The role of the immune system in Huntington's disease

Abstract

Huntington's disease (HD) is characterized by a progressive course of disease until death 15-20 years after the first symptoms occur and is caused by a mutation with expanded CAG repeats in the huntingtin (htt) protein. Mutant htt (mhtt) in the striatum is assumed to be the main reason for neurodegeneration. Knowledge about pathophysiology has rapidly improved discussing influences of excitotoxicity, mitochondrial damage, free radicals, and inflammatory mechanisms. Both innate and adaptive immune systems may play an important role in HD. Activation of microglia with expression of proinflammatory cytokines, impaired migration of macrophages, and deposition of complement factors in the striatum indicate an activation of the innate immune system. As part of the adaptive immune system, dendritic cells (DCs) prime T-cell responses secreting inflammatory mediators. In HD, DCs may contain mhtt which brings the adaptive immune system into the focus of interest. These data underline an increasing interest in the peripheral immune system for pathomechanisms of HD. It is still unclear if neuroinflammation is a reactive process or if there is an active influence on disease progression. Further understanding the influence of inflammation in HD using mouse models may open various avenues for promising therapeutic approaches aiming at slowing disease progression or forestalling onset of disease.

Figure 1

Neuroinflammation in the center of HD pathophysiology. Immune activation, induced by mutant huntingtin (mhtt), is found ubiquitously: in the central nervous system (central), the blood circulation (peripheral), and at molecular level (cellular). In the CNS, mhtt may not only influence migration of cells, for example, myeloid cells, but also induces microglia activation. Cytokines and chemokines (e.g., IL-6, TNFα) are secreted, and reactive oxygen species (ROS) are activated. Furthermore, glutamate-induced excitotoxicity, that is, in close interaction with oxidative stress, may contribute to degeneration. Migration deficits are discussed to influence innate immune response in the periphery very early in HD. Once again, cytokines, chemokines, and ROS in concert may trigger neuroinflammation. On a cellular level, mhtt upregulates the NF-kappa B (NF-κB) signaling pathway that triggers IL-6 expression. Finally, mitochondrial dysfunction generated by mhtt seems to be a key player leading to neuroinflammation in HD. The complement system is a connection between the innate and adaptive immune response. There are two ways that activate the complement system: first, inflammation with all its resulting effects targets factors of the complement system. Second, antibody response and T-cell response follow in secretion of complement factors. Various cell types may be affected, among these monocytes, astrocytes, and T and B cells.

Figure 2

Neuronal glia interactions in Huntington's disease. Microglia/macrophages are essential for host defense and can trigger M1 or M2 responses. The dichotomous M1/M2 concept implies that M1 cells induce Th1 cells that produce proinflammatory cytokines like IFN-γ, while M2 cells induce Th2 cells that are associated with IL-4, IL-5, and IL-10 supporting anti-inflammatory effects or antibody production. Aggregates of mutant huntingtin (mhtt) are found in neurons, astrocytes, and microglia. With a decreased protective function due to fewer glutamate transporters, mhtt-containing astrocytes may contribute to excitotoxicity. Consequently, there is glutamate excitotoxicity and glutamate-induced apoptosis causing neurodegeneration. At the same time, mhtt enhances microglia function and leads to microglia activation. Migrating microglia secrete proinflammatory cytokines (e.g., TNFα) and nitric oxide thus contributing to neurotoxicity. Yet, simultaneously, phagocytic microglia may also produce neuroprotective factors.