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A sub-phenotype approach to dissect the genetic control of murine type 1 diabetes
Umeå University, Faculty of Medicine, Molecular Biology.
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: urn:nbn:se:umu:diva-148283ISBN: 91-7305-257-4 (print)OAI: oai:DiVA.org:umu-148283DiVA, id: diva2:1211911
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: 2018-06-28Bibliographically approved
List of papers
1. Apoptosis resistance of nonobese diabetic peripheral lymphocytes linked to the Idd5 diabetes susceptibility region
Open this publication in new window or tab >>Apoptosis resistance of nonobese diabetic peripheral lymphocytes linked to the Idd5 diabetes susceptibility region
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1997 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 94, no 16, p. 8670-8674Article in journal (Refereed) Published
Abstract [en]

Defects in lymphocyte apoptosis may lead to autoimmune disorders and contribute to the pathogenesis of type 1 diabetes. Lymphocytes of nonobese diabetic (NOD) mice, an animal model of autoimmune diabetes, have been found resistant to various apoptosis signals, including the alkylating drug cyclophosphamide. Using an F2 intercross between the apoptosis-resistant NOD mouse and the apoptosis-susceptible C57BL/6 mouse, we define a major locus controlling the apoptosis-resistance phenotype and demonstrate its linkage (logarithm of odds score = 3.9) to a group of medial markers on chromosome 1. The newly defined gene cannot be dissociated from Ctla4 and Cd28 and in fact marks a 20-centimorgan region encompassing Idd5, a previously postulated diabetes susceptibility locus. Interestingly, we find that the CTLA-4 (cytotoxic T lymphocyte-associated antigen 4) and the CD28 costimulatory molecules are defectively expressed in NOD mice, suggesting that one or both of these molecules may be involved in the control of apoptosis resistance and, in turn, in diabetes susceptibility.

Place, publisher, year, edition, pages
National Academy of Sciences, 1997
National Category
Endocrinology and Diabetes Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-148282 (URN)10.1073/pnas.94.16.8670 (DOI)A1997XQ12400068 ()9238035 (PubMedID)
Available from: 2018-05-31 Created: 2018-05-31 Last updated: 2018-06-09Bibliographically approved
2. CTLA-4-/- mice display T cell-apoptosis resistance resembling that ascribed to autoimmune-prone non-obese diabetic (NOD) mice
Open this publication in new window or tab >>CTLA-4-/- mice display T cell-apoptosis resistance resembling that ascribed to autoimmune-prone non-obese diabetic (NOD) mice
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2001 (English)In: Journal of Autoimmunity, ISSN 0896-8411, E-ISSN 1095-9157, Vol. 16, no 2, p. 105-113Article in journal (Refereed) Published
Abstract [en]

The genes conferring susceptibility to autoimmune (insulin-dependent) diabetes mellitus (IDDM) are, in most cases, not defined. Among the loci so far identified as associated with murine IDDM (Idd1-19), only the nature of Idd1 has been assessed. Here we show that thymocytes and peripheral lymphocytes of the non-obese diabetic (NOD) mouse are relatively resistant to apoptosis induced by gamma-irradiation. By linkage analysis of F2 progeny mice, we map this trait to a locus on chromosome 1 containing the Idd5 diabetes susceptibility region. By the use of congenic mice, we confirm the linkage data and map this locus to a 6 cM region on proximal chromosome 1. Ctla4, being localized in this chromosomal region and mediating crucial functions in T cell biology, is a logical candidate gene in the Idd5 susceptibility region. In line with this, we demonstrate that T cells from Ctla4(-/-)deficient mice show a similar resistance to gamma-irradiation-induced apoptosis as observed in the NOD mice. This reinforces the notion that CTLA-4 contributes to the pathogenesis of autoimmune diabetes.

Place, publisher, year, edition, pages
Elsevier, 2001
National Category
Immunology in the medical area
Research subject
Immunology
Identifiers
urn:nbn:se:umu:diva-87510 (URN)10.1006/jaut.2000.0474 (DOI)000167547100003 ()11247636 (PubMedID)
Available from: 2014-04-02 Created: 2014-04-02 Last updated: 2018-06-08Bibliographically approved
3. Diabetes protection and restoration of thymocyte apoptosis in NOD Idd6 congenic strains
Open this publication in new window or tab >>Diabetes protection and restoration of thymocyte apoptosis in NOD Idd6 congenic strains
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2003 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 52, no 7, p. 1677-1682Article in journal (Refereed) Published
Abstract [en]

Type 1 diabetes in the nonobese diabetic (NOD) mouse is a multifactorial and polygenic disease. The NOD-derived genetic factors that contribute to type 1 diabetes are named Idd (insulin-dependent diabetes) loci. To date, the biological functions of the majority of the Idd loci remain unknown. We have previously reported that resistance of NOD immature thymocytes to depletion by dexamethazone (Dxm) maps to the Idd6 locus. Herein, we refine this phenotype using a time-course experiment of apoptosis induction upon Dxm treatment. We confirm that the Idd6 region controls apoptosis resistance in immature thymocytes. Moreover, we establish reciprocal Idd6 congenic NOD and B6 strains to formally demonstrate that the Idd6 congenic region mediates restoration of the apoptosis resistance phenotype. Analysis of the Idd6 congenic strains indicates that a 3-cM chromosomal region located within the distal part of the Idd6 region controls apoptosis resistance in NOD immature thymocytes. Together, these data support the hypothesis that resistance to Dxm-induced apoptosis in NOD immature thymocytes is controlled by a genetic factor within the region that also contributes to type 1 diabetes pathogenesis. We propose that the diabetogenic effect of the Idd6 locus is exerted at the level of the thymic selection process.

Place, publisher, year, edition, pages
American Diabetes Association, 2003
National Category
Immunology in the medical area Endocrinology and Diabetes
Research subject
Immunology
Identifiers
urn:nbn:se:umu:diva-4715 (URN)10.2337/diabetes.52.7.1677 (DOI)000183838900013 ()12829632 (PubMedID)
Available from: 2005-09-27 Created: 2005-09-27 Last updated: 2018-06-09Bibliographically approved
4. Low rate of proliferation in immature thymocytes of the non-obese diabetic mouse maps to the Idd6 diabetes susceptibility region
Open this publication in new window or tab >>Low rate of proliferation in immature thymocytes of the non-obese diabetic mouse maps to the Idd6 diabetes susceptibility region
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
Keywords
NOD, immature thymocytes, proliferation, genetics
National Category
Endocrinology and Diabetes Immunology in the medical area
Research subject
Immunology
Identifiers
urn:nbn:se:umu:diva-87518 (URN)10.1007/s001250100600 (DOI)000170686800016 ()11484085 (PubMedID)
Available from: 2014-04-02 Created: 2014-04-02 Last updated: 2018-06-08Bibliographically approved

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