Role of regulatory T cells in pathogenesis and biological therapy of multiple sclerosis

Abstract

Multiple sclerosis (MS) is an inflammatory disease in which the myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms. It is caused by an autoimmune response to self-antigens in a genetically susceptible individual induced by unknown environmental factors. Principal cells of the immune system that drive the immunopathological processes are T cells, especially of TH1 and TH17 subsets. However, in recent years, it was disclosed that regulatory T cells took part in, too. Subsequently, there was endeavour to develop ways how to re-establish their physiological functions. In this review, we describe known mechanisms of action, efficacy, and side-effects of contemporary and emerging MS immunotherapeutical agents on Treg cells and other cells of the immune system involved in the immunopathogenesis of the disease. Furthermore, we discuss how laboratory immunology can offer physicians its help in the diagnosis process and decisions what kind of biological therapy should be used.

Figure 1

Differentiation of naïve T helper cells into particular subsets. T helper lymphocytes leaving the thymus (naïve or T_H0) are not yet fully differentiated to perform their specific functions in peripheral lymphoid tissues. They are endowed of these properties in the process of their interactions with dendritic cells (DCs) that engulf, process, and present antigens to them. Moreover, DCs in dependence of the processed antigens produce different cytokines. If DCs produce IL-12, naïve T cells polarise into the T_H1 subset, if IL-4 into the T_H2 subset and eventually, if DCs synthesise IL-6, naïve T helper cells will become the T_H17 cells.

Figure 2

Causes of impaired Treg cells function in autoimmunity development. Failures of regulatory T (Treg) cell-mediated regulation can include: inadequate numbers of Treg cells owing to their inadequate development in the thymus, for example, due to a shortage of principal cytokines (IL-2, TGF-β) or costimulatory signals (CD28), and so forth. Further, the number of Treg cells can be in a physiological range; however, there are some defects in Treg-cell function that are intrinsic to Treg cells, for example, they do not synthesise sufficient quantity of immunosuppressive cytokines (IL-10, IL-35, and TGF-β), or there is a breakdown of their interaction with effector T cells. Ultimately, pathogenic effector T cells (Teff) are resistant to suppression by Treg cells owing to factors that are intrinsic to the effector cells or factors that are present in the inflammatory milieu that supports effector T cells resistance.