title: Innate immunity mediated by TLR9 modulates pathogenicity in an animal model of multiple sclerosis.
abstract: Inflammatory diseases of the CNS, such as MS and its animal model EAE, are characterized by infiltration of activated lymphocytes and phagocytes into the CNS. Within the CNS, activation of resident cells initiates an inflammatory cascade, leading to tissue destruction, demyelination, and neurologic deficit. TLRs recognize microbes and are pivotal mediators of innate immunity. Within the CNS, augmented TLR expression during EAE is observed, even in the absence of any apparent microbial involvement. To determine the functional relevance of this phenomenon during sterile autoimmunity, we studied the role of different TLRs as well as their common signaling adaptor MyD88 in the development of EAE. We found that MyD88 mice were completely EAE resistant. Surprisingly, this protection is partly due to engagement of the CpG receptor TLR9. Restricting the MyD88 or TLR9 mutation to host radio-resistant cells, including the cells within the CNS, revealed that engagement of radio-resistant cells modulated the disease course and histopathological changes. Our data clearly demonstrate that both TLR9 and MyD88 are essential modulators of the autoimmune process during the effector phase of disease and suggest that endogenous "danger signals" modulate the disease pathogenesis.
authors.affiliation: Institute of Neuropathology, Georg-August-University, Gottingen, Germany. mprinz@med.uni-goettingen.de
authors.forename: Marco
authors.initials: M
authors.lastname: Prinz
authors.forename: Folker
authors.initials: F
authors.lastname: Garbe
authors.forename: Hauke
authors.initials: H
authors.lastname: Schmidt
authors.forename: Alexander
authors.initials: A
authors.lastname: Mildner
authors.forename: Ilona
authors.initials: I
authors.lastname: Gutcher
authors.forename: Karina
authors.initials: K
authors.lastname: Wolter
authors.forename: Matthias
authors.initials: M
authors.lastname: Piesche
authors.forename: Roland
authors.initials: R
authors.lastname: Schroers
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Weiss
authors.forename: Carsten J
authors.initials: CJ
authors.lastname: Kirschning
authors.forename: Christian D P
authors.initials: CD
authors.lastname: Rochford
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Brück
authors.forename: Burkhard
authors.initials: B
authors.lastname: Becher
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D019264:Adoptive Transfer; D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000473:pathology; D005260:Female; D005838:Genotype; D007113:Immunity, Innate / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88; D015398:Signal Transduction / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000378:metabolism*; D018183:Transplantation Chimera
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C493486:Tlr2 protein, mouse; C495370:Tlr9 protein, mouse; D051195:Toll-Like Receptor 2; D051217:Toll-Like Receptor 9