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Low rate of proliferation in immature thymocytes of the non-obese diabetic mouse maps to the Idd6 diabetes susceptibility region
Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
Gulbenkian Institute for Science, Oeiras, Portugal, PT.
Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
2001 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 44, no 8, p. 1054-1061Article in journal (Refereed) Published
Abstract [en]

Aims/hypothesis: The non-obese diabetic (NOD) mouse spontaneously develops T-cell-dependent autoimmune diabetes. This mouse strain has a number of immune dysfunctions related to T-cell development but so far there are no available data on the proliferation of NOD immature thymocytes. We therefore studied the thymocyte proliferation in the NOD mouse in discrete stages of T-cell development.

Methods: We depleted thymocytes in vivo and analysed thymocyte proliferation during the thymus recovery from depletion. We used co-segregation analysis and quantitative loci trait analysis to investigate the genetic control of proliferation impairments in NOD thymocytes.

Results: Immature thymocytes of female NOD mice proliferate with a relatively low rate compared to non-autoimmune C57Bl/6 mice. This aberrant proliferation was most pronounced in CD4 /loCD8+ cells differentiating from the CD4CD8 to the CD4+CD8+ stage. A genetic mapping study using an F2 intercross between the NOD and the C57BL/6 strains showed that a major locus controlling this trait is linked to the insulin-dependent diabetes susceptibility locus Idd6.

Conclusion/interpretation: Our results suggest that impairment of proliferation of immature thymocytes is one possible mechanism through which the Idd6 locus contributes to the pathogenesis of diabetes.

Place, publisher, year, edition, pages
Springer, 2001. Vol. 44, no 8, p. 1054-1061
Keywords [en]
NOD, immature thymocytes, proliferation, genetics
National Category
Endocrinology and Diabetes Immunology in the medical area
Research subject
Immunology
Identifiers
URN: urn:nbn:se:umu:diva-87518DOI: 10.1007/s001250100600ISI: 000170686800016PubMedID: 11484085OAI: oai:DiVA.org:umu-87518DiVA, id: diva2:709626
Available from: 2014-04-02 Created: 2014-04-02 Last updated: 2019-01-25Bibliographically approved
In thesis
1. A sub-phenotype approach to dissect the genetic control of murine type 1 diabetes
Open this publication in new window or tab >>A sub-phenotype approach to dissect the genetic control of murine type 1 diabetes
2002 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The non-obese diabetic (NOD) mouse is a model for human type 1 diabetes (T1D). The disease in the NOD mouse is polygenic and multifactorial and so far at least 20 insulin dependent diabetes (Idd) susceptibility loci have been identified. However, no etiological mutations have been definitely ascribed to the Idd loci. To identify potential etiological mutations, a sub-phenotype approach was undertaken, consisting of the establishment and genetic mapping of immuno-related sub-phenotypes that may contribute to the pathogenesis of T1D in the NOD mouse model. This thesis presents (1) the results of the identification and genetic mapping of four novel NOD immuno-phenotypes to individual Idd loci, and (2) confirmation of these results by the generation and analysis of congenic strains covering those Idd regions.

Evidence is provided that gene(s) within the Idd5 region control cyclophosphamide (CY)-induced apoptosis in peripheral lymphocytes and y-irradiation induced apoptosis in NOD thymocytes. Analysis of non-obese resistant (NOR) and NOD-Idd5 congenic mice reveal that CY-induced apoptosis in peripheral lymphocytes and y-irradiation induced apoptosis in thymocytes are controlled by a 20cM and a 6cM region, respectively, both containing the Idd5 region and including the immuno-regulatory Ctla4 gene. Additionally, CTLA4 is shown to be defectively up-regulated in activated NOD peripheral lymphocytes, and CTLA4-deficient mice show similar defects in T cell apoptosis induction. Taken together, these results suggest that a defective up-regulation of CTLA4 mediates apoptosis resistance, contributing to diabetes pathogenesis.

Moreover, it is shown that gene(s) within the Idd6 region control low proliferation ofNOD immature thymocytes and resistance to dexamethazone-induced apoptosis in immature DP thymocytes. The decrease of diabetes incidence and the restoration of the apoptosis resistance phenotype in reciprocal Idd6 congenic strains further restrict the chromosomal region controlling the Idd6 locus as well as the locus controlling the apoptosis resistance phenotype. In fact, analysis of NOD-Idd6 congenic mice reveal that Dxm-induced apoptosis in thymocytes is controlled by the distal 3cM region of the Idd6 locus. As the thymic selection process is highly dependent on both proliferation and apoptosis, the hypothesis is raised that the Idd6 locus contributes to the pathogenesis of diabetes by altering thymic selection, resulting in an autoimmune prone peripheral T cell repertoire.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2002. p. 62
National Category
Endocrinology and Diabetes Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-148283 (URN)91-7305-257-4 (ISBN)
Public defence
2002-05-02, Lecture Hall "Major Groove", Dept. of Molecular Biology, Umeå, 10:00 (English)
Opponent
Note

digitalisering@UmU

Available from: 2018-05-31 Created: 2018-05-31 Last updated: 2019-01-21Bibliographically approved

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Lejon, KristinaHolmberg, Dan

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