Neuroimmune mechanisms in Krabbe's disease

Abstract

Neuroinflammation, activation of innate immune components of the nervous system followed by an adaptive immune response, is observed in most leukodystrophies and coincides with white matter pathology, disease progression, and morbidity. Despite this, there is a major gap in our knowledge of the contribution of the immune system to disease phenotype. Inflammation in Krabbe's disease has been considered a secondary effect, resulting from cell-autonomous oligodendroglial cell death or myelin loss resulting from psychosine accumulation. However, recent studies have shown immune activation preceding clinical symptoms and white matter pathology. Moreover, the therapeutic effect underlying hematopoietic stem cell transplantation, the only treatment for Krabbe's disease, has been demonstrated to occur via immunomodulation. This Review highlights recent advances in elaboration of the immune cascade involved in Krabbe's disease. Mechanistic insight into the inflammatory pathways participating in myelin and axon loss or preservation may lead to novel therapeutic approaches for this disorder.

Neuroinflammation as modifier of genetically caused neurological disorders of the central nervous system: Understanding pathogenesis and chances for treatment

“…Several studies support the view that neuroinflammation is a relatively early pathogenetic feature and not just the consequence of oligodendrocytic apoptosis, as previously speculated (reviewed in Potter & Petryniak (2016)). Moreover, inflammation drives pathology in the twitcher mice and most probably also in the human disease, where presymptomatic transplantation of possibly immune-dampening hematopoietic stem cells prolongs life expectation and transiently improves CNS symptoms (reviewed in Potter & Petryniak (2016)). Of note, the pathogenic impact of neuroinflammation is well documented by the genetic elimination of MHC-II: attenuating macrophage-and microglial cell-related MHC-II expression substantially improved the demyelinating phenotype and clinical features including twitching, but not longevity (Matsushima et al, 1994).…”

“…The disease is primarily caused by a deficiency of b-galactocerebrosidase (GALC) activity in lysosomes, leading to an accumulation of galactoceramide and psychosine (galactosylsphingosine) predominantly in macrophages/microglia, leading to the large, eponymous, multinucleated (globoid) cells. As reflected by the occurrence of globoid cells which are probably vacuolated microglial/macrophage-related cells of unusual appearance, inflammation appears to play a dominant role in the pathogenesis of the disorder (Potter & Petryniak, 2016;Won et al, 2016). As reflected by the occurrence of globoid cells which are probably vacuolated microglial/macrophage-related cells of unusual appearance, inflammation appears to play a dominant role in the pathogenesis of the disorder (Potter & Petryniak, 2016;Won et al, 2016).…”

“…This has been demonstrated in the respective animal models, from which the naturally occurring mouse GROH AND MARTINI | 1409 mutant twitcher, carrying the disease-causing GALC mutation, W332X, is the most well-known one (Potter & Petryniak, 2016). Moreover, inflammation drives pathology in the twitcher mice and most probably also in the human disease, where presymptomatic transplantation of possibly immune-dampening hematopoietic stem cells prolongs life expectation and transiently improves CNS symptoms (reviewed in Potter & Petryniak (2016)). Moreover, inflammation drives pathology in the twitcher mice and most probably also in the human disease, where presymptomatic transplantation of possibly immune-dampening hematopoietic stem cells prolongs life expectation and transiently improves CNS symptoms (reviewed in Potter & Petryniak (2016)).…”

“…Moreover, the neurotoxic psychosine is also amply detectable in myelinating glia cells, oligodendrocytes, and Schwann cells and exerts multiple deleterious effects ranging from impairing differentiation, reduced membrane stability, and fostering glial apoptosis (Won, Singh, & Singh, 2016). As reflected by the occurrence of globoid cells which are probably vacuolated microglial/macrophage-related cells of unusual appearance, inflammation appears to play a dominant role in the pathogenesis of the disorder (Potter & Petryniak, 2016;Won et al, 2016). This has been demonstrated in the respective animal models, from which the naturally occurring mouse GROH AND MARTINI | 1409 mutant twitcher, carrying the disease-causing GALC mutation, W332X, is the most well-known one (Potter & Petryniak, 2016).…”

“…As reflected by the occurrence of globoid cells which are probably vacuolated microglial/macrophage-related cells of unusual appearance, inflammation appears to play a dominant role in the pathogenesis of the disorder (Potter & Petryniak, 2016;Won et al, 2016). This has been demonstrated in the respective animal models, from which the naturally occurring mouse GROH AND MARTINI | 1409 mutant twitcher, carrying the disease-causing GALC mutation, W332X, is the most well-known one (Potter & Petryniak, 2016). Several studies support the view that neuroinflammation is a relatively early pathogenetic feature and not just the consequence of oligodendrocytic apoptosis, as previously speculated (reviewed in Potter & Petryniak (2016)).…”