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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

Quantitative trait loci (QTLs) for autoimmune pancreatitis and leukocyte subsets.The figure shows plots of QTLs for autoimmune pancreatitis and for leukocyte subsets with overlapping QTLs (upper panel: full genome; lower panel: chromosome 2). Log-likelihood values were determined using HAPPY. Logarithmic p values are presented in relation to positions of the marker loci along the chromosome. For confidence intervals and overlapping QTLs on chromosome 6, please refer to Table 6.
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pone.0136298.g002: Quantitative trait loci (QTLs) for autoimmune pancreatitis and leukocyte subsets.The figure shows plots of QTLs for autoimmune pancreatitis and for leukocyte subsets with overlapping QTLs (upper panel: full genome; lower panel: chromosome 2). Log-likelihood values were determined using HAPPY. Logarithmic p values are presented in relation to positions of the marker loci along the chromosome. For confidence intervals and overlapping QTLs on chromosome 6, please refer to Table 6.

Mentions: In subsequent analyses, QTL were considered as overlapping when their peaks are no more than 10 Mb apart. Interestingly, for the QTLs AIP s1, AIP s3 and AIP s4 such overlaps with QTLs for individual leukocyte subsets could be observed (Fig 2, Table 6). The peak of QTL AIP s1 on chromosome 2 was next to peaks of QTLs for subtypes of T helper cells (CD4+/CD44high), Tregs (FoxP3+/CD4+, FoxP3+/CD8+) and cytotoxic T cells (CD8+/CD69+, CD8+/CD44high). On chromosome 6, the QTLs AIP s3 and AIP s4 overlapped with QTLs for Tregs (again, FoxP3+/CD8+) and Th17 cells (IL17+/CD4+), respectively.


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)

Quantitative trait loci (QTLs) for autoimmune pancreatitis and leukocyte subsets.The figure shows plots of QTLs for autoimmune pancreatitis and for leukocyte subsets with overlapping QTLs (upper panel: full genome; lower panel: chromosome 2). Log-likelihood values were determined using HAPPY. Logarithmic p values are presented in relation to positions of the marker loci along the chromosome. For confidence intervals and overlapping QTLs on chromosome 6, please refer to Table 6.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0136298.g002: Quantitative trait loci (QTLs) for autoimmune pancreatitis and leukocyte subsets.The figure shows plots of QTLs for autoimmune pancreatitis and for leukocyte subsets with overlapping QTLs (upper panel: full genome; lower panel: chromosome 2). Log-likelihood values were determined using HAPPY. Logarithmic p values are presented in relation to positions of the marker loci along the chromosome. For confidence intervals and overlapping QTLs on chromosome 6, please refer to Table 6.
Mentions: In subsequent analyses, QTL were considered as overlapping when their peaks are no more than 10 Mb apart. Interestingly, for the QTLs AIP s1, AIP s3 and AIP s4 such overlaps with QTLs for individual leukocyte subsets could be observed (Fig 2, Table 6). The peak of QTL AIP s1 on chromosome 2 was next to peaks of QTLs for subtypes of T helper cells (CD4+/CD44high), Tregs (FoxP3+/CD4+, FoxP3+/CD8+) and cytotoxic T cells (CD8+/CD69+, CD8+/CD44high). On chromosome 6, the QTLs AIP s3 and AIP s4 overlapped with QTLs for Tregs (again, FoxP3+/CD8+) and Th17 cells (IL17+/CD4+), respectively.

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