The role of natural killer (NK) and NKT cells in the loss of tolerance in murine primary biliary cirrhosis

S. Shimoda, K. Tsuneyama, K. Kikuchi, K. Harada, Y. Nakanuma, M. Nakamura, H. Ishibashi, S. Hisamoto, H. Niiro, Patrick S Leung, A. A. Ansari, M. Eric Gershwin, K. Akashi

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

One of the major obstacles in dissecting the mechanism of pathology in human primary biliary cirrhosis (PBC) has been the absence of animal models. Our laboratory has focused on a model in which mice, following immunization with a xenobiotic chemical mimic of the immunodominant autoepitope of the E2 component of pyruvate dehydrogenase complex (PDC-E2), develop autoimmune cholangitis. In particular, following immunization with 2-octynoic acid (a synthetic chemical mimic of lipoic acid-lysine located within the inner domain of PDC-E2) coupled to bovine serum albumin (BSA), several strains of mice develop typical anti-mitochondrial autoantibodies and portal inflammation. The role of innate immune effector cells, such as natural killer (NK) cells and that NKT cells, was studied in this model based on the hypothesis that early events during immunization play an important role in the breakdown of tolerance. We report herein that, following in-vivo depletion of NK and NKT cells, there is a marked suppression of anti-mitochondrial autoantibodies and cytokine production from autoreactive T cells. However, there was no change in the clinical pathology of portal inflammation compared to controls. These data support the hypothesis that there are probably multiple steps in the natural history of PBC, including a role of NK and NKT cells in initiating the breakdown of tolerance. However, the data suggest that adaptive autoimmune effector mechanisms are required for the progression of clinical disease.

Original languageEnglish (US)
Pages (from-to)279-284
Number of pages6
JournalClinical and Experimental Immunology
Volume168
Issue number3
DOIs
StatePublished - Jun 2012

Fingerprint

Natural Killer T-Cells
Biliary Liver Cirrhosis
Natural Killer Cells
Immunization
Autoantibodies
Dihydrolipoyllysine-Residue Acetyltransferase
Inflammation
Thioctic Acid
Clinical Pathology
Cholangitis
Xenobiotics
Bovine Serum Albumin
Lysine
Disease Progression
Animal Models
Pathology
Cytokines
T-Lymphocytes

Keywords

  • ELISA
  • ELISPOT
  • Mouse model
  • Natural killer cells
  • Primary biliary cirrhosis

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

The role of natural killer (NK) and NKT cells in the loss of tolerance in murine primary biliary cirrhosis. / Shimoda, S.; Tsuneyama, K.; Kikuchi, K.; Harada, K.; Nakanuma, Y.; Nakamura, M.; Ishibashi, H.; Hisamoto, S.; Niiro, H.; Leung, Patrick S; Ansari, A. A.; Gershwin, M. Eric; Akashi, K.

In: Clinical and Experimental Immunology, Vol. 168, No. 3, 06.2012, p. 279-284.

Research output: Contribution to journalArticle

Shimoda, S, Tsuneyama, K, Kikuchi, K, Harada, K, Nakanuma, Y, Nakamura, M, Ishibashi, H, Hisamoto, S, Niiro, H, Leung, PS, Ansari, AA, Gershwin, ME & Akashi, K 2012, 'The role of natural killer (NK) and NKT cells in the loss of tolerance in murine primary biliary cirrhosis', Clinical and Experimental Immunology, vol. 168, no. 3, pp. 279-284. https://doi.org/10.1111/j.1365-2249.2012.04581.x
Shimoda, S. ; Tsuneyama, K. ; Kikuchi, K. ; Harada, K. ; Nakanuma, Y. ; Nakamura, M. ; Ishibashi, H. ; Hisamoto, S. ; Niiro, H. ; Leung, Patrick S ; Ansari, A. A. ; Gershwin, M. Eric ; Akashi, K. / The role of natural killer (NK) and NKT cells in the loss of tolerance in murine primary biliary cirrhosis. In: Clinical and Experimental Immunology. 2012 ; Vol. 168, No. 3. pp. 279-284.
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