Quantitative Trait Locus Analysis Implicates CD4⁺/CD44high Memory T Cells in the Pathogenesis of Murine Autoimmune Pancreatitis.
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+/CD44high memory T cells and CD4+/CD69+ T helper (Th) cells correlated positively with the disease, the cytotoxic T cell phenotype CD8+/CD44low showed a negative correlation. A QTL for AIP on chromosome 2 overlapped with QTLs for CD4+/CD44high and CD8+/CD44high 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+/CD44high 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.
Department of Dermatology, University of Lübeck, Ratzeburger Allee 160, 23562 Lübeck, Germany.
Julia
J
Bischof
Department of Medicine II, Division of Gastroenterology, Rostock University Medical Center, E.-Heydemann-Str. 6, 18057 Rostock, Germany.
Sarah
S
Müller
Department of Medicine II, Division of Gastroenterology, Rostock University Medical Center, E.-Heydemann-Str. 6, 18057 Rostock, Germany.
Luise
L
Borufka
Department of Dermatology, University of Lübeck, Ratzeburger Allee 160, 23562 Lübeck, Germany; Department of Medicine II, Division of Gastroenterology, Rostock University Medical Center, E.-Heydemann-Str. 6, 18057 Rostock, Germany.
Farahnaz
F
Asghari
Department of Dermatology, University of Lübeck, Ratzeburger Allee 160, 23562 Lübeck, Germany.
Steffen
S
Möller
Institute of Pathology, Rostock University Medical Center, Strempelstr. 14, 18057 Rostock, Germany.
Stephanie-Anna
SA
Holzhüter
Institute of Pathology, Rostock University Medical Center, Strempelstr. 14, 18057 Rostock, Germany.
Horst
H
Nizze
Department of Dermatology, University of Lübeck, Ratzeburger Allee 160, 23562 Lübeck, Germany.
Saleh M
SM
Ibrahim
Department of Medicine II, Division of Gastroenterology, Rostock University Medical Center, E.-Heydemann-Str. 6, 18057 Rostock, Germany.
Robert
R
Jaster
D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D018960:Hyaluronan Receptors / Q000235:genetics* / Q000276:immunology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010179:Pancreas / Q000276:immunology / Q000473:pathology; D050500:Pancreatitis, Chronic / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D040641:Quantitative Trait Loci / Q000235:genetics*; D016176:T-Lymphocyte Subsets / Q000276:immunology
D018960:Hyaluronan Receptors