Effect of the microRNA-92a loss on CD8+ T cells and B cells in mice with EAE and Multiple Sclerosis patients

• Grant number: 23/09781-7
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Start date: October 10, 2023
• End date: October 09, 2024
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Leonilda Maria Barbosa dos Santos
• Grantee: Fernando Pradella
• Supervisor: Murugaiyan Gopal
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Institution abroad: Harvard University, Boston, United States
• Associated to the scholarship: 20/02048-4 - Multiple Sclerosis: clinical study, neuropsicological, immunological, biomarker and disease modifying drugs, BP.PD

Abstract

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS) that is currently attributed to self-sustaining autoimmune mechanisms. Most of the knowledge regarding the autoaggressive mechanisms of MS has been obtained through experiments performed in its murine model, the Experimental Autoimmune Encephalomyelitis (EAE). EAE is considered a CD4+ T-cell mediated disease. However, there are several pieces of evidence of the critical role that CD8+ T lymphocytes and B cells play in MS pathogenesis. The Gopal Laboratory at Brigham and Women's Hospital and Harvard Medical School, where this project will be conducted obtained fascinating results regarding how miR-92a affects CD4+ T cells during EAE and MS. They found that miR-92a levels were elevated in EAE mice. Conversely, both miR-92a knockout mice (miR-92a-/- mice) and mice that had received exogenous miR-92a inhibitor exhibited a delayed onset and a significantly less severe EAE. Mechanistically, miR-92a promotes CNS inflammation by facilitating the induction of inflammatory Th17 cells and by inhibiting the generation and regulatory capacity of Treg cells through the suppression of the transcription factor Foxo1. Fujiwara and colleagues also obtained very similar results when studying CD4+ T lymphocytes from MS patients. Interestingly, miR-92a was identified as one of the most significantly increased miRNAs in patients with MS. Intriguingly, miR-92a levels were found to positively correlate with the extended disability standard scale (EDSS), an MS clinical parameter that measures disability progression. Nevertheless, there are no current studies examining the regulation of miR-92a on CD8+ T cells or B cells in the context of inflammatory autoimmune diseases of the CNS. To gain a deeper understanding of how miR-92a promotes neuroinflammation in EAE and MS, our objectives in this proposal is to broaden the scope of the studies to include other key cell types involved in the demyelination process, specifically B cells and CD8+ T cells. (AU)