O papel da dopamina e dos padrões moleculares associados a patógenos no perfil funcional de células T de pacientes com esclerose múltipla

Abstract

Multiple sclerosis is an autoimmune, demyelinating disease, of the Central Nervous System, in which the onset and severity depends on the influence of environmental factors, including psychological stress and infections, on the immune system of individuals with genetic predisposition to the disease. In light of that, in our first paper, we observed that the in vitro blockage of IL-6 receptor, using anti-IL-6R IgG, reduced the Th17-related cytokines production. In addition, the ability of supernatants from lipolyssacharide (LPS)-activated monocytes cultures, in increasing IL-17 production and reducing IL-10 levels by autologous CD4⁺ T cells was abolished after neutralization of IL-6R signaling in these phagocytes' cultures. Interestingly, the addition of this monoclonal antibody increased the ability of hydrocortisone in inhibiting proliferation and IL-17 production by CD4⁺ and CD8⁺ T cells from MS patients. In our second paper, we observed that the stress-related dopamine levels, by IL-6-depending mechanisms, elevated the cytokine production by CD4⁺ T cells with an encephalitogenic profile and hydrocortisone-resistance. In our third and last paper, an elevated percentage of circulating CD4⁺ and CD8⁺ T cells capable of expressing toll-like receptors (TLR)2, TLR4 and TLR9 was detected in MS patients samples as compared to the control group. Among these cells, the subtypes of CD4⁺ and CD8⁺ T lymphocytes able to produce IL-17 with along IL-6 or IFN-gamma were positively related with the number of active brain lesions and the neurological disability. When CD4⁺ and CD8⁺ T cells were maintained in the presence of TLR ligands alone, greater levels of Th17-related cytokines were dosed at the supernatants of cell cultures stimulated with the TLR2L, Pam3CSK4. In these cell cultures, the levels of IL-6 and IL-17 in response to Pam3CSK4 were positively related to clinical parameters of the disease. Finally, CD4⁺ T cells cultures from patients with severe MS symptoms released higher levels of GM-CSF and IFN-gamma. Collectively, our findings suggest that IL-6 has an important role in MS immunopathogenesis and the production of this cytokine, as well as others Th17-related ones, are increased by dopamine and different PAMPs. The findings obtained here help not only to explain how psychological stress and infectious diseases are considered risk factors for MS, but they offer information that could aid in the development of new therapeutic strategies.