Excessive levels of proinflammatory cytokines in the CNS are associated with reduced serotonin (5-HT) synthesis, a neurotransmitter with diverse immune effects. In this study, we evaluated the ability of exogenous 5-HT to modulate the T-cell behavior of patients with MS, a demyelinating autoimmune disease mediated by Th1 and Th17 cytokines. Here, 5-HT attenuated, in vitro, T-cell proliferation and Th1 and Th17 cytokines production in cell cultures from MS patients. Additionally, 5-HT reduced IFN-γ and IL-17 release by CD8 T cells. By contrast, 5-HT increased IL-10 production by CD4 T cells from MS patients. A more accurate analysis of these IL-10-secreting CD4 T cells revealed that 5-HT favors the expansion of FoxP3 CD39 regulatory T cells (Tregs) and type 1 regulatory T cells. Notably, this neurotransmitter also elevated the frequency of Treg17 cells, a novel regulatory T-cell subset. The effect of 5-HT in upregulating CD39 Treg and Treg17 cells was inversely correlated with the number of active brain lesions. Finally, in addition to directly reducing cytokine production by purified Th1 and Th17 cells, 5-HT enhanced in vitro Treg function. In summary, our data suggest that serotonin may play a protective role in the pathogenesis of MS.

SummaryMultiple sclerosis (MS) is thought to be an autoimmune disorder. It is believed that immunological events in the early stages have great impact on the disease course. Therefore, we aimed to evaluate the cytokine profile of myelin basic protein (MBP)-specific T cells from MS patients in the early phase of the disease and correlate it to clinical parameters, as well as to the effect of in vitro corticoid treatment. Peripheral T cells from MS patients were stimulated with MBP with our without hydrocortisone for 5 days. The cytokines level were determined by ELISA. The number of active brain lesions was determined by MRI scans, and the neurological disabilities were assessed by Expanded Disability Status Scale scores. Our results demonstrated that MS-derived T cells responded to MBP by producing high levels of T helper type 1 (Th1) and Th17 cytokines. Although the production of interleukin-6 (IL-6), granulocytemacrophage colony-stimulating factor, IL-17 and IL-22 was less sensitive to hydrocortisone inhibition, only IL-17 and IL-22 levels correlated with active brain lesions. The ability of hydrocortisone to inhibit IL-17 and IL-22 production by MBP-specific CD4 + T cells was inversely related to the number of active brain lesions. Finally, the production of both cytokines was significantly higher in cell cultures from Afrodescendant patients and it was less sensitive to hydrocortisone inhibition. In summary, our data suggest that IL-17-and IL-22-secreting CD4 + T cells resistant to corticoids are associated with radiological activity of the MS in early stages of the disease, mainly among Afrodescendant patients who, normally, have worse prognosis.

Signalling through Toll-like receptors (TLRs) may play a role in the pathogenesis of autoimmune diseases, such as multiple sclerosis (MS). In the present study, the expression of TLR-2, -4 and -9 was significantly higher on CD4 and CD8 T-cells from MS patients compared to healthy individuals. Following in-vitro activation, the proportion of interleukin (IL)-17 and IL-6 CD4 and CD8 T-cells was higher in the patients. In addition, the proportion of IFN-γ-secreting TLR CD8 T-cells was increased in MS patients. Among different IL-17 T-cell phenotypes, the proportion of IL-17 TLR CD4 and CD8 T-cells producing IFN-γ or IL-6 were positively associated with the number of active brain lesions and neurological disabilities. Interestingly, activation of purified CD4 and CD8 T-cells with ligands for TLR-2 (Pam3Csk4), TLR-4 [lipopolysaccharide (LPS)] and TLR-9 [oligodeoxynucleotide (ODN)] directly induced cytokine production in MS patients. Among the pathogen-associated molecular patterns (PAMPs), Pam3Csk4 was more potent than other TLR ligands in inducing the production of all proinflammatory cytokines. Furthermore, IL-6, IFN-γ, IL-17 and granulocyte-macrophage colony-stimulating factor (GM-CSF) levels produced by Pam3Csk4-activated CD4 cells were directly associated with disease activity. A similar correlation was observed with regard to IL-17 levels released by Pam3Csk4-stimulated CD8 T-cells and clinical parameters. In conclusion, our data suggest that the expansion of different T helper type 17 (Th17) phenotypes expressing TLR-2, -4 and -9 is associated with MS disease activity, and reveals a preferential ability of TLR-2 ligand in directly inducing the production of cytokines related to brains lesions and neurological disabilities.

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-Objetive:To re-enforce an alternative, less aggressive treatment modality in the management of intracranial infectious aneurysms. Method: We present a series of five patients with infectious endocarditis and intracranial infectious aneurysms (mycotic aneurysms) managed by means of endovascular treatment. Results: Endovascular treatment was executed technically uneventfully in all patients. Three patients had favorable clinical outcome: two were classified as Glasgow Outcome Scale 4/5, and one had total neurological recovery (GOS 5/5). Two patients died (GOS 1/5), one in consequence of the initial intracranial bleeding and the other after cardiac complications from endocarditis and open-heart surgery. Conclusion: Endovascular techniques are an expanding option for the treatment of IIAs. It has been especially useful for infectious endocarditis patients with IIA, who will be submitted to cardiac surgery with cardiopulmonary bypass and anticoagulation, with the risk of intracranial bleeding.KEy WOrdS: infectious aneurysms, cerebral, embolization tratamento endovascular de aneurismas infecciosos intracranianosResumo -Objetivo: Enfatizar o método endovascular como uma opção de tratamento alternativa e menos agressiva no tratamento de aneurismas infecciosos intracranianos. Método: Apresentamos uma série de cinco pacientes com endocardite infecciosa e aneurismas infecciosos intra-cranianos (aneurismas micóticos) tratados através da via endovascular. Resultados: O tratamento endovascular teve sucesso técnico e sem intercorrências relacionadas ao cateterismo em todos os casos. Três pacientes tiveram desfecho clínico favorável: dois com escala de regeneração de Glasgow 4/5 e um com recuperação neurológica completa (GOS 5/5). dois pacientes tiveram desfecho desfavorável (GOS 1/5), um devido às conseqüências do sangramento intracraniano inicial e outro devido a complicações cardíacas da endocardite e cirurgia de troca valvar. Conclusão: As técnicas endovasculares são uma nova opção de tratamento dos aneurismas infecciosos intracranianos. Ela é especialmente útil em pacientes que serão submetidos à cirurgia cardíaca com circulação extra-corpórea e anticoagulação, com o conseqüente risco de hemorragia intracraniana.PAlAvrAS-chAvE: aneurismas infecciosos, cerebral, embolização.