Inflammation in multiple sclerosis

Abstract

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) that is characterised pathologically by demyelination, gliosis, neuro-axonal damage and inflammation. Despite intense research, the underlying pathomechanisms driving inflammatory demyelination in MS still remain incompletely understood. It is thought to be caused by an autoimmune response towards CNS self-antigens in genetically susceptible individuals, assuming autoreactive T cells as disease-initiating immune cells. Yet, B cells were recognized as crucial immune cells in disease pathology, including antibody-dependent and independent effects. Moreover, myeloid cells are important contributors to MS pathology, and it is becoming increasingly evident that different cell types act in concert during MS immunopathology. This is supported by the finding that the beneficial effects of actual existing disease-modifying therapies cannot be attributed to one single immune cell-type, but rather involve immunological cooperation. The current strategy of MS therapies thus aims to shift the immune cell repertoire from a pro-inflammatory towards an anti-inflammatory phenotype, involving regulatory T and B cells and anti-inflammatory macrophages. Although no existing therapy actually exists that directly induces an enhanced regulatory immune cell pool, numerous studies identified potential net effects on these cell types. This review gives a conceptual overview on T cells, B cells and myeloid cells in the immunopathology of relapsing-remitting MS and discusses potential contributions of actual disease-modifying therapies on these immune cell phenotypes.

Keywords: B cells; T cells; immune network; immune regulation; inflammation; myeloid cells; relapsing-remitting multiple sclerosis.

Figure 1.

Simplified overview of the immune network during health and disease. (a) Simplified overview of the interaction between T cells, B cells and myeloid cells in a healthy immune system. Upon stimulation, CD4+ T cells can differentiate towards anti-inflammatory Th2 and Treg cells or towards pro-inflammatory Th1 and Th17 cells, depending on the surrounding micro milieu. T cell stimulation can be induced by the interaction with B cells or myeloid cells. Besides their antigen-presenting capacity, B cells also differentiate towards plasma cells, affecting immune responses via antibody secretion. A newly identified Breg subset can suppress enhanced pro-inflammatory Th1 and Th17 differentiation via IL-10 secretion. Moreover, B cell cytokines can directly affect the myeloid cell phenotype, inducing pro-inflammatory or anti-inflammatory myeloid cells. In a healthy immune system, autoreactive immune responses are suppressed via different mechanisms, including IL-10 secretion from Treg cells, Breg cells and anti-inflammatory myeloid cells, maintaining a balance between pro- and anti-inflammatory immune cells. (b) Simplified overview of the interaction between T cells, B cells and myeloid cells in MS. Pro-inflammatory Th1 and Th17 cell responses are increased in MS patients, showing higher secretion of pro-inflammatory cytokines. Moreover, the activation state of pro-inflammatory myeloid cells, secreting high amounts of ROS, as well as autoantibodies produced by plasma cells, and activated B cells are increased in MS patients. This shift towards a pro-inflammatory immune cell pool is induced by disturbed regulatory mechanisms, including defective Treg responses, decreased Breg cells and less anti-inflammatory myeloid cells. Breg, regulatory B cells; IL, interleukin; MS, multiple sclerosis; ROS, reactive oxygen species; Th, T helper; Treg, regulatory T cells.