Microglial nodules provide the environment for pathogenic T cells in human encephalitis

Abstract

Microglia nodule formation is a common feature in inflammatory brain diseases mediated by T lymphocytes such as viral and paraneoplastic encephalitis, multiple sclerosis, and Rasmussen encephalitis (RE). However, its role has not been fully understood yet. We hypothesized that, in RE, microglial nodules provide an environment for the initiation of the later dominating T-cell cytotoxicity. In RE stage 0, small primary microglia nodules could be identified in the absence of T cells. These primary nodules showed inflammasome activation and endosomal Toll-like receptor upregulation. In stage 1, T cells migrate into the parenchyma and intermingle with microglial cells, thereby forming secondary nodules in which neurons are destroyed. Whole-genome transcriptome analysis at this point showed upregulation of several inflammatory pathways including interferon signaling and major histocompatibility complex-I signaling. Inflammatory profiles, like the ones observed in RE, could be induced upon TLR3 stimulation in neonatal microglial cell cultures. Taken together, our results point towards activation of endosomal TLRs, resulting in increased interferon signaling, inflammasome activation, and chemokine upregulation as early steps in RE pathogenesis. This activity sets the scene for subsequent infiltration of T cells and destruction of neurons. Similar to RE, this microglial microenvironment might be a crucial step in other T-cell-mediated inflammatory brain diseases.Electronic supplementary materialThe online version of this article (10.1007/s00401-019-01958-5) contains supplementary material, which is available to authorized users.

Pathology of inflammatory diseases of the nervous system: Human disease versus animal models

“…A similar mechanism has recently been observed in Rasmussen's encephalitis, an inflammatory and immune mediated epilepsy, driven by MHC Class I restricted cytotoxic CD8 + T‐cells, which directly interact with neurons and astrocytes (Bauer, Gold, Adams, & Lassmann, ; Bien et al, ; Dauvilliers et al, ). The initial step in the development of lesions in this disease is the formation of microglia nodules with inflammasome activation, which precedes the CNS infiltration by T‐cells (Tröscher et al, ). Interestingly, such microglia nodules are also abundant in the normal appearing white matter adjacent to active lesions in MS (Michailidou et al, ; Peferoen et al, ; Singh et al, ; van der Valk & Amor, , Figure ).…”

“… Note : The table compares the key features of inflammatory lesions in the central nervous system mediated by different T‐cell populations, B‐cells, and innate immunity in rodent models and humans, also describing the reaction patterns of microglia/macrophages and astrocytes. References 1: Ajami et al (), 2: Ben‐Nun, Wekerle, and Cohen (), Lassmann et al (), 4: Wolf et al (), 5: Blaabjerg et al (). 6: Mayo et al (), 7: Basso et al (). 8: Bradl and Lassmann (), 9: Linington, Bradl, Lassmann, Brunner, and Vass (), 10: Misu et al (), 11: Pohl et al, , 12: Storch et al (). 13: Bien et al (), 14: Cabarrocas, Bauer, Piaggio, Liblau, and Lassmann (), 15: Dauvilliers et al (), 16: Ji, Perchellet, and Goverman (), 17: Laukoter et al (), 18: Na et al (), 19: Saxena et al (), 20: Steinbach et al (), 21: Tröscher et al (). 22: Machado‐Santos et al (), 23: van Nierop et al (), 24: Zrzavy et al (). 25: Felts et al (), 26: Marik, Felts, Bauer, Lassmann, and Smith (), 27: Nau and Brück (2002). …”

“…13: Bien et al (), 14: Cabarrocas, Bauer, Piaggio, Liblau, and Lassmann (), 15: Dauvilliers et al (), 16: Ji, Perchellet, and Goverman (), 17: Laukoter et al (), 18: Na et al (), 19: Saxena et al (), 20: Steinbach et al (), 21: Tröscher et al ().…”

Immunological Bases of Paraneoplastic Cerebellar Degeneration and Therapeutic Implications

“…In Rasmussen encephalitis, microglial nodules have been associated with neuronal phagocytosis, following CD8 T cell-mediated brain neuron destruction (170). In human PCD, similar to Rasmussen encephalitis, IFNγ-mediated signaling (STAT1 phosphorylation) occurs in microglial cells, which can further amplify cytokine/chemokine release (143,170). Further investigation on the role of microglia as an amplifier of inflammation and an executor of neuronal death is needed in PCD.…”

Does Siponimod Exert Direct Effects in the Central Nervous System?

“…Microglia exist, in the same way as astrocytes, in a continuum of activation states and can, therefore, be involved in both tissue injuries and repairs. On the one hand, it has been shown that microglia mediate synapse loss, neuronal loss, and memory impairment in Alzheimer's disease (overview in [49] and [50]); mediate dopaminergic injuries via the NF-κB signaling pathway in Parkinson's disease [51]; or provide an environment for the initiation of T-cell cytotoxicity in Rasmussen encephalitis [52]. On the other hand, microglia can equally mediate protective effects such as reducing spreading depolarization and calcium overload [53], eliminating neutrophil invasion in brain ischemia [54], promoting seizure-induced neurogenesis [55], or maintaining the vascular integrity under hypoxia conditions [56].…”