Abstract
Converging information from genetics, neuropathology and in-dept molecular profiling of immune cells points to the pathogenic involvement of T and B cells in MS. The role of newly identified lymphocyte subsets, such as follicular helper CD4 T cells and tissue-resident CD8 T cells and of functionally polarized B and T cells will be discussed. The target antigens of this deleterious adaptive immune response remain largely unknown. New candidate antigens have been described. This new knowledge fuels the aim to more finely therapeutically interfere with the immune processes underlying MS.
The gut microbiome is now considered among the risk factors associated with autoimmune diseases including Multiple Sclerosis (MS). This presentation is an overview of how gut dysbiosis potentially contributes to multiple sclerosis immunopathogenesis based on findings from the animal model experimental autoimmune encephalomyelitis (EAE) as well as MS human data. The presentation will demonstrate how gut dysbiosis influences neuroinflammation in EAE in an age dependent fashion and in the context of other MS risk factors including MHC class-II and MBP-specific TCR. The associated immune mechanisms will be described. Human data on gut microbiota species and taxa will be reviewed. Disease modifying therapies for MS seem to alter gut microbiota and immune responses in the gut through a variety of mechanisms including immune cell trafficking, gut barrier stabilization, and induction of T- regulatory cells. Finally, potential therapeutic interventions targeting the gut in MS will be reviewed including probiotics, antibiotics, fecal transplantation, diet and immune tolerance.
Animal models of MS, collectively referred to as experimental autoimmune encephalomyelitis (EAE), have shaped our concepts of neuroinflammation. Compared to EAE, studies with human MS-derived immune cells and tissues are facing a number of inherent obstacles. These include the tremendous genetic heterogeneity of the human population, as well as the fact that there is usually a long delay between the initiation of the autoimmune process and the emergence of clinical MS. MS-discordant monozygotic twins can help to overcome some of these hurdles. By controlling for genetic heterogeneity, the twin design is ideally suited for investigating external, non-genetic triggering mechanisms of neuroinflammation in human subjects. This may be illustrated by recent evidence supporting a pathogenetic role of the intestinal microbiota. Furthermore, some clinically unaffected co-twins show evidence of prodromal MS (“subclinical neuroinflammation“). This opens a window to investigate the earliest immunological changes linked to the initiation of the autoimmune process.