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1.
Mult Scler ; 21(11): 1404-13, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25583848

RESUMO

BACKGROUND: Most twin studies of multiple sclerosis (MS) are inconclusive regarding the impact of genes and environment on disease susceptibility. In particular, high uncertainty exists about whether shared environmental factors are aetiologically relevant. OBJECTIVE: To disentangle, with a reasonable degree of confidence, the relative contributions of heritability and of shared and unique environmental components of MS susceptibility. METHODS: We performed a meta-analysis of previous twin studies. After a MEDLINE search, we selected eight twin studies in France, UK, Canada, Denmark, North America, Italy, Finland and Sweden. We conducted a biometric multi-group analysis under the liability-threshold model, by taking account of the study-specific ascertainment strategies and the population-specific prevalence rates of MS. RESULTS: The meta-analytic estimates of tetrachoric correlations were 0.71 (95% confidence interval (CI): 0.67-0.74) in monozygotic pairs and 0.46 (95% CI: 0.41-0.50) in dizygotic pairs. The biometric multi-group model provided meta-analytic estimates of 0.50 (95% CI: 0.39-0.61) for heritability, 0.21 (95% CI: 0.11-0.30) for shared environmental component and 0.29 (95% CI: 0.26-0.33) for unique environmental component. CONCLUSION: Our results support the continuing efforts to identify unknown genetic factors that fill the gap of 'missing heritability'; moreover, a 'missing environmentality' deserves future investigations into the role of non-heritable components that act as both shared and individual-specific exposures.


Assuntos
Meio Ambiente , Predisposição Genética para Doença , Esclerose Múltipla/etiologia , Esclerose Múltipla/genética , Estudos em Gêmeos como Assunto , Humanos
2.
Front Neurol ; 12: 683398, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34512507

RESUMO

Background: The changes of the gut-brain axis have been recently recognized as important components in multiple sclerosis (MS) pathogenesis. Objectives: To evaluate the effects of DMF on intestinal barrier permeability and mucosal immune responses. Methods: We investigated intestinal permeability (IP) and circulating CD161+CCR6+CD8+T cells in 25 patients with MS, who met eligibility criteria for dimethyl-fumarate (DMF) treatment. These data, together with clinical/MRI parameters, were studied at three time-points: baseline (before therapy), after one (T1) and 9 months (T2) of treatment. Results: At baseline 16 patients (64%) showed altered IP, while 14 cases (56%) showed active MRI. During DMF therapy we found the expected decrease of disease activity at MRI compared to T0 (6/25 at T1, p = 0.035 and 3/25 at T2, p < 0.00), and a reduction in the percentage of CD161+CCR6+CD8+ T cells (16/23 at T2; p < 0.001). The effects of DMF on gut barrier alterations was variable, without a clear longitudinal pattern, while we found significant relationships between IP changes and drop of MRI activity (p = 0.04) and circulating CD161+CCr6+CD8+ T cells (p = 0.023). Conclusions: The gut barrier is frequently altered in MS, and the CD161+ CCR6+CD8+ T cell-subset shows dynamics which correlate with disease course and therapy.

3.
Immunol Lett ; 158(1-2): 134-42, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24412596

RESUMO

CD28 is a crucial costimulatory receptor necessary full T cell activation. The role of CD28 in multiple sclerosis (MS) has been evaluated as the source of costimulatory signals integrating those delivered by TCR. However, CD28 is also able to act as a unique signaling receptor and to deliver TCR-independent autonomous signals, which regulate the expression and production of pro-inflammatory cytokines and chemokines. By comparing the cytokine/chemokine profiles of CD4(+) T cells from relapsing-remitting multiple sclerosis (RRMS) patients and healthy donors (HD), we found that CD28 engagement without TCR strongly up-regulates IL-8 and IL-6 expression in RRMS compared to HD. More interestingly, in RRMS but not in HD, CD28 stimulation selectively induces the expression of IL-17A by cooperating with IL-6-mediated signals. By using specific inhibitory drugs, we also identify the phosphatidylinositol 3 kinase (PI3K) as the critical regulator of CD28 proinflammatory functions in MS.


Assuntos
Antígenos CD28/metabolismo , Linfócitos T CD4-Positivos/imunologia , Interleucina-17/metabolismo , Esclerose Múltipla Recidivante-Remitente/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Adulto , Animais , Antígeno B7-2/genética , Antígeno B7-2/metabolismo , Cromonas/farmacologia , Feminino , Humanos , Mediadores da Inflamação/metabolismo , Interleucina-17/genética , Interleucina-6/genética , Interleucina-6/metabolismo , Interleucina-8/genética , Interleucina-8/metabolismo , Células L , Masculino , Camundongos , Pessoa de Meia-Idade , Morfolinas/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase , Transgenes/genética , Regulação para Cima/efeitos dos fármacos
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