Huntington’s disease (HD) is a devastating, inherited neurodegenerative disorder for which there is no effective treatment. It is caused by a polyglutamine repeat expansion in the gene encoding the protein huntingtin Citation[1]. HD causes neuronal death in the striatum and cerebral cortex Citation[2], which underlies its motor, cognitive and psychiatric manifestations. However, huntingtin is expressed ubiquitously throughout the body Citation[3], and HD also causes systemic abnormalities including weight loss and endocrine dysfunction Citation[4]. The contribution of non-neuronal tissues to pathogenesis and clinical symptomatology is increasingly recognized, and may be of importance in the search for biomarkers and therapy development in HD.
Immune activation has been the subject of recent interest in neurodegenerative diseases Citation[5], many of which share pathological hallmarks, especially abnormal protein folding and aggregate formation Citation[6]. Unlike other such diseases, everyone with the HD mutation will inevitably develop the disease, and every HD patient carries the mutation. Thus, not only is the root cause of the pathobiology of HD known unequivocally, but we can identify and study individuals destined to develop the disease. HD may, therefore, provide a unique insight into the very earliest changes underlying neurodegeneration.
The brain is known to display immune activation in HD. Pathological studies show activated microglia post-mortem Citation[7,8]. PET imaging has demonstrated increased microglial activation in vivo, both in overt disease Citation[9] and before symptom onset Citation[10]. At the molecular level, the IκB–NFκB signaling cascade, important to the innate immune response, is known to be upregulated in the presence of mutant huntingtin, and its activation is linked to neurotoxicity Citation[11]. Microglial cells expressing the mutant protein exacerbate toxicity Citation[12], and the microglial kynurenine mono-oxygenase pathway is a key therapeutic target Citation[13]. The immune response can protect neurons by favoring remyelination and trophic support Citation[14]. However, its dysregulation may be harmful for neuronal integrity and might worsen neurodegeneration.
A dysregulated immune system can also be detected outside the CNS in HD. Owing to the common myeloid lineage of microglia and monocytes, CNS and peripheral immune cells are likely to have similar reactions to the mutant protein and may exhibit parallel derangements, effectively enabling human peripheral cells to be used as a window into the CNS milieu.
In a study led by unbiased plasma proteomic profiling, we demonstrated that numerous plasma proteins were differentially regulated in HD. Strikingly, many upregulated proteins were components of the innate immune system, and key proteins, including clusterin and IL-6, tracked with disease progression. This raises the possibility that plasma immune markers may be able to monitor or predict the HD course Citation[15]. Such state markers are desperately needed to enable clinical trials of putative therapies for HD to be conducted, especially among premanifest mutation carriers who are clinically indistinguishable from control subjects Citation[16].
A more detailed analysis of the nature, extent, cause and implications of immune activation in HD demonstrated that plasma levels of numerous inflammatory cytokines (especially IL-6, IL-8 and TNF-α) are elevated and increase with advancing disease. Notably, IL-6 was significantly increased in a group of mutation carriers who were an average of 16 years before predicted disease onset. Monocytes from premanifest HD gene carriers were shown to secrete more IL-6 compared with control cells in response to stimulation by bacterial lipopolysaccharide. With HD mouse cells, this hyperactivity was shown to be due to the presence of mutant huntingtin within the immune cells. The same hyperactivity was also displayed by microglial cells from the brains of HD mice, and expression of IL-6, IL-8 and TNF-α were increased in human HD striatum. Overall, these results suggest parallel mutant huntingtin-induced dysfunction of both CNS and peripheral immune cells, which is closely linked to pathogenesis Citation[17].
These findings enhance the case for immune state markers of HD. Not only do the abnormal cytokine levels rise before onset, but they are firmly connected, both mechanistically and clinically, to the progression of HD – key requirements for useful biomarkers Citation[18]. Interestingly, different combinations of cytokines appear able to distinguish optimally between different subject groups: IL-6, IL-8 and IL-10 were best able to discriminate between premanifest and manifest HD, while IL-6, IL-5 and IL-10 best separated premanifest mutation carriers from controls. Moreover, similar changes were seen in three different mouse models, suggesting that inflammatory changes could be used as translational markers in drug development Citation[17].
The major potential criticisms of the value of immune changes as markers of neurodegenerative diseases are that they are nonspecific or variable from day to day, or that they could be epiphenomena caused by a general illness state. Certainly, nutritional, metabolic and infective pathology is likely to contribute to such a state in advancing HD. However, the fact that the changes are seen even before the onset of overt clinical features, and that the presence of the mutant protein per se is sufficient to cause abnormal overactivity of immune cells, provides compelling evidence for a direct relationship between immune activation and pathogenesis, with the potential to inform the search for disease markers. Crucially, finding markers of differential diagnosis is much less important in HD than for conditions such as Alzheimer’s disease because of the availability of a fully sensitive, specific genetic test. HD markers need only be applied to the population known to be at risk, so markers for critical phenomena in HD – such as disease onset and treatment efficacy – are much less susceptible to clouding from changes unrelated to the disease process. Nonetheless, thorough study of the interactions between disease, marker and treatment is required to ensure that crucial information about potential markers and treatments is not misinterpreted Citation[18].
In other neurodegenerative diseases, there is much uncertainty about whether inflammatory changes are beneficial, harmful or irrelevant Citation[19]. The ubiquity of such changes in HD Citation[7–10], the harmful effects of the microglial enzyme kynurenine mono-oxygenase Citation[13], and the mechanistic connection between mutant huntingtin and myeloid hyperactivity Citation[17] suggest strongly that even if the immune response is ever protective in HD, ultimately it is likely to exacerbate pathogenesis. Future studies will be necessary to evaluate whether anti-inflammatory treatments targeting the entire immune system, CNS inflammation or specific microglial pathways may be useful tools in the search for a cure for HD.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
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