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

Bischof, Julia; Müller, Sarah; Borufka, Luise; Asghari, Farahnaz; Möller, Steffen; Holzhüter, Stephanie-Anna; Nizze, H; Ibrahim, Saleh M.; Jaster, Robert

doi:10.1371/journal.pone.0136298

Cited by 7 publications

(14 citation statements)

References 38 publications

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“…Consequently, CD69 contributes to an inhibitory effect on CD4 + T cells [69]. CD69 has been associated with autoimmune diseases such as diabetes [70], hepatitis [71], and pancreatitis [72]. In the present study, both miR-92a-3p and miR-93-5p were found to be involved in the pathogenesis of ITP via a common target gene, CD69 .…”

Section: Discussionmentioning

confidence: 50%

Differential Expression of MiR-106b-5p and MiR-200c-3p in Newly Diagnosed Versus Chronic Primary Immune Thrombocytopenia Patients Based on Systematic Analysis

Qian

Yan

et al. 2018

Cell Physiol Biochem

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Background/Aims: MicroRNAs (miRNAs) have been described to have important roles in primary immune thrombocytopenia (ITP). To gain additional understanding, we have now further evaluated the involvement of miRNAs in ITP. Methods: Microarray experiments were performed to examine the expression profiles of miRNAs and mRNAs in samples from subjects with newly diagnosed ITP (G1), chronic ITP (G2), and normal controls. The systematic Pipeline of Outlier MicroRNA Analysis framework was applied to identify key miRNAs expressed in the G1 and G2 samples. Quantitative PCR and receiver operator characteristic curves were used to confirm the performance of key miRNAs. Results: Compared with normal controls, 14 miRNAs (12 over-expressed and 2 under-expressed) and 7 over-expressed miRNAs were identified as key in G1 and G2 samples, respectively. miR-106b-5p, miR-200c-3p, and miR-92a-3p exhibited significantly different expression profiles among the groups. In particular, miR-106b-5p and miR-200c-3p were expressed at higher levels in patients with ITP compared to the normal controls. Furthermore, these two miRNAs expressions were even higher in patients with chronic ITP. Conclusion: MiR-106b-5p and miR-200c-3p may represent valuable biomarkers of ITP, although further studies are needed to confirm and assess the value of these potential biomarkers at various stages of ITP.

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Section: Discussionmentioning

confidence: 50%

Differential Expression of MiR-106b-5p and MiR-200c-3p in Newly Diagnosed Versus Chronic Primary Immune Thrombocytopenia Patients Based on Systematic Analysis

Qian

Yan

et al. 2018

Cell Physiol Biochem

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“…a subset of T cells that may also play a role in murine AIP. 4 Of note, the QTL effect observed in this study ( Figure 2…”

Section: Discussionmentioning

confidence: 67%

Impact of diet and genes on murine autoimmune pancreatitis

Jaster

Gupta

Rohde

et al. 2020

J Cellular Molecular Medi

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The impact of environmental factors, such as diet, and the genetic basis of autoimmune pancreatitis (AIP) are largely unknown. Here, we used an experimental murine AIP model to identify the contribution of diet to AIP development, as well as to fine‐map AIP‐associated genes in outbred mice prone to develop the disease. For this purpose, we fed mice of an autoimmune‐prone intercross line (AIL) three different diets (control, calorie‐reduced and western diet) for 6 months, at which point the mice were genotyped and phenotyped for AIP. Overall, 269 out of 734 mice (36.6%) developed AIP with signs of parenchymal destruction, equally affecting mice of both sexes. AIP prevalence and severity were reduced by approximately 50% in mice held under caloric restriction compared to those fed control or western diet. We identified a quantitative trait locus (QTL) on chromosome 4 to be associated with AIP, which is located within a previously reported QTL. This association does not change when considering diet or sex as an additional variable for the mapping. Using whole‐genome sequences of the AIL founder strains, we resolved this QTL to a single candidate gene, namely Map3k7 . Expression of Map3k7 was largely restricted to islet cells as well as lymphocytes found in the exocrine pancreas of mice with AIP. Our studies suggest a major impact of diet on AIP. Furthermore, we identify Map3k7 as a novel susceptibility gene for experimental AIP. Both findings warrant clinical translation.

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“…14 Using this mouse model in previous studies, we gained genetic evidence for an involvement of CD4 + CD44 high memory T cells in the pathogenesis of AIP. 15 Likewise, our studies implicated regulatory T cells (T regs ) in the mediation of the therapeutic effects of rapamycin through a suppression of the effector T cell response. 9 One characteristic of autoimmune diseases such as AIP is the possibility to adoptively transfer the disease from sick to healthy individuals in in vivo experiments.…”

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confidence: 79%

Adoptive transfer of CD3⁺ T cells and CD4⁺CD44^high memory T cells induces autoimmune pancreatitis in MRL/MpJ mice

Ehlers

Rohde

Ibrahim

et al. 2018

J Cellular Molecular Medi

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The immunopathogenesis of autoimmune pancreatitis (AIP) is poorly understood. Here, we have used MRL/MpJ mice, a model of spontaneous AIP, to address the role of cellular autoimmune processes in the initiation and progression of the disease. Therefore, different T cell subpopulations were adoptively transferred from sick to still healthy (but susceptible) MRL/MpJ mice. Unpurified splenocytes and CD3+ T cells both efficiently induced AIP, while CD4+ and CD8+ T cells alone, as well as splenocytes from healthy mice, were insufficient to trigger the disease. Strikingly, CD4+ CD44high memory T cells, although transferred at lower numbers than other T cells, also induced AIP in recipient mice. Employing a modified experimental design, we also evaluated the effects of regulatory T cells (T regs) on the progression of AIP in already diseased mice. Under the given experimental conditions, there was no significant suppressive effect of adoptively transferred T regs on pancreatic histopathology. The results of our studies suggest a key role of T cell‐mediated processes in murine AIP. The effects of CD4+ CD44high memory T cells are in accordance with genetic studies of our group, which had previously implicated this cell type into the pathogenesis of AIP. In follow‐up studies, we will focus on the interplay of cellular and humoral autoimmunity in the context of AIP.

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

Cited by 7 publications

References 38 publications

Differential Expression of MiR-106b-5p and MiR-200c-3p in Newly Diagnosed Versus Chronic Primary Immune Thrombocytopenia Patients Based on Systematic Analysis

Differential Expression of MiR-106b-5p and MiR-200c-3p in Newly Diagnosed Versus Chronic Primary Immune Thrombocytopenia Patients Based on Systematic Analysis

Impact of diet and genes on murine autoimmune pancreatitis

Adoptive transfer of CD3⁺ T cells and CD4⁺CD44^high memory T cells induces autoimmune pancreatitis in MRL/MpJ mice

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

Cited by 7 publications

References 38 publications

Differential Expression of MiR-106b-5p and MiR-200c-3p in Newly Diagnosed Versus Chronic Primary Immune Thrombocytopenia Patients Based on Systematic Analysis

Differential Expression of MiR-106b-5p and MiR-200c-3p in Newly Diagnosed Versus Chronic Primary Immune Thrombocytopenia Patients Based on Systematic Analysis

Impact of diet and genes on murine autoimmune pancreatitis

Adoptive transfer of CD3+ T cells and CD4+CD44high memory T cells induces autoimmune pancreatitis in MRL/MpJ mice

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Adoptive transfer of CD3⁺ T cells and CD4⁺CD44^high memory T cells induces autoimmune pancreatitis in MRL/MpJ mice