Abstract
Immunogenic lipids may play key roles in host defenses against infection and in generating autoimmune inflammation and organ-specific damage. In multiple sclerosis (MS) there are unequivocal autoimmune features and vulnerability to aggravation or induction by microbial or viral infection. We have found glycolipid-driven anergy of circulating lymphocytes in MS indicating that this immune response is affected in MS and the robust effects of iNKT activation with potent cellular and cytokine activities emphasizes its potential importance. Diverse glycolipids including the endogenous myelin acetylated-galactosylceramides (AcGalCer) can drive activation that could be critical to the inflammatory demyelination in the central nervous system and clinical consequences. The iNKT cells and their invariant or iTCR (Vα24Jα18Vβ11) receptor an innate defense–a discrete immune arm that is separate from peptide-driven acquired immune responses. This offers new possibilities for insight including a likelihood that the pattern recognition of exogenous microbial and myelin immunogens can overlap and cross-react especially in an inflammatory milieu.
Highlights
A relatively unexplored frontier in multiple sclerosis (MS) research is the role of immunogenic lipids and complex glycolipids (GLs) and sphingolipids in disease mechanisms
They qualify as possible “original antigens” igniting immune responses that can lead in the susceptible host to breaking tolerance and enabling autoimmune reactivity, inflammation, demyelination and symptomatic MS
We have focused upon NKT cells because the invariant NKT cells are GL-reactive and constitute a distinct and discrete arm of the immune system that is separate from conventional peptide-binding T cells [46]
Summary
A relatively unexplored frontier in multiple sclerosis (MS) research is the role of immunogenic lipids and complex glycolipids (GLs) and sphingolipids in disease mechanisms. Of the GLs, GalCer, which accounts for 32% of CNS myelin lipid content, was mainly targeted for an auto-antibody immune response and recently anti-GalCer antibodies with demyelinating potential [32,33] have been found in MS, in RRMS and not in healthy controls [34].
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