| Human risk allele HLA-DRB1*0405 predisposes class II transgenic Ab0 NOD mice to autoimmune pancreatitis. | |
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MedLine Citation:
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PMID: 20303356 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-03-18 |
Journal Detail:
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Title: Gastroenterology Volume: 139 ISSN: 1528-0012 ISO Abbreviation: Gastroenterology Publication Date: 2010 Jul |
Date Detail:
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Created Date: 2010-07-12 Completed Date: 2010-08-04 Revised Date: 2012-05-14 |
Medline Journal Info:
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Nlm Unique ID: 0374630 Medline TA: Gastroenterology Country: United States |
Other Details:
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Languages: eng Pagination: 281-91 Citation Subset: AIM; IM |
Copyright Information:
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Copyright 2010 AGA Institute. Published by Elsevier Inc. All rights reserved. |
Affiliation:
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Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA. tobias.freitag@helsinki.fi |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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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:
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DK55364/DK/NIDDK NIH HHS; DK72288/DK/NIDDK NIH HHS; P01 DK055364/DK/NIDDK NIH HHS; P01 DK055364-02/DK/NIDDK NIH HHS; R01 DK072288-02/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/HLA-DR Antigens; 0/HLA-DRB1 Chains; 0/HLA-DRB1*04:05 antigen; EC 3.1.1.3/Lipase |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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