The induction of autoimmune hepatitis in HLA-DR4 NOD mice. - RIIP - Réseau International des Instituts Pasteur Access content directly
Journal Articles Clinical and Experimental Immunology Year : 2016

The induction of autoimmune hepatitis in HLA-DR4 NOD mice.


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 over 80% of cases. AIH is strongly linked to several MHC alleles including 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 (Tregs), which had decreased PD-1 expression. Splenic Tregs from these mice also showed impaired inhibitory capacity. Furthermore, DR4 expression enhanced the activation status of CD8+ T-cells, macrophages and dendritic cells in naïve DR4 mice compared to naïve wild type (WT) NOD mice. Our results demonstrate that HLA-DR4 is a susceptibility factor for the development of AIH. Impaired suppressive function of Tregs and reduced PD-1 expression may result in spontaneous activation of key immune cell subsets, such as antigen presenting cells and CD8+ T effectors, facilitating the induction of AIH and persistent liver damage.

Dates and versions

pasteur-01351866 , version 1 (04-08-2016)



Muhammed Yuksel, Xiaoyan Xiao, Ningwen Tai, Godhev Manakkat Vijay, Elke Gülden, et al.. The induction of autoimmune hepatitis in HLA-DR4 NOD mice.. Clinical and Experimental Immunology, 2016, ⟨10.1111/cei.12843⟩. ⟨pasteur-01351866⟩


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