2634, 2021 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-33848319

RESUMO

Although CSF analysis routinely enables the diagnosis of neurological diseases, it is mainly used for the gross distinction between infectious, autoimmune inflammatory, and degenerative disorders of the CNS. To investigate, whether a multi-dimensional cellular blood and CSF characterization can support the diagnosis of clinically similar neurological diseases, we analysed 546 patients with autoimmune neuroinflammatory, degenerative, or vascular conditions in a cross-sectional retrospective study. By combining feature selection with dimensionality reduction and machine learning approaches we identified pan-disease parameters that were altered across all autoimmune neuroinflammatory CNS diseases and differentiated them from other neurological conditions and inter-autoimmunity classifiers that subdifferentiate variants of CNS-directed autoimmunity. Pan-disease as well as diseases-specific changes formed a continuum, reflecting clinical disease evolution. A validation cohort of 231 independent patients confirmed that combining multiple parameters into composite scores can assist the classification of neurological patients. Overall, we showed that the integrated analysis of blood and CSF parameters improves the differential diagnosis of neurological diseases, thereby facilitating early treatment decisions.


Assuntos
Mediadores da Inflamação/líquido cefalorraquidiano , Doenças do Sistema Nervoso/líquido cefalorraquidiano , Doenças do Sistema Nervoso/classificação , Biomarcadores/líquido cefalorraquidiano , Estudos de Coortes , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Doenças do Sistema Nervoso/diagnóstico , Estudos Retrospectivos
6.
Brain ; 144(10): 3126-3141, 2021 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-34849598

RESUMO

Dimethyl fumarate, an approved treatment for relapsing-remitting multiple sclerosis, exerts pleiotropic effects on immune cells as well as CNS resident cells. Here, we show that dimethyl fumarate exerts a profound alteration of the metabolic profile of human CD4+ as well as CD8+ T cells and restricts their antioxidative capacities by decreasing intracellular levels of the reactive oxygen species scavenger glutathione. This causes an increase in mitochondrial reactive oxygen species levels accompanied by an enhanced mitochondrial stress response, ultimately leading to impaired mitochondrial function. Enhanced mitochondrial reactive oxygen species levels not only result in enhanced T-cell apoptosis in vitro as well as in dimethyl fumarate-treated patients, but are key for the well-known immunomodulatory effects of dimethyl fumarate both in vitro and in an animal model of multiple sclerosis, i.e. experimental autoimmune encephalomyelitis. Indeed, dimethyl fumarate immune-modulatory effects on T cells were completely abrogated by pharmacological interference of mitochondrial reactive oxygen species production. These data shed new light on dimethyl fumarate as bona fide immune-metabolic drug that targets the intracellular stress response in activated T cells, thereby restricting mitochondrial function and energetic capacity, providing novel insight into the role of oxidative stress in modulating cellular immune responses and T cell-mediated autoimmunity.


Assuntos
Antioxidantes/farmacologia , Autoimunidade/efeitos dos fármacos , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/efeitos dos fármacos , Fumarato de Dimetilo/farmacologia , Imunossupressores/farmacologia , Adulto , Animais , Antioxidantes/uso terapêutico , Autoimunidade/fisiologia , Linfócitos T CD4-Positivos/fisiologia , Linfócitos T CD8-Positivos/fisiologia , Estudos de Coortes , Fumarato de Dimetilo/uso terapêutico , Feminino , Humanos , Imunossupressores/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/imunologia , Esclerose Múltipla Recidivante-Remitente/metabolismo , Adulto Jovem
7.
Proc Natl Acad Sci U S A ; 116(1): 271-276, 2019 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-30559188

RESUMO

Blood-brain barrier (BBB) disruption and transendothelial trafficking of immune cells into the central nervous system (CNS) are pathophysiological hallmarks of neuroinflammatory disorders like multiple sclerosis (MS). Recent evidence suggests that the kallikrein-kinin and coagulation system might participate in this process. Here, we identify plasma kallikrein (KK) as a specific direct modulator of BBB integrity. Levels of plasma prekallikrein (PK), the precursor of KK, were markedly enhanced in active CNS lesions of MS patients. Deficiency or pharmacologic blockade of PK renders mice less susceptible to experimental autoimmune encephalomyelitis (a model of MS) and is accompanied by a remarkable reduction of BBB disruption and CNS inflammation. In vitro analysis revealed that KK modulates endothelial cell function in a protease-activated receptor-2-dependent manner, leading to an up-regulation of the cellular adhesion molecules Intercellular Adhesion Molecule 1 and Vascular Cell Adhesion Molecule 1, thereby amplifying leukocyte trafficking. Our study demonstrates that PK is an important direct regulator of BBB integrity as a result of its protease function. Therefore, KK inhibition can decrease BBB damage and cell invasion during neuroinflammation and may offer a strategy for the treatment of MS.


Assuntos
Bradicinina/metabolismo , Encefalomielite Autoimune Experimental/metabolismo , Calicreínas/metabolismo , Receptor PAR-2/metabolismo , Animais , Barreira Hematoencefálica , Western Blotting , Bradicinina/fisiologia , Encefalomielite Autoimune Experimental/fisiopatologia , Citometria de Fluxo , Técnicas de Silenciamento de Genes , Humanos , Calicreínas/antagonistas & inibidores , Calicreínas/sangue , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Esclerose Múltipla/metabolismo , Receptor PAR-2/fisiologia
8.
Mult Scler ; 27(10): 1491-1496, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33150829

RESUMO

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) can in rare cases occur in natalizumab-treated patients with high serum anti-JCPyV antibodies, hypothetically due to excessive blockade of immune cell migration. OBJECTIVE: Immune cell recruitment to the central nervous system (CNS) was assessed in relapsing-remitting multiple sclerosis (RRMS) patients stratified by low versus high anti-JCPyV antibody titers as indicator for PML risk. METHODS: Cerebrospinal fluid (CSF) cell counts of 145 RRMS patients were quantified by flow cytometry. Generalized linear models were employed to assess influence of age, sex, disease duration, Expanded Disability Status Scale (EDSS), clinical/radiological activity, current steroid or natalizumab treatment, as well as anti-JCPyV serology on CSF cell subset counts. RESULTS: While clinical/radiological activity was associated with increased CD4, natural killer (NK), B and plasma cell counts, natalizumab therapy reduced all subpopulations except monocytes. With and without natalizumab therapy, patients with high anti-JCPyV serum titers presented with increased CSF T-cell counts compared to patients with low anti-JCPyV serum titers. In contrast, PML patients assessed before (n = 2) or at diagnosis (n = 5) presented with comparably low CD8 and B-cell counts, which increased after plasma exchange (n = 4). CONCLUSION: High anti-JCPyV indices, which could be indicative of increased viral activity, are associated with elevated immune cell recruitment to the CNS. Its excessive impairment in conjunction with viral activity could predispose for PML development.


Assuntos
Vírus JC , Leucoencefalopatia Multifocal Progressiva , Esclerose Múltipla Recidivante-Remitente , Contagem de Células , Humanos , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Natalizumab/uso terapêutico
9.
Proc Natl Acad Sci U S A ; 115(9): 2168-2173, 2018 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-29440397

RESUMO

HLA associations, T cell receptor (TCR) repertoire bias, and sex bias have independently been shown for many diseases. While some immunological differences between the sexes have been described, they do not fully explain bias in men toward many infections/cancers, and toward women in autoimmunity. Next-generation TCR variable beta chain (TCRBV) immunosequencing of 824 individuals was evaluated in a multiparametric analysis including HLA-A -B/MHC class I background, TCRBV usage, sex, age, ethnicity, and TCRBV selection/expansion dynamics. We found that HLA-associated shaping of TCRBV usage differed between the sexes. Furthermore, certain TCRBVs were selected and expanded in unison. Correlations between these TCRBV relationships and biochemical similarities in HLA-binding positions were different in CD8 T cells of patients with autoimmune diseases (multiple sclerosis and rheumatoid arthritis) compared with healthy controls. Within patients, men showed higher TCRBV relationship Spearman's rhos in relation to HLA-binding position similarities compared with women. In line with this, CD8 T cells of men with autoimmune diseases also showed higher degrees of TCRBV perturbation compared with women. Concerted selection and expansion of CD8 T cells in patients with autoimmune diseases, but especially in men, appears to be less dependent on high HLA-binding similarity than in CD4 T cells. These findings are consistent with studies attributing autoimmunity to processes of epitope spreading and expansion of low-avidity T cell clones and may have further implications for the interpretation of pathogenic mechanisms of infectious and autoimmune diseases with known HLA associations. Reanalysis of some HLA association studies, separating the data by sex, could be informative.


Assuntos
Imunidade Adaptativa/genética , Imunidade Adaptativa/fisiologia , Genes MHC Classe I/fisiologia , Adulto , Feminino , Humanos , Masculino , Fatores Sexuais
10.
Int Immunol ; 31(6): 407-412, 2019 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-30783682

RESUMO

Integrin α2ß1, also known as very late antigen (VLA)-2, is a collagen-binding molecule expressed constitutively on platelets. Vatelizumab, a monoclonal antibody targeting the α2 subunit (CD49b) of VLA-2, was recently investigated for its safety and efficacy during a Phase 2 clinical study in multiple sclerosis patients, as integrin-mediated collagen binding at the site of inflammation is central to a number of downstream pro-inflammatory events. In the course of this study, we could show that VLA-2 is expressed ex vivo on platelets, platelet-T-cell aggregates, as well as a small population of highly activated memory T cells. Even though the clinical trial did not meet its primary clinical end-point (reduction in the cumulative number of new contrast-enhancing lesions on magnetic resonance imaging (MRI)), we observed enhanced frequencies of regulatory T cells (TREG) following vatelizumab treatment. Elevated TREG frequencies might be explained by the inhibition of p38 mitogen-activated protein kinase (MAPK) signaling, which is critically involved in the polarization of T helper 17 (TH17) cells and is activated by the α2 integrin cytoplasmic domain. Our findings suggest that blockade of VLA-2 might be a way to safely shift the TH17/TREG balance by inducing TREGin vivo.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Plaquetas/metabolismo , Integrina alfa2/metabolismo , Integrina alfa2beta1/metabolismo , Esclerose Múltipla/tratamento farmacológico , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Antígenos CD4/metabolismo , Colágeno/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Humanos , Memória Imunológica , Integrina alfa2/imunologia , Integrina alfa2beta1/antagonistas & inibidores , Ativação Linfocitária , Sistema de Sinalização das MAP Quinases , Transdução de Sinais
11.
Brain ; 142(11): 3411-3427, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31563951

RESUMO

Although the CNS is immune privileged, continuous search for pathogens and tumours by immune cells within the CNS is indispensable. Thus, distinct immune-cell populations also cross the blood-brain barrier independently of inflammation/under homeostatic conditions. It was previously shown that effector memory T cells populate healthy CNS parenchyma in humans and, independently, that CCR5-expressing lymphocytes as well as CCR5 ligands are enriched in the CNS of patients with multiple sclerosis. Apart from the recently described CD8+ CNS tissue-resident memory T cells, we identified a population of CD4+CCR5high effector memory cells as brain parenchyma-surveilling cells. These cells used their high levels of VLA-4 to arrest on scattered VCAM1, their open-conformation LFA-1 to crawl preferentially against the flow in search for sites permissive for extravasation, and their stored granzyme K (GZMK) to induce local ICAM1 aggregation and perform trans-, rather than paracellular diapedesis through unstimulated primary brain microvascular endothelial cells. This study included peripheral blood mononuclear cell samples from 175 healthy donors, 29 patients infected with HIV, with neurological symptoms in terms of cognitive impairment, 73 patients with relapsing-remitting multiple sclerosis in remission, either 1-4 weeks before (n = 29), or 18-60 months after the initiation of natalizumab therapy (n = 44), as well as white matter brain tissue of three patients suffering from epilepsy. We here provide ex vivo evidence that CCR5highGZMK+CD4+ effector memory T cells are involved in CNS immune surveillance during homeostasis, but could also play a role in CNS pathology. Among CD4+ T cells, this subset was found to dominate the CNS of patients without neurological inflammation ex vivo. The reduction in peripheral blood of HIV-positive patients with neurological symptoms correlated to their CD4 count as a measure of disease progression. Their peripheral enrichment in multiple sclerosis patients and specific peripheral entrapment through the CNS infiltration inhibiting drug natalizumab additionally suggests a contribution to CNS autoimmune pathology. Our transcriptome analysis revealed a migratory phenotype sharing many features with tissue-resident memory and Th17.1 cells, most notably the transcription factor eomesodermin. Knowledge on this cell subset should enable future studies to find ways to strengthen the host defence against CNS-resident pathogens and brain tumours or to prevent CNS autoimmunity.


Assuntos
Granzimas/genética , Vigilância Imunológica/imunologia , Receptores CCR5/metabolismo , Migração Transendotelial e Transepitelial/genética , Migração Transendotelial e Transepitelial/imunologia , Complexo AIDS Demência/genética , Complexo AIDS Demência/psicologia , Adulto , Linfócitos T CD4-Positivos/imunologia , Células Endoteliais/imunologia , Células Endoteliais/patologia , Epilepsia/genética , Epilepsia/psicologia , Humanos , Molécula 1 de Adesão Intercelular/genética , Esclerose Múltipla Recidivante-Remitente/genética , Esclerose Múltipla Recidivante-Remitente/psicologia , Molécula 1 de Adesão de Célula Vascular/genética
12.
BMC Neurol ; 19(1): 190, 2019 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-31399069

RESUMO

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) is a rare complication of patients treated with fingolimod. CASE PRESENTATION: Routine MRI eventually led to diagnosis of asymptomatic early PML that remained stable after discontinuation of fingolimod. As blood lymphocyte counts normalized, signs of immune reconstitution inflammatory syndrome (IRIS) and renewed MS activity developed. Both, advanced laboratory and ultrahigh field MRI findings elucidated differences between PML and MS. CONCLUSIONS: In our case, early discontinuation of fingolimod yielded a good outcome, lymphocyte counts reflected immune system activity, and paraclinical findings helped to differentiate between PML-IRIS and MS.


Assuntos
Cloridrato de Fingolimode/efeitos adversos , Síndrome Inflamatória da Reconstituição Imune/diagnóstico por imagem , Imunossupressores/efeitos adversos , Leucoencefalopatia Multifocal Progressiva/induzido quimicamente , Leucoencefalopatia Multifocal Progressiva/diagnóstico por imagem , Adulto , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico
14.
Proc Natl Acad Sci U S A ; 113(21): E2973-82, 2016 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-27162345

RESUMO

Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system (CNS) resulting from a breakdown in peripheral immune tolerance. Although a beneficial role of natural killer (NK)-cell immune-regulatory function has been proposed, it still needs to be elucidated whether NK cells are functionally impaired as part of the disease. We observed NK cells in active MS lesions in close proximity to T cells. In accordance with a higher migratory capacity across the blood-brain barrier, CD56(bright) NK cells represent the major intrathecal NK-cell subset in both MS patients and healthy individuals. Investigating the peripheral blood and cerebrospinal fluid of MS patients treated with natalizumab revealed that transmigration of this subset depends on the α4ß1 integrin very late antigen (VLA)-4. Although no MS-related changes in the migratory capacity of NK cells were observed, NK cells derived from patients with MS exhibit a reduced cytolytic activity in response to antigen-activated CD4(+) T cells. Defective NK-mediated immune regulation in MS is mainly attributable to a CD4(+) T-cell evasion caused by an impaired DNAX accessory molecule (DNAM)-1/CD155 interaction. Both the expression of the activating NK-cell receptor DNAM-1, a genetic alteration consistently found in MS-association studies, and up-regulation of the receptor's ligand CD155 on CD4(+) T cells are reduced in MS. Therapeutic immune modulation of IL-2 receptor restores impaired immune regulation in MS by increasing the proportion of CD155-expressing CD4(+) T cells and the cytolytic activity of NK cells.


Assuntos
Barreira Hematoencefálica/imunologia , Linfócitos T CD4-Positivos/imunologia , Movimento Celular/imunologia , Células Matadoras Naturais/imunologia , Ativação Linfocitária , Esclerose Múltipla/imunologia , Receptores de Interleucina-2/imunologia , Antígenos de Diferenciação de Linfócitos T/imunologia , Barreira Hematoencefálica/patologia , Linfócitos T CD4-Positivos/patologia , Movimento Celular/efeitos dos fármacos , Feminino , Humanos , Células K562 , Células Matadoras Naturais/patologia , Masculino , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/patologia , Natalizumab/administração & dosagem , Receptores Virais/imunologia
15.
J Neuroinflammation ; 15(1): 236, 2018 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-30134924

RESUMO

BACKGROUND: Very late antigen 4 (VLA-4; integrin α4ß1) is critical for transmigration of T helper (TH) 1 cells into the central nervous system (CNS) under inflammatory conditions such as multiple sclerosis (MS). We have previously shown that VLA-4 and melanoma cell adhesion molecule (MCAM) are important for trans-endothelial migration of human TH17 cells in vitro and here investigate their contribution to pathogenic CNS inflammation. METHODS: Antibody blockade of VLA-4 and MCAM is assessed in murine models of CNS inflammation in conjunction with conditional ablation of α4-integrin expression in T cells. Effects of VLA-4 and MCAM blockade on lymphocyte migration are further investigated in the human system via in vitro T cell transmigration assays. RESULTS: Compared to the broad effects of VLA-4 blockade on encephalitogenic T cell migration over endothelial barriers, MCAM blockade impeded encephalitogenic T cell migration in murine models of MS that especially depend on CNS migration across the choroid plexus (CP). In transgenic mice lacking T cell α4-integrin expression (CD4::Itga4-/-), MCAM blockade delayed disease onset. Migration of MCAM-expressing T cells through the CP into the CNS was restricted, where laminin 411 (composed of α4, ß1, γ1 chains), the proposed major ligand of MCAM, is detected in the endothelial basement membranes of murine CP tissue. This finding was translated to the human system; blockade of MCAM with a therapeutic antibody reduced in vitro transmigration of MCAM-expressing T cells across a human fibroblast-derived extracellular matrix layer and a brain-derived endothelial monolayer, both expressing laminin α4. Laminin α4 was further detected in situ in CP endothelial-basement membranes in MS patients' brain tissue. CONCLUSIONS: Our findings suggest that MCAM-laminin 411 interactions facilitate trans-endothelial migration of MCAM-expressing T cells into the CNS, which seems to be highly relevant to migration via the CP and to potential future clinical applications in neuroinflammatory disorders.


Assuntos
Antígeno CD146/metabolismo , Plexo Corióideo/patologia , Encefalomielite Autoimune Experimental/patologia , Linfócitos T/efeitos dos fármacos , Animais , Anticorpos/uso terapêutico , Antígeno CD146/imunologia , Movimento Celular/efeitos dos fármacos , Movimento Celular/fisiologia , Células Cultivadas , Sistema Nervoso Central/patologia , Plexo Corióideo/diagnóstico por imagem , Plexo Corióideo/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/induzido quimicamente , Células Endoteliais/efeitos dos fármacos , Adjuvante de Freund/toxicidade , Humanos , Integrina alfa4beta1/genética , Integrina alfa4beta1/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Glicoproteína Mielina-Oligodendrócito/toxicidade , Fragmentos de Peptídeos/toxicidade , Proteínas Quinases/genética , Proteínas Quinases/metabolismo
16.
Mult Scler ; 24(5): 563-573, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28847222

RESUMO

BACKGROUND: Anti-John Cunningham virus (JCV) serology has been studied with varying results concerning longitudinal changes. OBJECTIVES AND METHODS: Results from 17 published natalizumab-treated multiple sclerosis (MS) patient cohorts were analyzed with common parameters and subsequently verified in two large independent cohorts with 722 and 499 patients from Germany and the United States. RESULTS: Published studies and the verification showed (1) a mean of 10.80% sero-negative patients presented with sero-status change to positivity per year; (2) patients, who sero-convert to index values <0.9, convert from near the threshold and have a high probability of reverting with time; (3) patients, who convert to index values >0.9, start with low index values; (4) while JCV sero-positive patients with low index values sometimes revert to sero-negativity, patients with high index values almost never revert; and (5) the conversion rate of natalizumab-treated patients is three to four times higher than the biological conversion by age. CONCLUSION: JCV sero-conversion was comparable using standardized parameters and indicates influence of natalizumab on JCV immune control. Converters to low index values are probably consistently infected with JCV with varying low levels of activity, in line with their low risk to develop progressive multifocal leukoencephalopathy (PML). Patients with high index values rarely revert back to sero-negativity.


Assuntos
Anticorpos Antivirais/sangue , Biomarcadores/sangue , Fatores Imunológicos/efeitos adversos , Fatores Imunológicos/uso terapêutico , Vírus JC/imunologia , Leucoencefalopatia Multifocal Progressiva/etiologia , Esclerose Múltipla/sangue , Esclerose Múltipla/tratamento farmacológico , Natalizumab/efeitos adversos , Natalizumab/uso terapêutico , Sorologia , Adolescente , Adulto , Fatores Etários , Estudos de Coortes , Estudos Transversais , Feminino , Alemanha , Humanos , Fatores Imunológicos/imunologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Natalizumab/imunologia , Risco , Fatores Sexuais , Utah , Adulto Jovem
17.
Mult Scler ; 24(14): 1871-1882, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-28984166

RESUMO

OBJECTIVE: Dimethyl fumarate (DMF) is prescribed against relapsing-remitting multiple sclerosis (MS). Here, we investigated the effects of DMF and monomethyl fumarate (MMF), its metabolite in vivo, at the (inflamed) blood-brain barrier (BBB). METHODS: Effects of fumaric acid esters were analyzed using primary human brain-derived microvascular endothelial cells (HBMECs) in combination with peripheral blood mononuclear cells (PBMCs) derived from DMF-treated MS patients. RESULTS: MMF-binding to brain endothelium cells leads to activation of nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2)-induced downregulation of vascular cell adhesion molecule 1 (VCAM-1). This might be mediated via the G-protein-coupled receptor (GPCR) hydroxycarboxylic acid receptor 2 (HCA2), a known molecular target of MMF, as we could demonstrate its expression and regulation on HBMECs. DMF treatment in vivo led to a strongly reduced expression of VCAM-1's ligand very late antigen 4 (VLA-4) by selectively reducing integrin high-expressing memory T cells of MS patients, potentially due to inhibition of their maturation by reduced trans-localization of NFκB. CONCLUSION: DMF-mediated VCAM-1 downregulation on the endothelial side and reduction in T cells with a migratory phenotype on the lymphocyte side result in a synergistic reduction in T-cell adhesion to activated endothelium and, therefore, to reduced BBB transmigration in the setting of MS.


Assuntos
Encéfalo/efeitos dos fármacos , Endotélio/efeitos dos fármacos , Leucócitos Mononucleares/efeitos dos fármacos , Esclerose Múltipla/tratamento farmacológico , Adulto , Células Endoteliais/efeitos dos fármacos , Feminino , Humanos , Imunossupressores/farmacologia , Leucócitos/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/imunologia , Transdução de Sinais/efeitos dos fármacos
18.
Int Immunol ; 27(1): 47-53, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25326459

RESUMO

Multiple sclerosis (MS) is a disorder of putative autoimmune origin, where immune cells invade the central nervous system and cause damage by attacking the myelin sheath of nerve cells. The blockade of the integrin very late antigen-4 (VLA-4) with the monoclonal antibody natalizumab has become the most effective therapy against MS since its approval in 2004. It is assumed that the inhibition of VLA-4-mediated immune cell adhesion to the endothelium of the blood-brain barrier (BBB) alleviates pathogenic processes of MS and, therefore, reduces disease severity and burden. Not all approaches to treat additional immune-mediated disorders (e.g. Rasmussen encephalitis and neuromyelitis optica) with natalizumab have been successful, but allowed researchers to gain additional insight into mechanisms of specific immune cell subsets' migration through the BBB in the human system. While the long-term efficacy and general tolerability of natalizumab in MS are clear, the over 400 cases of natalizumab-associated progressive multifocal leukoencephalopathy (PML) have been of great concern and methods of risk stratification in patients have become a major area of research. Modern risk stratification includes established factors such as treatment duration, previous immune-suppressive therapy, and anti-John Cunningham virus (JCV) antibody seropositivity, but also experimental factors such as anti-JCV antibody titers and levels of L-selectin. Today, anti-VLA-4 therapy is reserved for patients with highly active relapsing-remitting MS and patients are monitored closely for early signs of potential PML.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Imunoterapia/métodos , Integrina alfa4beta1/antagonistas & inibidores , Leucoencefalopatia Multifocal Progressiva/imunologia , Esclerose Múltipla/terapia , Viroses/imunologia , Animais , Anticorpos Monoclonais Humanizados/efeitos adversos , Barreira Hematoencefálica , Humanos , Imunoterapia/efeitos adversos , Integrina alfa4beta1/imunologia , Selectina L/metabolismo , Leucoencefalopatia Multifocal Progressiva/etiologia , Leucoencefalopatia Multifocal Progressiva/prevenção & controle , Natalizumab , Fatores de Risco , Viroses/complicações
19.
Mult Scler ; 22(8): 1048-60, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26432858

RESUMO

BACKGROUND: Natalizumab treatment is associated with progressive multifocal leukoencephalopathy (PML) development. Treatment duration, prior immunosuppressant use, and JCV serostatus are currently used for risk stratification, but PML incidence stays high. Anti-JCV antibody index and L-selectin (CD62L) have been proposed as additional risk stratification parameters. OBJECTIVE: This study aimed at verifying and integrating both parameters into one algorithm for risk stratification. METHODS: Multicentric, international cohorts of natalizumab-treated MS patients were assessed for JCV index (1921 control patients and nine pre-PML patients) and CD62L (1410 control patients and 17 pre-PML patients). RESULTS: CD62L values correlate with JCV serostatus, as well as JCV index values. Low CD62L in natalizumab-treated patients was confirmed and validated as a biomarker for PML risk with the risk factor "CD62L low" increasing a patient's relative risk 55-fold (p < 0.0001). Validation efforts established 86% sensitivity/91% specificity for CD62L and 100% sensitivity/59% specificity for JCV index as predictors of PML. Using both parameters identified 1.9% of natalizumab-treated patients in the reference center as the risk group. CONCLUSIONS: Both JCV index and CD62L have merit for risk stratification and share a potential biological relationship with implications for general PML etiology. A risk algorithm incorporating both biomarkers could strongly reduce PML incidence.


Assuntos
Anticorpos Antivirais/sangue , Vírus JC/imunologia , Selectina L/sangue , Leucoencefalopatia Multifocal Progressiva/induzido quimicamente , Esclerose Múltipla/tratamento farmacológico , Natalizumab/efeitos adversos , Infecções Oportunistas/induzido quimicamente , Algoritmos , Biomarcadores/sangue , Europa (Continente) , Humanos , Hospedeiro Imunocomprometido , Leucoencefalopatia Multifocal Progressiva/imunologia , Leucoencefalopatia Multifocal Progressiva/prevenção & controle , Leucoencefalopatia Multifocal Progressiva/virologia , Esclerose Múltipla/sangue , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/imunologia , Infecções Oportunistas/imunologia , Infecções Oportunistas/virologia , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Testes Sorológicos , Resultado do Tratamento
20.
Ann Neurol ; 75(5): 739-58, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24771567

RESUMO

OBJECTIVE: Environmental conditions (eg, latitude) play a critical role in the susceptibility and severity of many autoimmune disorders, including multiple sclerosis (MS). Here, we investigated the mechanisms underlying the beneficial effects of immune regulatory processes induced in the skin by moderate ultraviolet B (UVB) radiation on central nervous system (CNS) autoimmunity. METHODS: Effects of UVB light were analyzed in a murine model of CNS autoimmunity (experimental autoimmune encephalomyelitis). Additionally, patients with relapsing-remitting MS were treated with narrowband UVB phototherapy. Immunomodulatory effects were examined in skin biopsies, serum samples, and immune cells of the peripheral blood. RESULTS: Regulatory T cells (Tregs), which are induced locally in the skin-draining lymph nodes in response to UVB exposure, connect the cutaneous immune response to CNS immunity by migration to the sites of inflammation (blood, spleen, CNS). Here, they attenuate the inflammatory response and ameliorate disease symptoms. Treg-inducing tolerogenic dendritic cells (DCs) were further necessary for induction of this systemic immune regulation by UVB radiation, because ablation of Langerhans cells abolished the UVB-induced phenotype. MS patients treated with UVB phototherapy showed an increase in induced Tregs and tolerogenic DCs accompanied by the downregulation of the T-cell effector cytokine interleukin 21. The treatment further induced elevated serum levels of vitamin D. INTERPRETATION: Local UVB radiation of the skin influences systemic immune reactions and attenuates systemic autoimmunity via the induction of skin-derived tolerogenic DCs and Tregs. Our data could have implications for the understanding or therapeutic modulation of environmental factors that influence immune tolerance.


Assuntos
Encefalomielite Autoimune Experimental/radioterapia , Imunidade Celular/efeitos da radiação , Esclerose Múltipla Recidivante-Remitente/radioterapia , Linfócitos T Reguladores/efeitos da radiação , Raios Ultravioleta , Terapia Ultravioleta , Adulto , Animais , Células Cultivadas , Células Dendríticas/imunologia , Células Dendríticas/efeitos da radiação , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Feminino , Humanos , Imunidade Celular/imunologia , Masculino , Camundongos , Camundongos Congênicos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/imunologia , Esclerose Múltipla Recidivante-Remitente/patologia , Linfócitos T Reguladores/imunologia , Terapia Ultravioleta/métodos , Adulto Jovem
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