PMID- 20303356
OWN - NLM
STAT- MEDLINE
DCOM- 20100804
LR  - 20211020
IS  - 1528-0012 (Electronic)
IS  - 0016-5085 (Print)
IS  - 0016-5085 (Linking)
VI  - 139
IP  - 1
DP  - 2010 Jul
TI  - Human risk allele HLA-DRB1*0405 predisposes class II transgenic Ab0 NOD mice to 
      autoimmune pancreatitis.
PG  - 281-91
LID - 10.1053/j.gastro.2010.03.038 [doi]
AB  - 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.
CI  - Copyright 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.
FAU - Freitag, Tobias L
AU  - Freitag TL
AD  - Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard 
      Medical School, Boston, Massachusetts, USA. tobias.freitag@helsinki.fi
FAU - Cham, Candace
AU  - Cham C
FAU - Sung, Hsiang-Hsuan
AU  - Sung HH
FAU - Beilhack, Georg F
AU  - Beilhack GF
FAU - Durinovic-Bello, Ivana
AU  - Durinovic-Bello I
FAU - Patel, Salil D
AU  - Patel SD
FAU - Bronson, Roderick T
AU  - Bronson RT
FAU - Schuppan, Detlef
AU  - Schuppan D
FAU - Sonderstrup, Grete
AU  - Sonderstrup G
LA  - eng
GR  - P01 DK055364-02/DK/NIDDK NIH HHS/United States
GR  - R01 DK072288-02/DK/NIDDK NIH HHS/United States
GR  - DK72288/DK/NIDDK NIH HHS/United States
GR  - R01 DK072288/DK/NIDDK NIH HHS/United States
GR  - DK55364/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20100318
PL  - United States
TA  - Gastroenterology
JT  - Gastroenterology
JID - 0374630
RN  - 0 (HLA-DR Antigens)
RN  - 0 (HLA-DRB1 Chains)
RN  - 0 (HLA-DRB1*04:05 antigen)
RN  - EC 3.1.1.3 (Lipase)
SB  - IM
MH  - Adoptive Transfer
MH  - Animals
MH  - Atrophy
MH  - Autoimmune Diseases/*etiology/genetics/pathology
MH  - Female
MH  - *Genes, MHC Class II
MH  - HLA-DR Antigens/*genetics/physiology
MH  - HLA-DRB1 Chains
MH  - Humans
MH  - Lipase/blood
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Inbred NOD
MH  - Mice, Transgenic
MH  - Pancreas/pathology
MH  - Pancreatitis, Chronic/*etiology/genetics/pathology
MH  - Risk
PMC - PMC2902648
MID - NIHMS189785
EDAT- 2010/03/23 06:00
MHDA- 2010/08/05 06:00
PMCR- 2011/07/01
CRDT- 2010/03/23 06:00
PHST- 2009/12/01 00:00 [received]
PHST- 2010/02/22 00:00 [revised]
PHST- 2010/03/10 00:00 [accepted]
PHST- 2010/03/23 06:00 [entrez]
PHST- 2010/03/23 06:00 [pubmed]
PHST- 2010/08/05 06:00 [medline]
PHST- 2011/07/01 00:00 [pmc-release]
AID - S0016-5085(10)00393-8 [pii]
AID - 10.1053/j.gastro.2010.03.038 [doi]
PST - ppublish
SO  - Gastroenterology. 2010 Jul;139(1):281-91. doi: 10.1053/j.gastro.2010.03.038. Epub 
      2010 Mar 18.