The role of retinoids and related type II nuclear receptors in the regulation of inflammatory responses and immune tolerance : relevance to multiple sclerosis

Abstract

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS), culminating in neurodegenerative disability. The combination of T-cell mediated autoimmune background and defects in immune regulation emerges as a hallmark feature of MS pathogenesis. This paradigm has opened a new avenue for exploitation of immunomodutatory agents in the MS therapy. Retinoids, the compounds related to the vitamin A, may have the potential to control cellular immune responses. They activate a group of endogenous ligand-inducible Type II Nuclear Receptors (NRs), which can act as a molecular switch at the cell transcription level. This study aimed to examine the role of endogenous retinoid system (ERS) in human immune regulation and address its relevance for modulating the immunopathogenic factors and restoring the immune balance in MS. Protein and transcript profiling along with in vitro studies of T cell dynamics in peripheral blood have revealed signature features of MS from the immunological perspective. A compelling body of evidence in this study points to the bias towards proinflammatory Th17 and Th1 cell responses at the expense of anti-inflammatory Tregs in periphera l blood as the mediators of MS immunopathogenesis. AtRA administration in vitro selectively altered the dysregulated immune dynamics: antagonised the pathogenic T cell subsets and promoted Tregs, modulating the cell ratio, effector phenotypes and functions. AtRA efficacy in the restoration of T cell homeostasis in vitro has been replicated in MS, proving responsiveness to the retinoid treatment in majority of MS patients. The study offers a better understanding of molecular mechanisms underlying the retinoid-mediated T cell immunomodulation. NR signalling has been explored in functional assays in vitro and revealed preferential anti-inflammatory polarisation of T cell response. The effector components of ERS - NRs transducing retinoid signals and t heir ligands - were monitored in vivo in peripheral blood cells in health and MS. This work has provided insights into previously unexplored interplay between the endogenous retinoid system and immune profile in the periphery and its translation into neurological pathology in MS. Altogether, the study concludes that retinoid signalling appears to be a significant player in molecular control of inflammation, governing the fate of its key T cell mediators. The accumulated findings suggest that retinoid-based strategies may offer a promising alternative for current approaches to MS treatment.EThOS - Electronic Theses Online ServiceGBUnited Kingdo