The induction of autoimmune hepatitis in the human leucocyte antigen-DR4 non-obese diabetic mice autoimmune hepatitis mouse model

Autor: Yun Ma, Fernando Alvarez, Elke Gülden, Isabelle Colle, Muhammed Yuksel, Ningwen Tai, Kathie Béland, Zhao Hu, Xiaoyan Xiao, Pascal Lapierre, Li Wen, G.M. Vijay
Rok vydání: 2016
Předmět:
0301 basic medicine
Ammonia-Lyases
Autoimmune hepatitis
CD8-Positive T-Lymphocytes
medicine.disease_cause
Autoantigens
Autoimmunity
Mice
0302 clinical medicine
Mice
Inbred NOD
T-Lymphocyte Subsets
immune system diseases
Hypergammaglobulinemia
Immunology and Allergy
skin and connective tissue diseases
NOD mice
biology
Hepatitis
Autoimmune
Cytochrome P-450 CYP2D6
Cytokines
030211 gastroenterology & hepatology
Inflammation Mediators
Antibody
Corrigendum
musculoskeletal diseases
Glutamate Formimidoyltransferase
Plasma Cells
Immunology
Antigen-Presenting Cells
Mice
Transgenic
Human leukocyte antigen
Major histocompatibility complex
03 medical and health sciences
Immune system
Multienzyme Complexes
HLA-DR4 Antigen
medicine
Animals
Humans
Autoantibodies
Original Articles
medicine.disease
Multifunctional Enzymes
Disease Models
Animal
030104 developmental biology
Immunoglobulin G
biology.protein
Immunization
CD8
Zdroj: Clinical and Experimental Immunology. 186:164-176
ISSN: 1365-2249
0009-9104
Popis: Summary 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 (Tregs), which had decreased programmed death (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 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 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.
Databáze: OpenAIRE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje