title: Proinflammatory bacterial peptidoglycan as a cofactor for the development of central nervous system autoimmune disease.
abstract: Upon stimulation by microbial products through TLR, dendritic cells (DC) acquire the capacity to prime naive T cells and to initiate a proinflammatory immune response. Recently, we have shown that APC within the CNS of multiple sclerosis (MS) patients contain peptidoglycan (PGN), a major cell wall component of Gram-positive bacteria, which signals through TLR and NOD. In this study, we report that Staphylococcus aureus PGN as a single component can support the induction of experimental autoimmune encephalomyelitis (EAE) in mice, an animal model for MS. Mice immunized with an encephalitogenic myelin oligodendrocyte glycoprotein peptide in IFA did not develop EAE. In contrast, addition of PGN to the emulsion was sufficient for priming of autoreactive Th1 cells and development of EAE. In vitro studies demonstrate that PGN stimulates DC-mediated processes, reflected by increased Ag uptake, DC maturation, Th1 cell expansion, activation, and proinflammatory cytokine production. These data indicate that PGN-mediated interactions result in proinflammatory stimulation of Ag-specific effector functions, which are important in the development of EAE. These PGN-mediated processes may occur both within the peripheral lymph nodes as well as in the CNS and likely involve recognition by TLR on DC. Thus, PGN may provide a physiological trigger of DC maturation, and in this way disrupt the normal tolerance to self Ag. As such, PGN signaling pathways may serve as novel targets for the treatment of MS.
authors.affiliation: Department of Immunology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Lizette
authors.initials: L
authors.lastname: Visser
authors.forename: Hendrik
authors.initials: H
authors.lastname: Jan de Heer
authors.forename: Leonie A
authors.initials: LA
authors.lastname: Boven
authors.forename: Debby
authors.initials: D
authors.lastname: van Riel
authors.forename: Marjan
authors.initials: M
authors.lastname: van Meurs
authors.forename: Marie-José
authors.initials: MJ
authors.lastname: Melief
authors.forename: Ulrich
authors.initials: U
authors.lastname: Zähringer
authors.forename: Jos
authors.initials: J
authors.lastname: van Strijp
authors.forename: Bart N
authors.initials: BN
authors.lastname: Lambrecht
authors.forename: Edward E
authors.initials: EE
authors.lastname: Nieuwenhuis
authors.forename: Jon D
authors.initials: JD
authors.lastname: Laman
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000378:metabolism / Q000502:physiology; D000595:Amino Acid Sequence; D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000473:pathology*; D018984:Epitopes, T-Lymphocyte / Q000008:administration & dosage / Q000276:immunology; D005260:Female; D006023:Glycoproteins / Q000008:administration & dosage / Q000276:immunology; D018836:Inflammation Mediators / Q000008:administration & dosage / Q000378:metabolism / Q000502:physiology*; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D063308:Myelin-Oligodendrocyte Glycoprotein; D009928:Organ Specificity / Q000276:immunology; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology; D010457:Peptidoglycan / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D021381:Protein Transport / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism
chemical_list: D000276:Adjuvants, Immunologic; D018984:Epitopes, T-Lymphocyte; D006023:Glycoproteins; D018836:Inflammation Mediators; D063308:Myelin-Oligodendrocyte Glycoprotein; C111390:OVA 323-339; D010446:Peptide Fragments; D010457:Peptidoglycan; C445081:myelin oligodendrocyte glycoprotein (35-55); D010047:Ovalbumin