CpG-ODN-induced inflammation is sufficient to cause T-cell-mediated autoaggression against hepatocytes.
Autoimmune diseases are often associated with microbial infections. Molecular mimicry between microbial antigens and self-epitopes has been suggested as a mechanism for breaking self-tolerance and induction of autoimmunity. Since infections also cause inflammatory responses we explored the role of local inflammation in organ-specific autoimmunity. For this purpose, transgenic mice were used expressing the MHC class I molecule Kb exclusively on hepatocytes. These mice exhibit Kb-specific tolerance as exemplified by the acceptance of Kb+ grafts. Inflammatory reactions were induced by injection of immunostimulatory cytosine-phosphorothioate-guanine (CpG)-rich oligodeoxynucleotides (ODN). Application of CpG-ODN is sufficient to break tolerance in vivo, and to cause activation of Kb-specific CD8+ T cells and subsequent autoaggression against hepatocytes. The CpG-ODN-induced inflammation appears to have two major effects. First, it causes infiltration of T cells into the liver parenchyma. Second, adhesion and costimulatory molecules are up-regulated on hepatocytes so that the infiltrating CD8+ T cells encounter Kb on hepatocytes, which display an APC-like phenotype, resulting in activation and tissue damage. Autoimmune hepatitis can be maintained for at least eight weeks by repeated application of CpG-ODN but subsides after termination of the inflammatory stimulus, suggesting the requirement of additional factors for a self-perpetuation of autoimmunity. These observations describe an additional pathway for the induction of autoimmunity, i.e. in the absence of microbial antigens inflammatory reactions alone can lead to infiltration of T cells into organs, resulting in breaking of tolerance and autoaggression. Moreover, the results provide evidence that T cell activation can take place not only in draining lymph nodes but also directly on parenchymal cells.
Sacher
Torsten
T
German Cancer Research Center, Heidelberg, Germany.
Knolle
Percy
P
Nichterlein
Thomas
T
Arnold
Bernd
B
Hämmerling
Günter J
GJ
Limmer
Andreas
A
D000818:Animals; D015551:Autoimmunity; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D004730:Endothelium, Vascular / Q000276:immunology / Q000473:pathology; D022781:Hepatocytes / Q000276:immunology* / Q000473:pathology; D007108:Immune Tolerance; D007249:Inflammation / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D018664:Interleukin-12 / Q000037:antagonists & inhibitors; D008089:Listeria monocytogenes; D008088:Listeriosis / Q000276:immunology; D008099:Liver / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation; D051379:Mice; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D018716:Molecular Mimicry; D009838:Oligodeoxyribonucleotides / Q000633:toxicity*; D013601:T-Lymphocytes / Q000276:immunology*
C408982:CPG-oligonucleotide; D009838:Oligodeoxyribonucleotides; D018664:Interleukin-12