Limits...
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

Representative examples of pancreatic lesions ranging from stage 0 (A) to 3 (D).Sections of paraffin-embedded pancreatic tissue were stained with H&E. (A) healthy pancreas; stage 0. (B) minimal lymphocytic infiltration of the subepithelial layer of one larger duct (arrow); no parenchymal destruction; stage 1. (C) more extended lymphocytic infiltration; beginning destruction of acinar tissue; stage 2. (D) severe periductal inflammation with progressive parenchymal destruction; stage 3.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4556487&req=5

pone.0136298.g001: Representative examples of pancreatic lesions ranging from stage 0 (A) to 3 (D).Sections of paraffin-embedded pancreatic tissue were stained with H&E. (A) healthy pancreas; stage 0. (B) minimal lymphocytic infiltration of the subepithelial layer of one larger duct (arrow); no parenchymal destruction; stage 1. (C) more extended lymphocytic infiltration; beginning destruction of acinar tissue; stage 2. (D) severe periductal inflammation with progressive parenchymal destruction; stage 3.

Mentions: Generation 4 of the 4-way autoimmune-prone intercross mouse line was employed, at an age of 6 months, to assess pancreatic histopathology and relative frequencies of different leukocyte subsets in the spleen. Therefore, 331 mice (156 females and 175 males) were included into the investigations. The mice represent a subset of the previously analyzed 351 animals [26], which was chosen based on the availability of flow cytometry data. Scoring of AIP-typical pancreatic lesions, such as presence of lymphocytic foci and parenchymal destruction, revealed an AIP stage 2 or 3 in 44 mice (32 females and 12 males). Stage 4 was not detected, but has been observed in mice of the advanced intercross line outside of this study (R.J., unpublished data). These numbers correspond to 18.3% of the females but only 7.7% of the males (13.3% of all mice). Details are given in Table 2. Exemplary tissue stains are shown in Fig 1.


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)

Representative examples of pancreatic lesions ranging from stage 0 (A) to 3 (D).Sections of paraffin-embedded pancreatic tissue were stained with H&E. (A) healthy pancreas; stage 0. (B) minimal lymphocytic infiltration of the subepithelial layer of one larger duct (arrow); no parenchymal destruction; stage 1. (C) more extended lymphocytic infiltration; beginning destruction of acinar tissue; stage 2. (D) severe periductal inflammation with progressive parenchymal destruction; stage 3.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0136298.g001: Representative examples of pancreatic lesions ranging from stage 0 (A) to 3 (D).Sections of paraffin-embedded pancreatic tissue were stained with H&E. (A) healthy pancreas; stage 0. (B) minimal lymphocytic infiltration of the subepithelial layer of one larger duct (arrow); no parenchymal destruction; stage 1. (C) more extended lymphocytic infiltration; beginning destruction of acinar tissue; stage 2. (D) severe periductal inflammation with progressive parenchymal destruction; stage 3.
Mentions: Generation 4 of the 4-way autoimmune-prone intercross mouse line was employed, at an age of 6 months, to assess pancreatic histopathology and relative frequencies of different leukocyte subsets in the spleen. Therefore, 331 mice (156 females and 175 males) were included into the investigations. The mice represent a subset of the previously analyzed 351 animals [26], which was chosen based on the availability of flow cytometry data. Scoring of AIP-typical pancreatic lesions, such as presence of lymphocytic foci and parenchymal destruction, revealed an AIP stage 2 or 3 in 44 mice (32 females and 12 males). Stage 4 was not detected, but has been observed in mice of the advanced intercross line outside of this study (R.J., unpublished data). These numbers correspond to 18.3% of the females but only 7.7% of the males (13.3% of all mice). Details are given in Table 2. Exemplary tissue stains are shown in Fig 1.

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