Document Detail


Human risk allele HLA-DRB1*0405 predisposes class II transgenic Ab0 NOD mice to autoimmune pancreatitis.
MedLine Citation:
PMID:  20303356     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND & AIMS: Autoimmune pancreatitis (AIP) underlies 5%-11% of cases of chronic pancreatitis. An association between AIP and the human leukocyte antigen (HLA)-DRB1*0405/DQB1*0401 haplotype has been reported, but linkage disequilibrium has precluded the identification of predisposing HLA gene(s). We studied the role of single HLA genes in the development of AIP in transgenic mice.
METHODS: CD4(+) T-cell-negative I-Abeta chain(-/-) (Ab0) mice develop AIP spontaneously, likely due to dysregulation of CD8(+) T- cell responses. We generated Ab0 nonobese diabetic (NOD) mice transgenic for HLA-DR*0405, leading to rescue of CD4(+) T cells; we compared their susceptibility to AIP with HLA-DQ8 or HLA-DR*0401 (single) transgenic, or HLA-DR*0405/DQ8 (double) transgenic mice.
RESULTS: CD4(+) T-cell-competent HLA-DR*0405 transgenic Ab0 NOD mice develop AIP with high prevalence after sublethal irradiation and adoptive transfer of CD90(+) T cells, leading to complete pancreatic atrophy. HLA-DR*0405 transgenic mice can also develop unprovoked AIP, whereas HLA-DR*0401, HLA-DQ8, and HLA-DR*0405/DQ8 transgenic Ab0 NOD controls all remained normal, even after irradiation and adoptive transfer of CD90(+) T cells. Pancreas histology in HLA-DR*0405 transgenic mice was characterized by destructive infiltration of the exocrine tissue with CD4(+) and CD8(+) T cells, B cells, and macrophages. Mice with complete pancreatic atrophy lost weight, developed fat stools, and had reduced levels of serum lipase activity.
CONCLUSIONS: Because HLA-DR*0405 expression fails to protect mice from AIP, the HLA-DRB1*0405 allele appears to be an important risk factor for AIP on the HLA-DRB1*0405/DQB1*0401 haplotype. This humanized mouse model should be useful for studying immunopathogenesis, diagnostic markers, and therapy of human AIP.
Authors:
Tobias L Freitag; Candace Cham; Hsiang-Hsuan Sung; Georg F Beilhack; Ivana Durinovic-Belló; Salil D Patel; Roderick T Bronson; Detlef Schuppan; Grete Sønderstrup
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-03-18
Journal Detail:
Title:  Gastroenterology     Volume:  139     ISSN:  1528-0012     ISO Abbreviation:  Gastroenterology     Publication Date:  2010 Jul 
Date Detail:
Created Date:  2010-07-12     Completed Date:  2010-08-04     Revised Date:  2013-05-23    
Medline Journal Info:
Nlm Unique ID:  0374630     Medline TA:  Gastroenterology     Country:  United States    
Other Details:
Languages:  eng     Pagination:  281-91     Citation Subset:  AIM; IM    
Copyright Information:
Copyright 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.
Affiliation:
Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA. tobias.freitag@helsinki.fi
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MeSH Terms
Descriptor/Qualifier:
Adoptive Transfer
Animals
Atrophy
Autoimmune Diseases / etiology*,  genetics,  pathology
Female
Genes, MHC Class II*
HLA-DR Antigens / genetics*,  physiology
HLA-DRB1 Chains
Humans
Lipase / blood
Male
Mice
Mice, Inbred C57BL
Mice, Inbred NOD
Mice, Transgenic
Pancreas / pathology
Pancreatitis, Chronic / etiology*,  genetics,  pathology
Risk
Grant Support
ID/Acronym/Agency:
DK55364/DK/NIDDK NIH HHS; DK72288/DK/NIDDK NIH HHS; P01 DK055364/DK/NIDDK NIH HHS; P01 DK055364-02/DK/NIDDK NIH HHS; R01 DK072288/DK/NIDDK NIH HHS; R01 DK072288-02/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/HLA-DR Antigens; 0/HLA-DRB1 Chains; 0/HLA-DRB1*04:05 antigen; EC 3.1.1.3/Lipase
Comments/Corrections

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