The presymptomatic stage of Huntington disease (HD) is marked by an increased prevalence of T helper 17.1 (TH17.1) cells in the cerebrospinal fluid (CSF), according to a new study published in Annals of Neurology. The finding suggests that therapies that reduce T cell-driven inflammation could delay or prevent onset of the disease.

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HD is an inherited neurodegenerative disease caused by an expanded trinucleotide repeat in the HTT gene, which encodes the huntingtin protein. The pathogenesis of HD is still unclear, but evidence of a role for immune abnormalities is accumulating.

“Studies have demonstrated the expression of mutated huntingtin in cells of the immune system, where the protein has pro-inflammatory properties,” explains Finn Sellebjerg, who led the new study alongside Marina von Essen. “This observation has led several research groups to investigate the possibility of immune activation within the CNS in HD, and whether this activation is involved in the pathogenesis of the disease.”

The researchers analysed CSF from individuals carrying the HTT expansion, some of whom had not yet developed symptoms of the disease, and from healthy non-carriers. In HTT expansion carriers, levels of the cytokines LTα and IL-17 were higher than in the healthy controls, indicating greater pro-inflammatory lymphocyte activity in these individuals.

The frequency of pro-inflammatory TH17.1 cells in the CSF was higher in individuals with the HTT expansion than in healthy controls. Carriers of the HTT expansion who had not yet developed the motor symptoms of HD had more CSF TH17.1 cells than those with motor symptoms, indicating that these cells are involved in the very early stages of the disease.

Studies have demonstrated the expression of mutated huntingtin in cells of the immune system

“The study raises the question of whether immunomodulatory or immunosuppressive therapy before the onset of HD may delay or even prevent the onset of disease in carriers of the pathogenic gene expansion,” concludes von Essen.