Regulation of CTLA-4 and PD-L1 Expression in Relapsing-Remitting Multiple Sclerosis Patients after Treatment with Fingolimod, IFNβ-1α, Glatiramer Acetate, and Dimethyl Fumarate Drugs

Afshin Derakhshani,Patrizia Leone,Mahdi Abdoli Shadbad,Behzad Baradaran,Hossein Safarpour,Zahra Asadzadeh,Ali Heydari,Vito Racanelli

doi:10.3390/jpm11080721

Abstract

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS) that is characterized by inflammation which typically results in significant impairment in most patients. Immune checkpoints act as co-stimulatory and co-inhibitory molecules and play a fundamental role in keeping the equilibrium of the immune system. Cytotoxic T-lymphocyte antigen-4 (CTLA-4) and Programmed death-ligand 1 (PD-L1), as inhibitory immune checkpoints, participate in terminating the development of numerous autoimmune diseases, including MS. We assessed the CTLA-4 and PD-L1 gene expression in the different cell types of peripheral blood mononuclear cells of MS patients using single-cell RNA-seq data. Additionally, this study outlines how CTLA-4 and PD-L1 expression was altered in the PBMC samples of relapsing-remitting multiple sclerosis (RRMS) patients compared to the healthy group. Finally, it investigates the impact of various MS-related treatments in the CTLA-4 and PD-L1 expression to restrain autoreactive T cells and stop the development of MS autoimmunity.

Highlights

Transcriptome profiling was conducted on various sub-groups of peripheral blood mononuclear cell (PBMC) samples to identify molecular signatures associated with each cell type
We demonstrated Cytotoxic T-lymphocyte antigen-4 (CTLA-4) and Programmed death-ligand 1 (PD-L1) expression in various immune cells using the novel approaches of bioinformatics and validated the result by Real-time PCR
We find that various treatments, especially Fingolimod, induce the expression of inhibitory checkpoints, CTLA-4 and PD-L1, and increased expression or function of these molecules can result in the decreased responses of autoreactive

Summary

Introduction

The etiology of MS is unknown, but biology, environmental conditions, and immune systems are all described as risk factors [1]. The prevalence of this neurodegenerative disease is due to an autoreactivity background composed of activated lymphocytes, macrophages, and microglia, which enter the CNS and lead to inflammation that can result in demyelination. The immune system contains a potent set of effector mechanisms that, in addition to protecting the body against invasive pathogens, can cause damage to the body itself. To avoid such tissue damage and restore inactivity following an inflammatory response, precise immune regulation is required.

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