The liver is known to be a classical immunoprivileged site with a relatively high resistance against immune responses. Here we demonstrate that highly activated liver-specific effector CD8+ T cells alone were not sufficient to trigger immune destruction of the liver in mice. Only additional innate immune signals orchestrated by TLR3 provoked liver damage. While TLR3 activation did not directly alter liver-specific CD8+ T cell function, it induced IFN-α and TNF-α release. These cytokines generated expression of the chemokine CXCL9 in the liver, thereby enhancing CD8+ T cell infiltration and liver disease in mice. Thus, nonspecific activation of innate immunity can drastically enhance susceptibility to immune destruction of a solid organ.
Karl S. Lang, Panco Georgiev, Mike Recher, Alexander A. Navarini, Andreas Bergthaler, Mathias Heikenwalder, Nicola L. Harris, Tobias Junt, Bernhard Odermatt, Pierre-Alain Clavien, Hanspeter Pircher, Shizuo Akira, Hans Hengartner, Rolf M. Zinkernagel
Submitter: Karl Lang | Karl.Lang@usz.ch
University Hospital Zurich
Published September 12, 2006
In the introduction of our manuscript, we wanted to generally illustrate that the presence of an adaptive immune response against antigens in the liver is not sufficient to induce a destructive autoimmune disease within the liver. This statement is based on the rather frequent observation of detectable auto-antibodies associated with autoimmune liver disease in healthy individuals (1, 2). Elevated antibody titers found include antibodies associated with autoimmune hepatitis (antinuclear antibodies, anti-smooth-muscle antibodies) as well as antibodies associated with primary biliary cirrhosis (anti-mitochondrial antibodies). Our statement suggests that anti-mitochondrial antibodies are related to autoimmune hepatitis. However, as Daniela Zauli correctly stated, anti- mitochondrial antibodies are markers for primary biliary cirrhosis and can be used to distinguish between autoimmune hepatitis and primary biliary cirrhosis (-4 in the scoring system of the International Autoimmune Hepatitis Group). We apologize for confusion and appreciate the clarification by Daniela Zauli.
1.Fritzler, M.J., Pauls, J.D., Kinsella, T.D., and Bowen, T.J. 1985. Antinuclear, anticytoplasmic, and anti-Sjogren's syndrome antigen A (SS-A/Ro) antibodies in female blood donors. Clin Immunol Immunopathol 36:120-128.
2.Vrethem, M., Skogh, T., Berlin, G., and Ernerudh, J. 1992. Autoantibodies versus clinical symptoms in blood donors. J Rheumatol 19:1919-1921.
Submitter: Daniela Zauli | email@example.com
University of Bologna
Published September 12, 2006
I don’t wish to discuss here either the experimental model of virus- induced liver autoimmunity or the results and the implications of this study, but rather to point to an obviously incorrect information provided in the introduction to the paper. The authors suggest that the liver represents an immunoprivileged site based on the observation of its relative resistance to rejection after transplantation and of the relative rarity of autoimmune hepatitis (AIH). This may be correct. Unfortunately, they continue saying that the diagnostic markers of AIH are antimitochondrial antibodies (AMA). This is not correct. These antibodies are diagnostic markers (virtually pathognonomic) of another autoimmune liver disease, i.e. primary biliary cirrhosis (PBC), a condition, which is histologically, clinically and immunopathologically different from AIH (1). It is, in fact, an autoimmune cholangiopathy. I want to recall that the International Autoimmune Hepatitis Group (IAHG) has since long recognized and recently confirmed that the main diagnostic serological markers of AIH are antinuclear (ANA), anti smooth muscle (SMA), anti liver -kidney type I (anti-LKM1) antibodies, though other serological reactivities, less frequently searched for, have been described (2). Furthermore, the revised Scoring System of AIH proposed by the same IAIHG in 1999 has decided to raise the negative score for AMA seropositivity from – 2 to -4 in order to increase the weighting against biliary diseases, PBC in particular (3).
1.He, XS., Ansari, A.A., Ridgway, W.M., and Coppel, R.L. 2006. New insights to the immunopathology and autoimmune responses in primary biliary cirrhosis. Cell Immunol. 239:1-13.
2.Vergani, D., Alvarez, F., Bianchi, F.B., Cancado, E.L.R., Mackay, I.R., Manns, M.P., Nishioka, M., and Penner, E. 2004. Liver autoimmune serology: a consensus statement from the committee for autoimmune serology of the International Autoimmune Hepatitis Group. J Hepatol. 41:677-683.
3.Alvarez, F., et al. 1999. International Autoimmune Hepatitis Group report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatol. 31:929-938.