Back to Search
Start Over
The induction of autoimmune hepatitis in the human leucocyte antigen-DR4 non-obese diabetic mice autoimmune hepatitis mouse model.
- Source :
-
Clinical and experimental immunology [Clin Exp Immunol] 2016 Nov; Vol. 186 (2), pp. 164-176. Date of Electronic Publication: 2016 Aug 23. - Publication Year :
- 2016
-
Abstract
- Autoimmune hepatitis (AIH) is a chronic liver disease characterized by progressive inflammation, female preponderance and seropositivity for autoantibodies such as anti-smooth muscle actin and/or anti-nuclear, anti-liver kidney microsomal type 1 (anti-LKM1) and anti-liver cytosol type 1 (anti-LC1) in more than 80% of cases. AIH is linked strongly to several major histocompatibility complex (MHC) alleles, including human leucocyte antigen (HLA)-DR3, -DR7 and -DR13. HLA-DR4 has the second strongest association with adult AIH, after HLA-DR3. We investigated the role of HLA-DR4 in the development of AIH by immunization of HLA-DR4 (DR4) transgenic non-obese diabetic (NOD) mice with DNA coding for human CYP2D6/FTCD fusion autoantigen. Immunization of DR4 mice leads to sustained mild liver injury, as assessed biochemically by elevated alanine aminotransferase, histologically by interface hepatitis, plasma cell infiltration and mild fibrosis and immunologically by the development of anti-LKM1/anti-LC1 antibodies. In addition, livers from DR4 mice had fewer regulatory T cells (T <subscript>regs</subscript> ), which had decreased programmed death (PD)-1 expression. Splenic T <subscript>regs</subscript> from these mice also showed impaired inhibitory capacity. Furthermore, DR4 expression enhanced the activation status of CD8 <superscript>+</superscript> T cells, macrophages and dendritic cells in naive DR4 mice compared to naive wild-type (WT) NOD mice. Our results demonstrate that HLA-DR4 is a susceptibility factor for the development of AIH. Impaired suppressive function of T <subscript>regs</subscript> and reduced PD-1 expression may result in spontaneous activation of key immune cell subsets, such as antigen-presenting cells and CD8 <superscript>+</superscript> T effectors, facilitating the induction of AIH and persistent liver damage.<br /> (© 2016 British Society for Immunology.)
- Subjects :
- Ammonia-Lyases
Animals
Antigen-Presenting Cells immunology
Antigen-Presenting Cells metabolism
Autoantibodies immunology
Autoantigens immunology
CD8-Positive T-Lymphocytes immunology
CD8-Positive T-Lymphocytes metabolism
Cytochrome P-450 CYP2D6 genetics
Cytochrome P-450 CYP2D6 immunology
Cytokines metabolism
Disease Models, Animal
Glutamate Formimidoyltransferase
Humans
Hypergammaglobulinemia immunology
Immunization
Immunoglobulin G immunology
Inflammation Mediators metabolism
Mice
Mice, Inbred NOD
Mice, Transgenic
Multienzyme Complexes genetics
Multienzyme Complexes immunology
Multifunctional Enzymes
Plasma Cells immunology
Plasma Cells metabolism
T-Lymphocyte Subsets immunology
T-Lymphocyte Subsets metabolism
HLA-DR4 Antigen genetics
HLA-DR4 Antigen immunology
Hepatitis, Autoimmune etiology
Hepatitis, Autoimmune pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1365-2249
- Volume :
- 186
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Clinical and experimental immunology
- Publication Type :
- Academic Journal
- Accession number :
- 27414259
- Full Text :
- https://doi.org/10.1111/cei.12843