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.

Chemokine Interleukin-8 (IL-8) in Alzheimer’s and Other Neurodegenerative Diseases

“…Inflammation in HD is characterized by microglial activation and migration of cells in response to abnormal mutant protein [16]. The use of positron emission tomography (PET) has shown activation of microglia as an early event in the pathology of HD [17].…”

Targeting of Tumor Necrosis Factor Alpha Receptors as a Therapeutic Strategy for Neurodegenerative Disorders

“…Although for this review we have chosen to focus on AD, PD, ischemic stroke, and MS, investigation of TNF-α and its receptors in other neurodegenerative conditions may also greatly contribute to the understanding of TNF-α's effects, and the factors on which these effects depend. Examples of other disorders in which TNF-α has been implicated include traumatic brain injury (TBI) [167], epilepsy [168], and Huntington's disease (HD) [169,170]. Evidence exists that TNFR1 signaling may exacerbate cognitive dysfunction in a mouse model of TBI, while TNFR2 signaling may attenuate it [171,172].…”

Porcine Model of Huntington's Disease

“…The ubiquitously expressed mHtt may likely cause parallel inflammation in central nervous system (CNS) and in the periphery [58,59] (Figure 5). Björkqvist et al showed that immunomodulatory molecules IL-6 and IL-8 are over-expressed in the striatum and also in plasma of HD patients [54].…”