Quantitative Trait Locus Analysis Implicates CD4+/CD44high Memory T Cells in the Pathogenesis of Murine Autoimmune Pancreatitis

被引:8
作者
Bischof, Julia [1 ]
Mueller, Sarah [2 ]
Borufka, Luise [2 ]
Asghari, Farahnaz [1 ,2 ]
Moeller, Steffen [1 ]
Holzhueter, Stephanie-Anna [3 ]
Nizze, Horst [3 ]
Ibrahim, Saleh M. [1 ]
Jaster, Robert [2 ]
机构
[1] Med Univ Lubeck, Dept Dermatol, D-23562 Lubeck, Germany
[2] Univ Rostock, Med Ctr, Div Gastroenterol, Dept Med 2, D-18057 Rostock, Germany
[3] Univ Rostock, Med Ctr, Inst Pathol, D-18057 Rostock, Germany
关键词
GENOME-WIDE ASSOCIATION; DIAGNOSTIC-CRITERIA; JAPANESE POPULATION; MRL/MP-MOUSE; SUSCEPTIBILITY; INFLAMMATION; RISK; GENE; IDENTIFICATION; POLYMORPHISMS;
D O I
10.1371/journal.pone.0136298
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The mouse strain MRL/MpJ is prone to spontaneously develop autoimmune pancreatitis (AIP). To elucidate the genetic control towards the development of the phenotype and to characterize contributions of immunocompetent cell types, MRL/MpJ mice were interbred with three additional strains (BXD2/TYJ, NZM2410/J, CAST/EIJ) for four generations in an advanced intercross line. Cellular phenotypes were determined by flow cytometric quantification of splenic leukocytes and complemented by the histopathological evaluation of pancreatic lesions. An Illumina SNP array was used for genotyping. QTL analyses were performed with the R implementation of HAPPY. Out of 41 leukocyte subpopulations (B cells, T cells and dendritic cells), only three were significantly associated with AIP: While CD4(+)/CD44(high) memory T cells and CD4(+)/CD69(+) T helper (Th) cells correlated positively with the disease, the cytotoxic T cell phenotype CD8(+)/CD44(low) showed a negative correlation. A QTL for AIP on chromosome 2 overlapped with QTLs for CD4(+)/CD44(high) and CD8(+)/CD44(high) memory T cells, FoxP3(+)/CD4(+) and FoxP3(+)/CD8(+) regulatory T cells (Tregs), and CD8(+)/CD69(+) cytotoxic T cells. On chromosome 6, overlapping QTLs for AIP and CD4(+)/IL17(+) Th17 cells and again FoxP3(+)/CD8(+) Tregs were observed. In conclusion, CD4(+)/CD44(high) memory T cells are the only leukocyte subtype that could be linked to AIP both by correlation studies and from observed overlapping QTL. The potential role of this cell type in the pathogenesis of AIP warrants further investigations.
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页数:16
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