miRNA expression analysis in T lymphocytes subpopulations from multiple sclerosis patients

Author(s)

Julio Cesar Cetrulo Lorenzi

• Document type: Doctoral Thesis
• Press: Ribeirão Preto.
• Institution: Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC)
• Defense date: 2013-12-11

Examining board members

Wilson Araújo da Silva Junior; Iscia Teresinha Lopes Cendes; Emmanuel Dias Neto; Paulo Louzada Júnior; Rodrigo Alexandre Panepucci

• Advisor: Wilson Araújo da Silva Junior

Abstract

This study discusses the role of miRNA in the Molecular Pathophysiology of Relapse Remitting Multiple Sclerosis (RRMS). The study has shown that CD4+ lymphocytes from relapsed RRMS patients had lower expression of miR15a and miR-16-1 in contraposition of higher expression of the target gene BCL-2, a key regulator of apoptosis. These findings suggest the role of those on the control of apoptosis in MS. In order to explore this association, the global expression of miRNAs was analysed in T lymphocyte subpopulations from remission RRMS patients. The result of this analysis has demonstrated for the first time a significant higher expression of 9 miRNAs (miRNAs-16, miRNAs-20a, miRNAs-21, miRNAs-24, miRNAs-155, miRNAs-221, miRNAs-222, miRNAs-720 e miRNAs-1281) in central memory T CD8+ lymphocytes. In silico analysis of the miRNAs targets indicates that three canonical pathways related to the activation of apoptosis were enriched with predicted and experimental validated gene targets for those miRNAs. In this way, we suggest the strong relation of these miRNAs in the control of apoptosis in the lymphocytes from RRMS patients. In order to intensify our studies we selected miR-21 and miR-24 to perform in vivo functional experiments. It was verified miR-21 induction only in T CD4+ lymphocytes from MS animal model. Additionally, in vitro experiments have demonstrated that miR-21 expression was restricted to Th2 and Th17 cell populations. In this way, miR-21 seems to be regulated by the STAT3 transcription factor, thereby suggesting that the increase of miR-21 expression observed in vivo could be related with Th17 CD4+ present in this tissue. In summary, this set of results showed the relevance of miRNAs in the RRMS pathophysiology, mainly in the control of apoptosis. (AU)

• FAPESP's process: 10/00310-1 - miRNA signature of T lymphocyte subpopulations from healthy and multiple sclerosis patients
• Grantee: Julio Cesar Cetrulo Lorenzi
• Support Opportunities: Scholarships in Brazil - Doctorate