title: Liver autoimmunity triggered by microbial activation of natural killer T cells.
abstract: Humans with primary biliary cirrhosis (PBC), a disease characterized by the destruction of small bile ducts, exhibit signature autoantibodies against mitochondrial Pyruvate Dehydrogenase Complex E2 (PDC-E2) that crossreact onto the homologous enzyme of Novosphingobium aromaticivorans, an ubiquitous alphaproteobacterium. Here, we show that infection of mice with N. aromaticivorans induced signature antibodies against microbial PDC-E2 and its mitochondrial counterpart but also triggered chronic T cell-mediated autoimmunity against small bile ducts. Disease induction required NKT cells, which specifically respond to N. aromaticivorans cell wall alpha-glycuronosylceramides presented by CD1d molecules. Combined with the natural liver tropism of NKT cells, the accumulation of N. aromaticivorans in the liver likely explains the liver specificity of destructive responses. Once established, liver disease could be adoptively transferred by T cells independently of NKT cells and microbes, illustrating the importance of early microbial activation of NKT cells in the initiation of autonomous, organ-specific autoimmunity.
authors.affiliation: Howard Hughes Medical Institute, Committee on Immunology, Department of Pathology, University of Chicago, Chicago, IL 60637, USA. jochen.mattner@cchmc.org
authors.forename: Jochen
authors.initials: J
authors.lastname: Mattner
authors.forename: Paul B
authors.initials: PB
authors.lastname: Savage
authors.forename: Patrick
authors.initials: P
authors.lastname: Leung
authors.forename: Sabine S
authors.initials: SS
authors.lastname: Oertelt
authors.forename: Vivien
authors.initials: V
authors.lastname: Wang
authors.forename: Omita
authors.initials: O
authors.lastname: Trivedi
authors.forename: Seth T
authors.initials: ST
authors.lastname: Scanlon
authors.forename: Krishna
authors.initials: K
authors.lastname: Pendem
authors.forename: Luc
authors.initials: L
authors.lastname: Teyton
authors.forename: John
authors.initials: J
authors.lastname: Hart
authors.forename: William M
authors.initials: WM
authors.lastname: Ridgway
authors.forename: Linda S
authors.initials: LS
authors.lastname: Wicker
authors.forename: M Eric
authors.initials: ME
authors.lastname: Gershwin
authors.forename: Albert
authors.initials: A
authors.lastname: Bendelac
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000276:immunology; D018949:Antigens, CD1 / Q000276:immunology; D055610:Antigens, CD1d; D001323:Autoantibodies / Q000276:immunology; D051047:Dihydrolipoyllysine-Residue Acetyltransferase / Q000276:immunology; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy / Q000276:immunology*; D019693:Hepatitis, Autoimmune / Q000276:immunology / Q000382:microbiology; D007070:Immunoglobulin A / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D008099:Liver / Q000276:immunology; D008105:Liver Cirrhosis, Biliary / Q000276:immunology* / Q000382:microbiology*; D051379:Mice; D008815:Mice, Inbred Strains; D024101:Mitochondrial Proteins / Q000276:immunology; D042301:Sphingomonadaceae / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D000907:Antibodies, Bacterial; D018949:Antigens, CD1; D055610:Antigens, CD1d; D001323:Autoantibodies; C526877:CD1D protein, human; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D024101:Mitochondrial Proteins; D051047:Dihydrolipoyllysine-Residue Acetyltransferase; C494878:Dlat protein, mouse