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1.
Clin Immunol ; 264: 110262, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38788886

RESUMEN

Follicular helper T (Tfh) cells and their interplay with B cells likely contribute to the pathogenesis of relapsing-remitting multiple sclerosis (RRMS). Tfh cells are enriched in cerebrospinal fluid (CSF) in RRMS, but effects of anti-CD20 therapy are unknown. We investigated Tfh cells in controls, untreated and anti-CD20-treated patients with RRMS using flow cytometry. CSF Tfh cells were increased in untreated patients. Compared to paired blood samples, CD25- Tfh cells were enriched in CSF in RRMS, but not in controls. Contrast-enhancing brain MRI lesions and IgG index correlated with CSF CD25- Tfh cell frequency in untreated patients with RRMS. Anti-CD20 therapy reduced the numbers of circulating PD1+ Tfh cells and CD25- Tfh cells, and the frequency of CSF CD25- Tfh cells. The study suggests that CD25- Tfh cells are recruited to the CSF in RRMS, associated with focal inflammation, and are reduced by anti-CD20 therapy.


Asunto(s)
Antígenos CD20 , Esclerosis Múltiple Recurrente-Remitente , Células T Auxiliares Foliculares , Humanos , Femenino , Adulto , Masculino , Esclerosis Múltiple Recurrente-Remitente/líquido cefalorraquídeo , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/inmunología , Esclerosis Múltiple Recurrente-Remitente/sangre , Persona de Mediana Edad , Antígenos CD20/inmunología , Células T Auxiliares Foliculares/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Rituximab/uso terapéutico , Subgrupos de Linfocitos T/inmunología
2.
Front Immunol ; 15: 1327672, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38433828

RESUMEN

Introduction: Cladribine tablet therapy is an efficacious treatment for multiple sclerosis (MS). Recently, we showed that one year after the initiation of cladribine treatment, T and B cell crosstalk was impaired, reducing potentially pathogenic effector functions along with a specific reduction of autoreactivity to RAS guanyl releasing protein 2 (RASGRP2). In the present study we conducted a longitudinal analysis of the effect of cladribine treatment in patients with RRMS, focusing on the extent to which the effects observed on T and B cell subsets and autoreactivity after one year of treatment are maintained, modulated, or amplified during the second year of treatment. Methods: In this case-control exploratory study, frequencies and absolute counts of peripheral T and B cell subsets and B cell cytokine production from untreated patients with relapsing-remitting MS (RRMS) and patients treated with cladribine for 52 (W52), 60 (W60), 72 (W72) and 96 (W96) weeks, were measured using flow cytometry. Autoreactivity was assessed using a FluoroSpot assay. Results: We found a substantial reduction in circulating memory B cells and proinflammatory B cell responses. Furthermore, we observed reduced T cell responses to autoantigens possibly presented by B cells (RASGRP2 and a-B crystallin (CRYAB)) at W52 and W96 and a further reduction in responses to the myelin antigens myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG) after 96 weeks. Conclusion: We conclude that the effects of cladribine observed after year one are maintained and, for some effects, even increased two years after the initiation of a full course of treatment with cladribine tablets.


Asunto(s)
Subgrupos de Linfocitos B , Esclerosis Múltiple Recurrente-Remitente , Esclerosis Múltiple , Humanos , Esclerosis Múltiple/tratamiento farmacológico , Cladribina/uso terapéutico , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Glicoproteína Mielina-Oligodendrócito , Factores de Intercambio de Guanina Nucleótido
3.
Ann Clin Transl Neurol ; 11(4): 926-937, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38332555

RESUMEN

OBJECTIVES: B cells are important in the pathogenesis of multiple sclerosis. It is yet unknown which subsets may be involved, but atypical B cells have been proposed as mediators of autoimmunity. In this study, we investigated differences in B-cell subsets between controls and patients with untreated and anti-CD20-treated multiple sclerosis. METHODS: We recruited 155 participants for an exploratory cohort comprising peripheral blood and cerebrospinal fluid, and a validation cohort comprising peripheral blood. Flow cytometry was used to characterize B-cell phenotypes and effector functions of CD11c+ atypical B cells. RESULTS: There were no differences in circulating B cells between controls and untreated multiple sclerosis. As expected, anti-CD20-treated patients had a markedly lower B-cell count. Of B cells remaining after treatment, we observed higher proportions of CD11c+ B cells and plasmablasts. CD11c+ B cells were expanded in cerebrospinal fluid compared to peripheral blood in controls and untreated multiple sclerosis. Surprisingly, the proportion of CD11c+ cerebrospinal fluid B cells was higher in controls and after anti-CD20 therapy than in untreated multiple sclerosis. Apart from the presence of plasmablasts, the cerebrospinal fluid B-cell composition after anti-CD20 therapy resembled that of controls. CD11c+ B cells demonstrated a high potential for both proinflammatory and regulatory cytokine production. INTERPRETATION: The study demonstrates that CD11c+ B cells and plasmablasts are less efficiently depleted by anti-CD20 therapy, and that CD11c+ B cells comprise a phenotypically and functionally distinct, albeit heterogenous, B-cell subset with the capacity of exerting both proinflammatory and regulatory functions.


Asunto(s)
Subgrupos de Linfocitos B , Esclerosis Múltiple Recurrente-Remitente , Esclerosis Múltiple , Humanos , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Esclerosis Múltiple/tratamiento farmacológico , Linfocitos B , Células Plasmáticas
4.
Front Immunol ; 14: 1249201, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37744364

RESUMEN

Alemtuzumab is a monoclonal antibody targeting CD52 on the surface of immune cells, approved for the treatment of active relapsing-remitting multiple sclerosis (RRMS). The purpose of this study was to analyze the repopulation of peripheral lymphocytes following alemtuzumab-induced lymphocyte depletion and investigate associations with disease activity and development of secondary autoimmunity. For this, blood samples were collected two years after initiation of alemtuzumab treatment and lymphocytes were subjected to a comprehensive flow cytometry analysis. Included in the study were 40 patients treated with alemtuzumab and 40 treatment-naïve patients with RRMS. Disease activity and development of secondary autoimmune disease was evaluated after three years of treatment. Our study confirms that alemtuzumab treatment profoundly alters the circulating lymphocyte phenotype and describes a reconstituted immune system characterized by T cell activation/exhaustion, an increased regulatory control of IL-17 producing effector T cells and CD20+ T cells, and a reduced control of B cells. There were no obvious associations between immune cell subsets and disease activity or development of secondary autoimmune disease during treatment with alemtuzumab. Our results indicate that the reconstituted immune response is skewed towards a more effective regulatory control of MS-associated proinflammatory T cell responses. Also, the enlarged pool of naïve B cells together with the apparent decrease in control of B cell activity may explain why alemtuzumab-treated patients retain the ability to mount a humoral immune response towards new antigens.


Asunto(s)
Reconstitución Inmune , Esclerosis Múltiple Recurrente-Remitente , Humanos , Linfocitos T , Alemtuzumab/uso terapéutico , Linfocitos B , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico
5.
J Neuroimmunol ; 381: 578128, 2023 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-37321014

RESUMEN

Cerebrospinal fluid (CSF) soluble CD27 (sCD27) is a sensitive biomarker of intrathecal inflammation. Although generally considered a biomarker of T cell activation, CSF sCD27 has been shown to correlate with biomarkers of B cell activity in multiple sclerosis. We analyzed CSF from 40 patients with relapsing-remitting multiple sclerosis (RRMS) and nine symptomatic controls using flow cytometry and multiplex electrochemiluminescence immunoassays. CSF sCD27 levels were increased in RRMS and correlated with IgG index, soluble B cell maturation antigen, cell count, B cell frequency and CD8+ T cell frequency. We provide new data indicating that CSF sCD27 is associated with CD8+ T cells and B cells in RRMS.


Asunto(s)
Esclerosis Múltiple Recurrente-Remitente , Esclerosis Múltiple , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral , Humanos , Linfocitos B , Biomarcadores/líquido cefalorraquídeo , Linfocitos T CD8-positivos , Esclerosis Múltiple Recurrente-Remitente/diagnóstico , Esclerosis Múltiple Recurrente-Remitente/líquido cefalorraquídeo , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/química , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/metabolismo
6.
Artículo en Inglés | MEDLINE | ID: mdl-37369602

RESUMEN

BACKGROUND AND OBJECTIVE: Despite accumulating evidence of intrathecal inflammation in patients with primary progressive multiple sclerosis (PPMS), immunomodulatory and suppressive treatment strategies have proven unsuccessful. With this study, we investigated the involvement of CD20+ T cells and the effect of dimethyl fumarate on CD20+ T cells in PPMS. METHODS: The main outcomes in this observational, case-control study were flow cytometry assessments of blood and CSF CD20+ T cells and ELISA measurements of myelin basic protein and neurofilament light chain in untreated patients with PPMS and patients treated for 48 weeks with dimethyl fumarate or placebo. MRI measures included new and enlarging T2-weighted lesions over 48 weeks and lesion, normal-appearing white matter, cortical, and thalamic volume. RESULTS: Assessing CD20+ T cells in patients with PPMS and controls showed an increased percentage of CD20+ T cells in the blood of untreated patients and a strong enrichment in the CSF. In addition, a higher frequency of CD8+CD20+ T cells in the CSF correlated with a higher concentration of myelin basic protein and T2-weighted lesion volume and with a lower normal-appearing white matter and thalamus volume. Furthermore, CD8+CD20+ T cells were associated with the development of new T2 lesions. After 48 weeks of treatment with dimethyl fumarate, total T cells in CSF were reduced; however, CD20+ T cells were unaffected. DISCUSSION: This study shows an association between intrathecal CD8+CD20+ T cells, white matter injury, and thalamic atrophy in PPMS, suggesting a role of CD8+CD20+ T cells in the immunopathogenesis of PPMS. The results also suggest that limited efficacy of dimethyl fumarate in PPMS may, at least partly, be a consequence of failure to suppress CD8+CD20+ T cells in CSF.


Asunto(s)
Esclerosis Múltiple Crónica Progresiva , Esclerosis Múltiple , Humanos , Estudios de Casos y Controles , Linfocitos T CD8-positivos , Dimetilfumarato/farmacología , Dimetilfumarato/uso terapéutico , Esclerosis Múltiple/patología , Esclerosis Múltiple Crónica Progresiva/tratamiento farmacológico , Esclerosis Múltiple Crónica Progresiva/patología , Proteína Básica de Mielina , Linfocitos T
7.
Ann Neurol ; 94(3): 518-530, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37191113

RESUMEN

OBJECTIVE: Cladribine tablet therapy is an efficacious treatment for multiple sclerosis (MS), however, its mechanism of action on T and B cell subsets remains unclear. The purpose of this study was to investigate the treatment effects of cladribine on the peripheral pool of T and B cells subsets and reactivity toward central nervous system (CNS) antigens. METHODS: In this cross-sectional exploratory study, frequencies and absolute counts of peripheral T and B cell subsets and B cell cytokine production from untreated patients with relapsing-remitting MS (RRMS) and patients treated with cladribine for 1 year were measured using flow cytometry. Autoreactivity was assessed using a FluoroSpot assay. RESULTS: We found that 1 year after initiation of cladribine treatment, a lower number of CD4+ T cells was persisting whereas CD19+ B cell counts were normalized compared to untreated patients with RRMS. Follicular helper T cells and their effecter subsets producing cytokines exerting distinct B cell helper activity were lower and, additionally, the peripheral B cell pool was skewed toward a naïve and anti-inflammatory phenotype. Finally, reactivity to the recently identified CNS-enriched autoantigen RAS guanyl-releasing protein 2 (RASGRP2), but not to myelin basic protein and myelin oligodendrocyte glycoprotein, was lower in cladribine-treated patients. INTERPRETATION: Together, these investigations on T and B cell subsets suggest that cladribine treatment impairs the B-T cell crosstalk and reduces their ability to mediate pathogenic effector functions. This may result in specific reduction of autoreactivity to RASGRP2 which is expressed in B cells and brain tissue. ANN NEUROL 2023;94:518-530.


Asunto(s)
Cladribina , Esclerosis Múltiple , Humanos , Cladribina/efectos adversos , Esclerosis Múltiple/tratamiento farmacológico , Linfocitos T/patología , Inmunosupresores/farmacología , Inmunosupresores/uso terapéutico , Estudios Transversales , Factores de Intercambio de Guanina Nucleótido/farmacología
8.
Artículo en Inglés | MEDLINE | ID: mdl-35835563

RESUMEN

BACKGROUND AND OBJECTIVES: Follicular helper T (Tfh) cells play a critical role in protective immunity helping B cells produce antibodies against foreign pathogens and are likely implicated in the pathogenesis of various autoimmune diseases. The purpose of this study was to investigate the role of Tfh cells in the pathogenesis of multiple sclerosis (MS). METHODS: Using flow cytometry, we investigated phenotype, prevalence, and function of Tfh cells in blood and CSF from controls and patients with relapsing-remitting MS (RRMS) and primary progressive MS (PPMS). In addition, an in vitro blood-brain barrier coculture assay of primary human astrocytes and brain microvascular endothelial cells grown in a Boyden chamber was used to assess the migratory capacity of peripheral Tfh cells. RESULTS: This study identified 2 phenotypically and functionally distinct Tfh cell populations: CD25- Tfh cells (Tfh1-like) and CD25int Tfh cells (Tfh17-like). Whereas minor differences in Tfh cell populations were found in blood between patients with MS and controls, we observed an increased frequency of CD25- Tfh cells in CSF of patients with RRMS and PPMS and CD25int Tfh cells in patients with RRMS, compared with controls. Increasing frequencies of CSF CD25- Tfh cells and the CD25- Tfh/Tfr ratio scaled with increasing IgG index in patients with RRMS. Despite an increased prevalence of intrathecal Tfh cells in patients with MS, no difference in the migratory capacity of circulating Tfh cells was observed between controls and patients with MS. Instead, CSF concentrations of CXCL13 scaled with total counts of Tfh and Tfr cell subsets in the CSF. DISCUSSION: Our study indicates substantial changes in intrathecal Tfh dynamics, particularly in patients with RRMS, and suggests that the intrathecal inflammatory environment in patients with RRMS promotes recruitment of peripheral Tfh cells rather than the Tfh cells having an increased capacity to migrate to CNS.


Asunto(s)
Esclerosis Múltiple Recurrente-Remitente , Esclerosis Múltiple , Linfocitos B , Células Endoteliales , Humanos , Esclerosis Múltiple/patología , Células T Auxiliares Foliculares
9.
Artículo en Inglés | MEDLINE | ID: mdl-35672145

RESUMEN

BACKGROUND AND OBJECTIVES: The anti-CD20 antibody ofatumumab is an efficacious therapy for multiple sclerosis (MS) through depletion of B cells. The purpose of this study was to examine the derivative effects of B cell depletion on the peripheral immune system and a direct treatment effect on T cells expressing CD20. METHODS: Frequency and absolute numbers of peripheral leukocytes of treatment-naive patients with relapsing-remitting MS (RRMS) and patients treated with ofatumumab for a mean of 482 days were assessed in this observational study by flow cytometry. In addition, effector function and CNS migration of T cells using a human in vitro blood-brain barrier (BBB) assay were analyzed. RESULTS: This study showed that ofatumumab treatment of patients with RRMS increased the control of effector T cells and decreased T cell autoreactivity. It also showed that ofatumumab reduced the level of peripheral CD20+ T cells and that the observed decrease in CNS-migratory capacity of T cells was caused by the depletion of CD20+ T cells. Finally, our study pointed out a bias in the measurement of CD20+ cells due to a steric hindrance between the treatment antibody and the flow cytometry antibody. DISCUSSION: The substantial ofatumumab-induced alteration in the T cell compartment including a severely decreased CNS-migratory capacity of T cells could partly be attributed to the depletion of CD20+ T cells. Therefore, we propose that depletion of CD20+ T cells contributes to the positive treatment effect of ofatumumab and suggests that ofatumumab therapy should be considered a B cell and CD20+ T cell depletion therapy. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that compared with treatment-naive patients, ofatumumab treatment of patients with RRMS decreases peripheral CD20+ T cells, increases effector T cell control, and decreases T cell autoreactivity.


Asunto(s)
Esclerosis Múltiple , Anticuerpos Monoclonales Humanizados/efectos adversos , Antígenos CD20 , Humanos , Esclerosis Múltiple/tratamiento farmacológico , Linfocitos T
10.
Mult Scler ; 28(9): 1340-1350, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35112578

RESUMEN

BACKGROUND: Peripheral helper T cells (Tph) are likely implicated in the pathogenesis of various inflammatory diseases. Tph cells share functions with follicular helper T cells, including plasma cell differentiation and antibody production. OBJECTIVE AND METHODS: To investigate a possible role of Tph cells in the pathogenesis of multiple sclerosis (MS), we used flow cytometry to analyze the function, phenotype, and central nervous system (CNS)-recruitment of Tph cells in the blood and cerebrospinal fluid (CSF) from controls and patients with relapsing-remitting (RR) and primary progressive (PP) MS. RESULT: This study identified two functionally distinct Tph cell populations and a regulatory counterpart, Tpr cells. No differences in blood frequencies, cytokine production, or potential to interact with B cells were found between controls and patients with MS. Along with an equal CNS-migration potential, we found both Tph cell populations enriched in the CSF; and surprisingly, an increased frequency of intrathecal Tph cells in the control group compared to patients with MS. CONCLUSION: Altogether, we did not find an increased frequency of CSF Tph cells in patients with RRMS or PPMS. Our findings indicate that rather than being involved in MS pathogenesis, Tph cells may be implicated in normal CNS immunosurveillance.


Asunto(s)
Esclerosis Múltiple Recurrente-Remitente , Esclerosis Múltiple , Linfocitos B , Citometría de Flujo , Humanos , Activación de Linfocitos , Esclerosis Múltiple/patología , Linfocitos T Colaboradores-Inductores
11.
Clin Immunol ; 230: 108817, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34352391

RESUMEN

Many studies have analyzed myelin-reactivity of T cells in multiple sclerosis (MS); however, with conflicting results. In this study we compare methods to determine myelin reactivity of T cells and aim to delineate the cause of inconsistency in the literature. Challenging T cells with myelin antigens we found a significant increase in antigen-reactivity of T cells from patients with MS using an ELISpot-assay, in contrast to a CFSE-dilution assay. Comparing the two assays showed that the myelin-reactive T cells detected in the ELISpot-assay originated primarily from effector memory T cells in contrast to the myelin-reactive T cells of the CFSE-assay representing a population of both naïve, central memory and effector memory T cells. This diversity in T cell populations activated in the two assays likely contribute to the discrepancy found in the literature and encourages thorough considerations when choosing an assay to determine antigen-specificity of T cells in future studies.


Asunto(s)
Inmunoensayo/métodos , Esclerosis Múltiple Recurrente-Remitente/inmunología , Proteínas de la Mielina/inmunología , Linfocitos T/inmunología , Adulto , Autoantígenos/inmunología , Estudios de Casos y Controles , Ensayo de Immunospot Ligado a Enzimas , Femenino , Fluoresceínas , Colorantes Fluorescentes , Humanos , Memoria Inmunológica , Masculino , Persona de Mediana Edad , Proteína Básica de Mielina/inmunología , Glicoproteína Mielina-Oligodendrócito/inmunología , Succinimidas , Linfocitos T/clasificación , Adulto Joven
12.
Front Immunol ; 12: 676141, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34386002

RESUMEN

CD8+ T cells are involved in the pathogenesis of multiple sclerosis (MS). The interleukin-2 receptor α (IL-2Rα) is important for CD8+ T cell function, and single nucleotide polymorphisms (SNPs) in the IL2RA gene encoding IL-2Rα increase the risk of MS. Therefore, in isolated CD8+ T cells we investigated IL2RA gene methylation and gene expression in relation to the MS-associated IL2RA SNP rs2104286 and soluble IL-2Rα (sIL-2Rα). We have identified allele specific methylation of the CpG-site located in intron 1 that is perturbed by the rs2104286 SNP in CD8+ T cells from genotype-selected healthy subjects (HS). However, methylation of selected CpG-sites in the promotor or 5'UTR region of the IL2RA gene was neither associated with the rs2104286 SNP nor significantly correlated with IL2RA gene expression in HS. In CD8+ T cells from HS, we explored expression of immune relevant genes but observed only few associations with the rs2104286 SNP. However, we found that sIL-2Rα correlated negatively with expression of 55 immune relevant genes, including the IL-7 receptor gene, with Spearman's rho between -0.49 and -0.32. Additionally, in HS by use of flow cytometry we observed that the IL-7 receptor on naïve CD8+ T cells correlated negatively with sIL-2Rα and was downregulated in carriers of the rs2104286 MS-associated risk genotype. Collectively, our study of resting CD8+ T cells indicates that the rs2104286 SNP has a minor effect and sIL-2Rα may negatively regulate the CD8+ T cell response.


Asunto(s)
Linfocitos T CD8-positivos/metabolismo , Metilación de ADN , Subunidad alfa del Receptor de Interleucina-2/genética , Esclerosis Múltiple/genética , Polimorfismo de Nucleótido Simple , Adulto , Alelos , Linfocitos T CD8-positivos/inmunología , Humanos , Persona de Mediana Edad , Esclerosis Múltiple/inmunología , Regiones Promotoras Genéticas , Receptores de Interleucina-7/genética
13.
Mult Scler Relat Disord ; 52: 102987, 2021 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-33984651

RESUMEN

BACKGROUND: Natalizumab treatment increases the frequencies of B cells in blood but reduces IgG in blood and CSF. Plasmablasts are important in the production of IgG, and the development of plasmablasts is CD49d dependent. OBJECTIVE: We hypothesized that natalizumab treatment affects the development of plasmablasts. METHODS: We retrospectively analyzed frequencies and absolute counts of B cell subsets by flow cytometry from a longitudinal cohort of 9 progressive multiple sclerosis (MS) patients treated with natalizumab for 60 weeks, and a cross-sectional relapsing-remitting MS (RRMS) cohort with 17 untreated and 37 treated with natalizumab (17 stable and 20 unstable patients with relapse activity). Additionally, CD49d expression on B cell subsets was examined in 10 healthy controls, and blood and cerebrospinal fluid (CSF) frequencies of B cell subsets were quantified in untreated and natalizumab treated RRMS patients. RESULTS: In progressive MS, levels of IgG decreased in plasma (p<0.001) from baseline to 60 weeks follow-up. In the progressive MS and RRMS cohorts we observed that natalizumab treatment significantly increased the frequency of B cells (p=0.004; p<0.0001) and several B cell subsets, most pronounced for memory B cell subsets (p=0.0001; p<0.0001), while there was a decrease in plasmablast frequency (p=0.008; p=0.008). In both progressive MS and RRMS the absolute cell counts of B cells increased (p=0.004; p<0.001), which was explained by a significant increase in all subsets, except for plasmablasts. Furthermore, we found decreased memory B cell counts in unstable compared to stable natalizumab-treated patients (p=0.02). The expression of CD49d was higher on plasmablasts compared to other B cell subsets (p<0.0001). In CSF, plasmablasts could not be detected in patients treated with natalizumab, in contrast to an increased frequency in untreated RRMS patients. CONCLUSION: We confirm previous studies showing that natalizumab increases circulating number of B cells, particularly memory cells, concomitant with a decrease in plasma IgG concentrations. Moreover, we demonstrate in two separate cohorts that natalizumab treatment markedly decreases frequencies of plasmablasts while the absolute number is stable. Additionally, plasmablasts have high expression of CD49d, and plasmablasts could not be detected in the CSF of natalizumab-treated patients. Finally, memory B cells were found to be reduced in unstable natalizumab-treated patients, which could possibly indicate increased recruitment to the CNS.


Asunto(s)
Esclerosis Múltiple Recurrente-Remitente , Esclerosis Múltiple , Linfocitos B , Estudios Transversales , Humanos , Natalizumab , Estudios Retrospectivos
14.
Mult Scler Relat Disord ; 45: 102391, 2020 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-32679525

RESUMEN

BACKGROUND: Several roles for biomarkers in multiple sclerosis (MS) exist, including aiding in the diagnosis of MS, predicting disease activity or progression, and defining individuals who may be responsive to specific treatments. Cerebrospinal fluid (CSF) concentrations of soluble B cell maturation antigen (sBCMA) and soluble CD27 (sCD27) have been shown to be sensitive biomarkers of inflammation in MS and are thought to reflect B and T cell activity, respectively. Furthermore, chitinase 3-like 1 (CHI3L1) and soluble CD14 (sCD14) have been suggested as measures of innate immune cell activity in MS. In this study we sought to validate measurements of these CSF biomarkers of inflammation using multiplex bead-based immunoassays. METHODS: By using commercially available multiplex bead-based assays, concentrations of sBCMA, sCD27, sCD14 and CHI3L1 were determined in CSF from 22 patients with either untreated clinically isolated syndromes (CIS) or relapsing-remitting MS (RRMS), 13 patients with RRMS treated with either natalizumab or alemtuzumab, and 35 symptomatic controls (SC). RESULTS: Increased CSF concentrations of sBCMA, sCD27 and CHI3L1 were observed in untreated MS patients compared to symptomatic controls (all p < 0.001). Concentrations of sBCMA (p = 0.02) and sCD27 (p = 0.0003) were higher in treated MS patients than in SC, and levels of sBCMA (p = 0.02) and sCD27 (p = 0.01) were even higher in untreated compared to treated patients. sCD14 levels did not differ between the groups. Levels of sBCMA and sCD27 correlated strongly with each other (Spearman's rho: 0.98, p < 0.0001) as well as with the IgG index (Spearman's rho: 0.91, p < 0.0001 and 0.90, p < 0.0001, respectively). ROC curve analysis showed a high discriminatory potential for sBCMA and sCD27 with areas under the curve of 0.88 and 0.93, respectively. CONCLUSION: We confirm reports of elevated concentrations of sBCMA, sCD27 and CHI3L1 in CSF from untreated MS patients compared to SC. sBCMA and sCD27 levels were elevated in both treated and untreated MS patients compared to SC, but highest in untreated patients. Finally, CSF concentrations of sBCMA, sCD27 and the IgG index correlated strongly, suggesting that the cellular source of sCD27 and sBCMA includes memory B cells, plasmablasts and plasma cells.


Asunto(s)
Enfermedades Desmielinizantes , Esclerosis Múltiple Recurrente-Remitente , Esclerosis Múltiple , Biomarcadores , Humanos , Esclerosis Múltiple/diagnóstico , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/diagnóstico , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Natalizumab
15.
Mult Scler Relat Disord ; 37: 101451, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31675639

RESUMEN

BACKGROUND: Dimethyl fumarate (DMF) is a disease-modifying therapy for patients with relapsing-remitting multiple sclerosis (RRMS). T cells are major contributors to the pathogenesis of RRMS, where they regulate the pathogenic immune response and participate in CNS lesion development. OBJECTIVES: In this study we evaluate the therapeutic effects of DMF on T cell subpopulations, their CNS migration potential and effector functions. METHODS: Blood and CSF from untreated and DMF-treated patients with RRMS and healthy donors were analyzed by flow cytometry. RESULTS: DMF reduced the prevalence of circulating proinflammatory CD4+ and CD8+ memory T cells, whereas regulatory T cells were unaffected. Furthermore, DMF reduced the frequency of CD4+ T cells expressing CNS-homing markers. In coherence, we found a reduced recruitment of CD4+ but not CD8+ T cells to CSF. We also found that monomethyl fumarate dampened T cell proliferation and reduced the frequency of TNF-α, IL-17 and IFN-γ producing T cells. CONCLUSION: DMF influences the balance between proinflammatory and regulatory T cells, presumably favoring a less proinflammatory environment. DMF also reduces the CNS migratory potential of CD4+ T cells whereas CD8+ T cells are less affected. Altogether, our study suggests an anti-inflammatory effect of DMF mainly on the CD4+ T cell compartment.


Asunto(s)
Citocinas/efectos de los fármacos , Dimetilfumarato/farmacología , Fumaratos/farmacología , Factores Inmunológicos/farmacología , Inflamación/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Linfocitos T/efectos de los fármacos , Adulto , Proliferación Celular/efectos de los fármacos , Estudios de Cohortes , Femenino , Humanos , Inflamación/sangre , Inflamación/líquido cefalorraquídeo , Inflamación/inmunología , Masculino , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/sangre , Esclerosis Múltiple Recurrente-Remitente/líquido cefalorraquídeo , Esclerosis Múltiple Recurrente-Remitente/inmunología , Adulto Joven
16.
Cells ; 8(6)2019 06 25.
Artículo en Inglés | MEDLINE | ID: mdl-31242590

RESUMEN

Single nucleotide polymorphisms (SNPs) in or near the IL2RA gene, that encodes the interleukin-2 (IL-2) receptor α (CD25), are associated with increased risk of immune-mediated diseases including multiple sclerosis (MS). We investigated how the MS-associated IL2RA SNPs rs2104286 and rs11256593 are associated with CD25 expression on T cells ex vivo by multiparameter flow cytometry in paired genotype-selected healthy controls. We observed that MS-associated IL2RA SNPs rs2104286 and rs11256593 are associated with expression of CD25 in CD4+ but not CD8+ T cells. In CD4+ T cells, carriers of the risk genotype had a reduced frequency of CD25+ TFH1 cells (p = 0.001) and an increased frequency of CD25+ recent thymic emigrant cells (p = 0.006). Furthermore, carriers of the risk genotype had a reduced surface expression of CD25 in post-thymic expanded CD4+ T cells (CD31-CD45RA+), CD39+ TReg cells and in several non-follicular memory subsets. Our study found novel associations of MS-associated IL2RA SNPs on expression of CD25 in CD4+ T cell subsets. Insight into the associations of MS-associated IL2RA SNPs, as these new findings provide, offers a better understanding of CD25 variation in the immune system and can lead to new insights into how MS-associated SNPs contribute to development of MS.


Asunto(s)
Alelos , Predisposición Genética a la Enfermedad , Variación Genética , Subunidad alfa del Receptor de Interleucina-2/genética , Esclerosis Múltiple/genética , Esclerosis Múltiple/inmunología , Linfocitos T/inmunología , Adulto , Anciano , Antígenos CD/metabolismo , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Estudios de Casos y Controles , Femenino , Genotipo , Humanos , Memoria Inmunológica , Masculino , Persona de Mediana Edad , Fenotipo , Factores de Riesgo , Adulto Joven
17.
Mult Scler ; 25(7): 937-946, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-29775134

RESUMEN

BACKGROUND: Development of treatments for progressive multiple sclerosis (MS) is challenged by the lack of sensitive and treatment-responsive biomarkers of intrathecal inflammation. OBJECTIVE: To validate the responsiveness of cerebrospinal fluid (CSF) inflammatory biomarkers to treatment with natalizumab and methylprednisolone in progressive MS and to examine the relationship between CSF inflammatory and tissue damage biomarkers. METHODS: CSF samples from two open-label phase II trials of natalizumab and methylprednisolone in primary and secondary progressive MS. CSF concentrations of 20 inflammatory biomarkers and CSF biomarkers of axonal damage (neurofilament light chain (NFL)) and demyelination were analysed using electrochemiluminescent assay and enzyme-linked immunosorbent assay (ELISA). RESULTS: In all, 17 natalizumab- and 23 methylprednisolone-treated patients had paired CSF samples. CSF sCD27 displayed superior standardised response means and highly significant decreases during both natalizumab and methylprednisolone treatment; however, post-treatment levels remained above healthy donor reference levels. Correlation analyses of CSF inflammatory biomarkers and NFL before, during and after treatment demonstrated that CSF sCD27 consistently correlates with NFL. CONCLUSION: These findings validate CSF sCD27 as a responsive and sensitive biomarker of intrathecal inflammation in progressive MS, capturing residual inflammation after treatment. Importantly, CSF sCD27 correlates with NFL, consistent with residual inflammation after anti-inflammatory treatment being associated with axonal damage.


Asunto(s)
Antiinflamatorios/farmacología , Axones/patología , Factores Inmunológicos/farmacología , Inflamación/líquido cefalorraquídeo , Esclerosis Múltiple Crónica Progresiva/líquido cefalorraquídeo , Esclerosis Múltiple Crónica Progresiva/tratamiento farmacológico , Proteínas de Neurofilamentos/líquido cefalorraquídeo , Evaluación de Resultado en la Atención de Salud , Adulto , Biomarcadores/líquido cefalorraquídeo , Femenino , Estudios de Seguimiento , Humanos , Masculino , Metilprednisolona/farmacología , Persona de Mediana Edad , Natalizumab/farmacología
18.
J Neuroimmunol ; 324: 157-164, 2018 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-30244922

RESUMEN

The contribution of B cells to the pathogenesis of relapsing-remitting multiple sclerosis (RRMS) is currently of great interest due to the positive outcomes of treatment with B cell-depleting monoclonal antibodies. In this exploratory study we examined the phenotype and cytokine response of B cells from untreated patients with RRMS and healthy controls. The CNS migration potential of the individual blood B cell subpopulations was evaluated according to the expression of CD49d, ALCAM, CXCR3, and CCR7, and cerebrospinal fluid (CSF) samples were analyzed to establish the phenotype of migrated B cells. The frequency of the individual blood B cell subsets expressing CD5, CD43, CD69, CD80, CD83, DC-SIGN and CD138 was similar in patients with RRMS and healthy controls. However, a higher percentage of CD27-IgD-IgM+ memory B cells were found in the blood of patients with RRMS, a population also identified in the CSF samples. We also observed an increased percentage of B cells producing LTα and a higher level of TGFß1 in patients with RRMS. Altogether, we found that patients with RRMS have an increased frequency of blood CD27-IgD-IgM+ memory B cells that are recruited to the CSF together with other memory B cell populations. Furthermore, we report an increased B cell production of LTα and TGFß1 in patients with RRMS.


Asunto(s)
Linfocitos B/metabolismo , Linfotoxina-alfa/sangre , Esclerosis Múltiple Recurrente-Remitente/sangre , Fenotipo , Factor de Crecimiento Transformador beta1/sangre , Adulto , Biomarcadores/sangre , Femenino , Humanos , Masculino , Esclerosis Múltiple Recurrente-Remitente/diagnóstico por imagen
19.
J Neuroimmunol ; 324: 136-142, 2018 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-30193769

RESUMEN

Histopathological studies and animal models have suggested an inflammatory component in the pathomechanism of the CHMP2B associated frontotemporal dementia (FTD-3). In this cross-sectional study, serum and cerebrospinal fluid were analyzed for inflammatory markers in CHMP2B mutation carriers. Serum levels of CCL4 were increased throughout life. Serum levels of IL-15, CXCL10, CCL22 and TNF-α were significantly associated with cognitive decline, suggesting a peripheral inflammatory response to neurodegeneration. CSF levels of sTREM2 appeared to increase more rapidly with age in CHMP2B mutation carriers. The identification of a peripheral inflammatory response to disease progression supports the involvement of an inflammatory component in FTD-3.


Asunto(s)
Complejos de Clasificación Endosomal Requeridos para el Transporte , Demencia Frontotemporal/sangre , Demencia Frontotemporal/líquido cefalorraquídeo , Mediadores de Inflamación/sangre , Mediadores de Inflamación/líquido cefalorraquídeo , Adulto , Anciano , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Estudios Transversales , Complejos de Clasificación Endosomal Requeridos para el Transporte/genética , Femenino , Demencia Frontotemporal/genética , Humanos , Masculino , Persona de Mediana Edad , Mutación/genética
20.
J Neuroimmunol ; 310: 17-25, 2017 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-28778440

RESUMEN

We characterized naïve, central memory (CM), effector memory (EM) and terminally differentiated effector memory (TEMRA) CD4+ and CD8+ T cells and their expression of CD49d and CD26 in peripheral blood in patients with multiple sclerosis (MS) and healthy controls. CD26+ CD28+ CD4+ TEMRA T cells were increased in all subtypes of MS, and CD26+ CD28+ CD8+ TEMRA T cells were increased in relapsing-remitting and secondary progressive MS. Conversely, in progressive MS, CD49d+ CM T cells were decreased and natalizumab increased the circulating number of all six subsets but reduced the frequency of most subsets expressing CD49d and CD26.


Asunto(s)
Memoria Inmunológica/fisiología , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/patología , Subgrupos de Linfocitos T/inmunología , Adulto , Antígenos CD/metabolismo , Estudios Transversales , Evaluación de la Discapacidad , Femenino , Citometría de Flujo , Humanos , Factores Inmunológicos/uso terapéutico , Memoria Inmunológica/efectos de los fármacos , Activación de Linfocitos/efectos de los fármacos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/tratamiento farmacológico , Natalizumab/uso terapéutico , Estadísticas no Paramétricas , Subgrupos de Linfocitos T/clasificación
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