Liver autoimmunity triggered by microbial activation of natural killer T cells.
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.
Mattner
Jochen
J
Howard Hughes Medical Institute, Committee on Immunology, Department of Pathology, University of Chicago, Chicago, IL 60637, USA. jochen.mattner@cchmc.org
Savage
Paul B
PB
Leung
Patrick
P
Oertelt
Sabine S
SS
Wang
Vivien
V
Trivedi
Omita
O
Scanlon
Seth T
ST
Pendem
Krishna
K
Teyton
Luc
L
Hart
John
J
Ridgway
William M
WM
Wicker
Linda S
LS
Gershwin
M Eric
ME
Bendelac
Albert
A
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
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