New Murine Model for Multiple Sclerosis Based on T Lymphocytes Gene Methylation Changes: A Tool for Better Understanding the Pathogenesis of the Disease

par Ines Ait Driss, Daniela Iachimov, Andreea Stepanov, Xiao Yu Xie

Faculté de médecine, Université de Montréal

With over 77 000 cases, Canada presents one of the highest prevalence of Multiple Sclerosis (MS) in the world.1 The early onset of this incurable autoimmune disease [1] engenders debilitating consequences, affecting the patient's quality of life. Although the precise causes of this inflammatory demyelinating affliction remain elusive, studies strongly suggest that environmental factors causing epigenetic changes contribute to the disease [2, 3]. It has been proposed that lymphocyte DNA methylation is an important factor in its pathogenesis [2]. Unfortunately, the current models for MS are based on mice immunisation against Central nervous system (CNS) antigens and do not reflect accurately the etiology of the disease [4]. In order to palliate the situation, this study proposes the creation of a chimeric murine model using an allograft of modified hematopoietic stem cells that recreate some of the methylation patterns seen in MS [5-7]. The desired epigenetic modifications (hypermethylation of HLA-DRB1, DNHD1 and APC2 genes) [2] will be achieved via the CRISPR-Cas12a system with a modified U-rich crRNA guide [8]. After ensuring that hypermethylation and gene silencing was successful through immunofluorescence, the obtained phenotypes will be compared with controls by histopathology [9]. In the new model, increased occurrence of nerve demyelination and infiltration of the CNS by T cells, myelin antigen-specific CD4+ T cells and MS specific cytokines is expected [10]. If successful, this will be the first step in creating a new model that will not only allow for a better understanding of the origin of MS, but could also open the way for new treatments targeting those epigenetic modifications.

Key words: multiple sclerosis, demyelinating autoimmune disease, murine model, DNA methylation, CRISPR-Cas12a epigenetic modifications.

Références

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Image de couverture : https://today.uconn.edu/2019/05/new-culprit-multiple-sclerosis-relapses/#