title: Mitochondrial DNA: An Endogenous Trigger for Immune Paralysis.
abstract: BACKGROUND
  Critically ill patients are at high risk to suffer from sepsis, even in the absence of an initial infectious source, but the molecular mechanisms for their increased sepsis susceptibility, including a suppressed immune system, remain unclear. Although microbes and pathogen-associated molecular pattern are accepted inducers of sepsis and septic immunosuppression, the role of endogenous Toll-like receptor (TLR) ligands, such as mitochondrial DNA (mtDNA), in altering the immune response is unknown.
  
  
  METHODS
  Mitochondrial DNA serum concentrations of the mitochondrial genes D-Loop and adenosine triphosphatase 6 were determined (quantitative polymerase chain reaction) in 165 septic patients and 50 healthy volunteers. Furthermore, cytotoxic T-cell activity was analyzed in wild-type and TLR9 knockout mice, with/without previous mtDNA administration, followed by injection of an ovalbumin-expressing adenoviral vector.
  
  
  RESULTS
  Mitochondrial DNA serum concentrations were increased in septic patients (adenosine triphosphatase 6, 123-fold; D-Loop, 76-fold, P < 0.0001) compared with volunteers. Furthermore, a single mtDNA injection caused profound, TLR9-dependent immunosuppression of adaptive T-cell cytotoxicity in wild-type but not in TLR9 knockout mice and evoked various immunosuppressive mechanisms including the destruction of the splenic microstructure, deletion of cross-presenting dendritic cells, and up-regulation of programmed cell death ligand 1 and indoleamine 2,3-dioxygenase. Several of these findings in mice were mirrored in septic patients, and mtDNA concentrations were associated with an increased 30-day mortality.
  
  
  CONCLUSIONS
  The findings of this study imply that mtDNA, an endogenous danger associated molecular pattern, is a hitherto unknown inducer of septic immunoparalysis and one possible link between initial inflammation and subsequent immunosuppression in critically ill patients.
authors.affiliation: From the Klinik für Anästhesiologie und Intensivmedizin, Universität Duisburg-Essen and Universitätsklinikum Essen, Essen, Germany (S.T.S., M.A., A.E., N.S., J.W., J.P.); Institut für molekulare Medizin und experimentelle Immunologie, Universität Bonn, Bonn, Germany (L.F., C.K.); Klinik für Anästhesiologie und operative Intensivmedizin, Knappschaftskrankenhaus Bochum und Ruhruniversität Bochum, Bochum, Germany (M.A.); Institut für Medizinische Mikrobiologie, Immunologie und Parasitologie, Universität Bonn, Bonn, Germany (B.S.); Klinische Epidemiologie, Integriertes Forschungs- und Behandlungszentrum (IFB) Sepsis und Sepsisfolgen - Center for Sepsis Control and Care (CSCC), Universitätsklinikum Jena, Jena, Germany (A.S.); Klinik und Poliklinik für Dermatologie und Allergologie, Universität Bonn, Bonn, Germany (S.K., T.B.); Institut für Pathologie, Universität Duisburg-Essen and Universitätsklinikum Essen, Essen, Germany (H.A.B.); Institut für Medizinische Mikrobiologie, Universität Duisburg-Essen and Universitätsklinikum Essen, Essen, Germany (J.S., A.M.W.); Institut für Physiologie, Universität Duisburg-Essen, Essen, Germany (J.F., S.F.); Klinik und Poliklinik für Anästhesiologie und operative Intensivmedizin, Universitätsklinikum Bonn, Bonn, Germany (S.F.); and Klinik für Orthopädie und Unfallchirurgie, Universitätsklinikum Bonn, Bonn, Germany (A.L.).
authors.forename: Simon T
authors.initials: ST
authors.lastname: Schäfer
authors.forename: Lars
authors.initials: L
authors.lastname: Franken
authors.forename: Michael
authors.initials: M
authors.lastname: Adamzik
authors.forename: Beatrix
authors.initials: B
authors.lastname: Schumak
authors.forename: André
authors.initials: A
authors.lastname: Scherag
authors.forename: Andrea
authors.initials: A
authors.lastname: Engler
authors.forename: Niels
authors.initials: N
authors.lastname: Schönborn
authors.forename: Jennifer
authors.initials: J
authors.lastname: Walden
authors.forename: Susanne
authors.initials: S
authors.lastname: Koch
authors.forename: Hideo A
authors.initials: HA
authors.lastname: Baba
authors.forename: Jörg
authors.initials: J
authors.lastname: Steinmann
authors.forename: Astrid M
authors.initials: AM
authors.lastname: Westendorf
authors.forename: Joachim
authors.initials: J
authors.lastname: Fandrey
authors.forename: Thomas
authors.initials: T
authors.lastname: Bieber
authors.forename: Christian
authors.initials: C
authors.lastname: Kurts
authors.forename: Stilla
authors.initials: S
authors.lastname: Frede
authors.forename: Jürgen
authors.initials: J
authors.lastname: Peters
authors.forename: Andreas
authors.initials: A
authors.lastname: Limmer
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D016638:Critical Illness; D004272:DNA, Mitochondrial / Q000097:blood* / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007109:Immunity / Q000276:immunology; D007249:Inflammation / Q000097:blood* / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011446:Prospective Studies; D018805:Sepsis / Q000097:blood* / Q000276:immunology*
chemical_list: D004272:DNA, Mitochondrial