T cell biology in neuromuscular disorders: a focus on Duchenne Muscular Dystrophy and Amyotrophic Lateral Sclerosis.

Growing evidence demonstrates a continuous interaction between the immune system, the nerve and the muscle in neuromuscular disorders of different pathogenetic origins, such as Duchenne Muscular Dystrophy (DMD) and Amyotrophic Lateral Sclerosis (ALS), the focus of this review. Herein we highlight the complexity of the cellular and molecular interactions involving the immune system in neuromuscular disorders, as exemplified by DMD and ALS. We describe the distinct types of cell-mediated interactions, such as cytokine/chemokine production as well as cell-matrix and cell-cell interactions between T lymphocytes and other immune cells, which target cells of the muscular or nervous tissues. Most of these interactions occur independently of exogenous pathogens, through ligand-receptor binding and subsequent signal transduction cascades, at distinct levels of specificity. Although this issue reveals the complexity of the system, it can also be envisioned as a window of opportunity to design therapeutic strategies (including synthetic moieties, cell and gene therapy, as well as immunotherapy) by acting upon one or more targets. In this respect, we discuss ongoing clinical trials using VLA-4 inhibition in DMD, and in ALS, with a focus on regulatory T cells, both revealing promising results.

Papel do receptor 1 de esfingosina-1-fosfato nos distúrbios de migração celular intratímica em camundongos NOD / Role of sphingosine 1-phosphate receptor 1 in the intrathymic cell migration disorders in NOD mice

Camundongos NOD (non-obese diabetic) desenvolvem diabetes tipo 1 (DT1)espontaneamente em decorrência da destruição das células beta de forma T-dependente nas ilhotaspancreáticas. Nesse sentido, diversos trabalhos demonstraram o envolvimento de células T e do timona patogênese do DT1. Diversas alterações podem ser observadas no timo de camundongos NOD,como presença de espaços perivasculares (PVS) gigantes contendo timócitos maduros simplespositivos(SP) CD4+e CD8+, além de células T reguladoras CD4+CD25+Foxp3+. Além disso, timócitosde NOD, em especial os maduros, apresentam menor expressão da integrina VLA-5 e capacidademigratória reduzida frente à fibronectina, sugerindo que esse defeito possa estar envolvido na retençãodessas células no órgão. Porém, essa retenção parece ser temporária, sugerindo o envolvimento deoutros mecanismos moleculares regulatórios do processo de saída de células T do timo. Diversostrabalhos demonstraram o papel essencial de S1P1 e seu ligante, S1P, na saída de timócitos do timoem condições normais e patológicas. Sendo assim, o objetivo principal desse trabalho foi investigar opapel das interações mediadas por S1P1 nos distúrbios de migração celular intratímica emcamundongos NOD. Através de citometria de fluxo, observamos que timócitos de camundongos NODapresentam menor expressão de S1P1 quando comparados a timócitos de camundongos C57BL/6.Essa menor expressão do receptor também foi observada em timócitos maduros CD62LhiVLA-5-, queapresentam fenótipo condizente com o das células que se encontram retidas nos PVS. Ao contrário, ostimócitos maduros CD62LhiVLA-5+não apresentaram diferença significativa na expressão doreceptor...

NOD mice spontaneously develop type 1 diabetes following T cell-dependent destruction ofpancreatic beta cells. Several works showed the involvement of T cell and the thymus in type 1diabetes phatogenesis. Several alterations are observed in NOD thymus, such as the presence of giantperivascular spaces (PVS) filled with mature simple-positive CD4+, CD8+and CD4+CD25+Foxp3+regulatory T cells. Moreover, NOD thymocytes have a reduced expression of the integrin VLA-5 anddecreased haptotatic migration towards fibronectin, suggesting that the VLA-5 defect could beinvolved in the retention of these cells inside the thymus. In contrast, thymocytes retention seems to betemporaly, suggesting the involvement of other regulatory molecules related to cell migration. Severalreports show the role of the sphingosine-1 phosphate receptor 1 (S1P1) on T cell migration and exitfrom thymus in normal and pathological conditions. Thus, the aim of our work is to investigate therole of S1P1-mediated interactions in NOD mice intrathymic migration disorders. In flow cytometryassays, we observed a lower S1P1 expression on NOD mice thymocytes compared with C57BL/6controls, including VLA-5 negative mature CD4+CD62Lhi and CD8+CD62Lhi subpopulations, whichbear the phenotype of the cells retained within giant PVS. By contrast, mature VLA-5 positivethymocytes did not present significant differences in S1P1 expression...