Type 2 autoimmune hepatitis murine model: the influence of genetic background in disease development.
Genetic predisposition is recognized as an important factor for the development of autoimmune hepatitis (AIH). To assess the potential contribution of MHC and non-MHC genes, type 2 AIH was reproduced in three mice strains, taking advantage of their different genetic makeup with regard to MHC and non-MHC genes. Mice (C57BL/6, 129/Sv and BALB/c) were DNA vaccinated with a pCMV-CTLA4-CYP2D6-FTCD plasmid coding for the extracellular region of CTLA-4 and for the antigenic region of the CYP2D6 and FTCD, and with pCMV-IL12. ALT and total IgG levels, liver histology, FACS analysis and liver T-cell cytotoxicity assays were monitored up to 8 months post-injection. C57BL/6 mice showed elevated serum ALT levels, autoantibodies, antigen-specific cytotoxic T-cells and lobular and periportal inflammatory infiltrate. The 129/Sv mice showed slightly elevated ALT levels, sparse liver lobular infiltrate and cytotoxic T-cells. The BALB/c mice showed no liver inflammation. All mice had elevated total serum IgG levels. This murine model of type 2 AIH shows that MHC and non-MHC genes contribute to the susceptibility to autoimmune hepatitis. The understanding of the genetic determinants implicated in AIH development will be a major advance in the study of its pathogenesis and could lead to a better diagnostic approach and preventive strategies.
Lapierre
Pascal
P
Service de Gastroentérologie et Nutrition, Hôpital Sainte-Justine, 3175 Côte Ste-Catherine, Montréal, Québec, Canada H3T 1C5.
Béland
Kathie
K
Djilali-Saiah
Idriss
I
Alvarez
Fernando
F
D000410:Alanine Transaminase / Q000097:blood; D000642:Ammonia-Lyases; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000032:analysis / Q000235:genetics / Q000276:immunology; D001323:Autoantibodies; D001402:B-Lymphocytes / Q000276:immunology; D060908:CTLA-4 Antigen; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D051042:Glutamate Formimidoyltransferase; D019693:Hepatitis, Autoimmune / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D007074:Immunoglobulin G / Q000097:blood; D008285:Major Histocompatibility Complex / Q000235:genetics*; D051379:Mice; D008815:Mice, Inbred Strains; D009097:Multienzyme Complexes / Q000235:genetics / Q000276:immunology; D064251:Multifunctional Enzymes; D010957:Plasmids / Q000235:genetics / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014162:Transfection
D015703:Antigens, CD; D000943:Antigens, Differentiation; D001323:Autoantibodies; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D007074:Immunoglobulin G; D009097:Multienzyme Complexes; D064251:Multifunctional Enzymes; D019389:Cytochrome P-450 CYP2D6; C494850:Ftcd protein, mouse; D051042:Glutamate Formimidoyltransferase; D000410:Alanine Transaminase; D000642:Ammonia-Lyases