Impacto da depressão no perfil fenotípico e funcional das células T de pacientes com esclerose múltipla: estudo centrado no efeito da serotonina

Abstract

Multiple Sclerosis (MS) is a chronic demyelinating autoimmune disease of the central nervous system mediated by myelin-specific T cells, mainly Th17 subtypes. Disease severity has been associated with several environmental factors, such as the occurrence of major depression (MDD), a mood disorder commonly diagnosed in MS patients and associated with the risk of clinical relapses. Knowing that MDD has been associated with lower production of serotonin (5-HT), a neurotransmitter with immunomodulatory actions, the aim of the present work was to evaluate the impact of both MDD and 5-HT in modulating the functional status of effector and regulatory (Treg) cells of MS patients following in vitro stimulation with mitogens and myelin basic protein (MBP). While cytokine profile and proliferative response were evaluated, respectively, by ELISA/Luminex and tritiated thymidine capture, the phenotypic profile was determined by flow cytometry. In the first article, conducted in MS patients and without MDD, we demonstrated that 5-HT was able to decrease the production of Th17-related cytokines profile and both the frequency of CD39+IL-10+ Treg cells. Furthermore, the frequency of CD4+ and CD8+ T cells capable of producing IL-17, IL-22 and GM-CSF is higher in depressed patients. Interestingly, the percentage of MBP-specific IFN-γ+IL-17+ and IFN-γ+GM-CSF+ CD4+ T cells correlated directly with neurological disorder. In contrast, the occurrence of MDD was not only associated with a lower proportion of MBP-specific CD39+ Tregs cell subtypes, but the frequency of these cells was negatively correlated with severity of depressive symptoms and neurological impairments. Finally, the addition of 5-HT to cell cultures of patients with MDD was able to reduce the production of pro-inflammatory cytokines produced by encephalitogenic T cells. Thus, depression increases the inflammatory status of MS patients and negatively impacts the Treg cell compartment, which may lead to the development of new clinical relapses and favor a worse prognosis. Although preliminary, these findings suggest that therapeutic management of MDD with serotonin reuptake-inhibiting antidepressant drugs may help to reduce the radiological and clinical activity of MS.