A novel pathogenic pathway of immune activation detectable before clinical onset in Huntington's disease

TLDR

Huntington's disease is an inherited neurodegenerative disorder characterized by both neurological and systemic abnormalities. Peripheral innate immune activation, including elevated IL‑6 and hyperactive monocytes expressing mutant huntingtin, is detectable in plasma up to 16 years before clinical onset and mirrors similar CNS immune dysfunction, indicating parallel central and peripheral pathogenic pathways.

Abstract

Huntington's disease (HD) is an inherited neurodegenerative disorder characterized by both neurological and systemic abnormalities. We examined the peripheral immune system and found widespread evidence of innate immune activation detectable in plasma throughout the course of HD. Interleukin 6 levels were increased in HD gene carriers with a mean of 16 years before the predicted onset of clinical symptoms. To our knowledge, this is the earliest plasma abnormality identified in HD. Monocytes from HD subjects expressed mutant huntingtin and were pathologically hyperactive in response to stimulation, suggesting that the mutant protein triggers a cell-autonomous immune activation. A similar pattern was seen in macrophages and microglia from HD mouse models, and the cerebrospinal fluid and striatum of HD patients exhibited abnormal immune activation, suggesting that immune dysfunction plays a role in brain pathology. Collectively, our data suggest parallel central nervous system and peripheral pathogenic pathways of immune activation in HD.