Perfil funcional das células T CD4+ de pacientes com neuromielite óptica: estudo centrado no papel de antígenos microbianos e receptores do tipo Toll

• Ano de defesa: 2017
• Autor(a) principal: Barros, Priscila de Oliveira
• Orientador(a): Bento, Cleonice Alves de Melo
• Banca de defesa: Ignacio, Ana Claudia de Paula Rosa , Saramago, Carmem Soares de Meirelles , Vasconcelos, Cláudia Cristina Ferreira , Benjamim, Claudia Farias , Lopes, Giselle Pinto de Faria
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade do Estado do Rio de Janeiro
• Programa de Pós-Graduação: Programa de Pós-Graduação em Microbiologia
• Departamento: Centro Biomédico::Faculdade de Ciências Médicas
• País: BR
• Palavras-chave em Português: Neuromielite óptica; Doenças autoimunes; Doenças auto-imunes; Esclerose múltipla; Mielite; Medula espinhal Inflamação
• Palavras-chave em Inglês: Neuromyelitis optica; Autoimmune diseases
• Área do conhecimento CNPq: CNPQ::CIENCIAS BIOLOGICAS::MICROBIOLOGIA::MICROBIOLOGIA APLICADA::MICROBIOLOGIA MEDICA
• Link de acesso: http://www.bdtd.uerj.br/handle/1/14369

Neuromyelitis optica spectrum diseases (NMOSD) is a group of inflammatory, idiopathic, autoimmune diseases that affect the central nervous system and, differently from multiple sclerosis, are mainly characterized by episodes of optic neuritis and/or extensive acute transverse myelitis. Despite genetic susceptibility, development and severity of NMOSD are influenced by environmental factors, like microbial molecules, that can impact the functional behavior of the T cells phenotype mainly implicated in NMOSD, the Th17 phenotype. In this context, the objective of the present thesis is to analyze functional aspects of CD4+ T cells from NMOSD patients, in remission, following in vitro activation with polyclonal and microbial stimulation and determine the Toll-like receptors (TLRs) expression pattern on these cells. In our first paper, the results showed a high immune reactivity of Th17 cells in response to E. coli, characterized by enhanced production of IL-17 and IL-6,. Interestingly, levels of these cytokines were directly associated to the disease severity, determined by the Expanded Disability Status Scale (EDSS) scores, and to IL-6 and IL-23 production in monocytes cultures when activated with lipopolysaccharide (LPS) from E. coli. The role of IL-6 as a cytokine involved in the pathogenesis of NMOSD was suggested in our second paper, in which the inhibition of the IL-6 receptor (IL-6R) signaling reduced the Th17-related cytokine production, enhanced IL-10 production and the ability of the corticoid in controlling the activation of these cells in vitro. As higher levels of LPS were detected in plasma from NMOSD patients, and they were positively correlated with EDSS scores, our last objective was to evaluate TLR expression on CD4+ T cells derived from patients. Our results showed an enhanced percentage of CD4+ T cells expressing TLR2, 4 and 9 when compared to healthy subjects. A more detailed phenotypical characterization demonstrated that a percentage of cells capable of producing, simultaneously, IL-17 and IL-6, was consistently associated to plasmatic levels of sCD14 and to NMOSD severity. On the other hand, IL-10-secreting Th17 TLR+ cells correlated inversely to the sCD14 levels and to EDSS scores. Taken together, our results suggest microbial products can effectively influence NMOSD prognosis by favoring the proportion of different TLR-expressing Th17 subtypes. This type of investigation needs to be conducted in a higher number of patients because, if confirmed, these data can help in the development of new therapies for NMOSD.