2.2.3. Immunoprofiling of Huntington's Disease

Chronic inflammation is a hallmark of HD. Inflammatory responses predate motor and psychiatric symptoms, suggesting that chronic inflammation contributes to disease progression. mHTT is highly expressed in immune cells, and its aggregates have been found to have a proinflammatory effect [77]. Even in premanifest patients, peripheral inflammation is characterized by elevated plasma levels of IL-6, and IL-8, IL-4, IL-10, and TNF-α levels rise as the disease progresses. The increase of both IL-6 and IL-8 in the early stages suggests, that it is the innate immunity that drives the initial immunopathology in HD. Indeed, monocytes, macrophages, and microglia isolated from HD patients were found to be hyperreactive to stimulation [78]. The mHTT has been found to drive up the release of IL-6 by upregulating the NF-κB pathway in mice [79]. Interestingly, a study has shown that the presence of mHTT does not directly impact the function of T cells, as their frequencies and functions did not differ from healthy controls [80].

Central inflammation in HD is characterized by chronic activation of microglia and astrocytes. Microglia are the primary mediators of neuroinflammation and in their activated state they release proinflammatory cytokines, such as IL-6, IL-1β, and TNF-α, as well as cytotoxic factors, such as reactive oxygen species (ROS), nitric oxide (NO) and QUIN. Prolonged microglial activation can lead to chronic neuroinflammation and tissue damage [81]. The number of activated microglial cells has been shown to positively correlate with the degree of neuronal loss in the striatum and cortex [82]. It has also been found that activation of microglia is present in very early stages of disease prior to the onset of symptoms [83]. Unlike microglia, the activation of astrocytes occurs in later stages of disease, when neurodegeneration is already present [81]. Reactive astrocytes can contribute to the proinflammatory environment through the production of pro-inflammatory cytokines, such as IL-12 and TNF-α; however, they can also contribute to neuroprotection by expressing anti-inflammatory cytokines, such as IL-10 and TGF-β [84].

Several studies have found a link between T helper 17 (Th17) cells and immunopathology in HD. In premanifest gene expansion carriers, it has been found that Th17.1 cells are activated while the number of Tregs is diminished. IL-17 is a proinflammatory cytokine that plays a role in communication between immune cells and tissue. In animal models, it has been shown to interact with endothelial cells, which induces the breakdown of the blood-brain barrier. The presence of IL-17 in cerebrospinal fluid (CSF) activates microglia, astrocytes, and oligodendrocytes, causing neuroinflammation. Early therapeutic intervention targeting Th17 cells might be beneficial and delay the onset of symptoms [85].
