Autoimmune neurologic diseases
Huntington's disease (HD) is a progressive, neurodegenerative and autosomal dominant disorder caused by a CAG repeat expansion in the huntingtin gene (htt), which leads to the expression of a mutated huntingtin protein (mHtt). Htt is ubiquitously expressed in the central nervous system (CNS) and mHtt is hypothesized to contribute to disruption of postsynaptic signaling, transcriptional regulation, and apoptosis induction leading to damage of the CNS. Htt is also expressed in cells of the immune system, and it is currently debated whether a pathogenic immune response is implicated in HD pathology. To investigate if the immune system plays a role in the pathogenesis of HD, we measured 30 cytokines in the CSF of 38 htt gene expansion carriers, thereof 19 premanifest and 19 manifest, compared to 19 healthy non-carriers (HC). Intriguingly, this analysis showed clear lymphocyte activity (e.g. decreased IL-7 and increased IL-17 and LT-a) in the CSF of htt gene expansion carriers already at pre-manifest disease stages. Furthermore, we found that the htt gene expansion carriers expressing at least one of the CSF neuroinflammatory biomarkers IgG, MMP-9, and CXCL13 were associated with a highly inflammatory profile; the expression level of 13 of the 30 analyzed cytokines was increased in this group as compared to non-inflammatory htt gene expansion carriers. Altogether, these observations demonstrate early lymphocyte activity in htt gene expansion carriers and suggest that the immune system plays a pathogenic role in Huntington's disease.
Danish Multiple Sclerosis Center