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

Bischof J, Müller S, Borufka L, Asghari F, Möller S, Holzhüter SA, Nizze H, Ibrahim SM, Jaster R - PLoS ONE (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Dermatology, University of Lübeck, Ratzeburger Allee 160, 23562 Lübeck, Germany.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus

Proposed involvement of memory T cells in the pathogenesis of AIP.Autoantigens from acinar cells and pancreatic duct epithelium trigger activation of T cells, which may differentiate into T effector cells or memory T cells. The first population mediates destruction of pancreatic tissue, whereas the latter type of T cells perpetuates and enhances autoimmune reactions upon antigen re-exposure. Relative frequencies of splenic leukocyte subsets, development of AIP (pancreatic damage) and possibly expression/processing of autoantigens are controlled by QTLs. Overlapping QTLs for certain immune cell phenotypes and AIP suggest the existence of pathogenetic links.
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pone.0136298.g004: Proposed involvement of memory T cells in the pathogenesis of AIP.Autoantigens from acinar cells and pancreatic duct epithelium trigger activation of T cells, which may differentiate into T effector cells or memory T cells. The first population mediates destruction of pancreatic tissue, whereas the latter type of T cells perpetuates and enhances autoimmune reactions upon antigen re-exposure. Relative frequencies of splenic leukocyte subsets, development of AIP (pancreatic damage) and possibly expression/processing of autoantigens are controlled by QTLs. Overlapping QTLs for certain immune cell phenotypes and AIP suggest the existence of pathogenetic links.

Mentions: Taken together, we hypothesize that CD4+/CD44high memory T cells play a previously unrecognized role in murine AIP, and suggest that these cells are an important link between genetic susceptibility and development of the disease (Fig 4). Currently, fine-mapping studies are underway to narrow down AIP loci and overlapping QTLs for immune cell phenotypes, and to identify candidate genes that control the respective phenotypes.


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

Bischof J, Müller S, Borufka L, Asghari F, Möller S, Holzhüter SA, Nizze H, Ibrahim SM, Jaster R - PLoS ONE (2015)

Proposed involvement of memory T cells in the pathogenesis of AIP.Autoantigens from acinar cells and pancreatic duct epithelium trigger activation of T cells, which may differentiate into T effector cells or memory T cells. The first population mediates destruction of pancreatic tissue, whereas the latter type of T cells perpetuates and enhances autoimmune reactions upon antigen re-exposure. Relative frequencies of splenic leukocyte subsets, development of AIP (pancreatic damage) and possibly expression/processing of autoantigens are controlled by QTLs. Overlapping QTLs for certain immune cell phenotypes and AIP suggest the existence of pathogenetic links.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4556487&req=5

pone.0136298.g004: Proposed involvement of memory T cells in the pathogenesis of AIP.Autoantigens from acinar cells and pancreatic duct epithelium trigger activation of T cells, which may differentiate into T effector cells or memory T cells. The first population mediates destruction of pancreatic tissue, whereas the latter type of T cells perpetuates and enhances autoimmune reactions upon antigen re-exposure. Relative frequencies of splenic leukocyte subsets, development of AIP (pancreatic damage) and possibly expression/processing of autoantigens are controlled by QTLs. Overlapping QTLs for certain immune cell phenotypes and AIP suggest the existence of pathogenetic links.
Mentions: Taken together, we hypothesize that CD4+/CD44high memory T cells play a previously unrecognized role in murine AIP, and suggest that these cells are an important link between genetic susceptibility and development of the disease (Fig 4). Currently, fine-mapping studies are underway to narrow down AIP loci and overlapping QTLs for immune cell phenotypes, and to identify candidate genes that control the respective phenotypes.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Dermatology, University of Lübeck, Ratzeburger Allee 160, 23562 Lübeck, Germany.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus