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Molecular and cellular mechanisms contributing to the pathogenesis of autoimmune diabetes
Umeå University, Faculty of Medicine, Medical Biosciences.
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Type 1 diabetes is an autoimmune disorder determined both by genetic and environmental factors. The Non-obese diabetic (NOD) mouse is one of the best animal models of this disease. It spontaneously develops diabetes through a process resembling the human pathogenesis. The strong association of NOD Type 1 diabetes to the MHC region and the existence of other diabetes susceptibility loci are also in parallel with the human disease. The identity of the genetic factors and biological function mediated by these loci remain, however, largely unknown. Like in other autoimmune diseases, defects in tolerance mechanisms are thought to be at the origin of type 1 diabetes. Accordingly, defects in both central and peripheral tolerance mechanisms have been reported in the NOD mouse model.

Using a subphenotype approach that aimed to dissect the disease into more simple phenotypes, we have addressed this issue. In paper I, we analyzed resistance to dexamethasone-induced apoptosis in NOD immature thymocytes previously mapped to the Idd6 locus. Using a set of congenic mice carrying B6-derived Idd6 regions on a NOD background and vice-versa we could restrict the Idd6 locus to an 8cM region on the telomeric end of chromosome 6 and the control of apoptosis resistance to a 3cM region within this area. In paper II, further analysis of diabetes incidence in these congenic mice separated the genes controlling these two traits, excluding the region controlling the resistance to apoptosis as directly mediating susceptibility to diabetes. These results also allowed us to further restrict the Idd6 locus to a 3Mb region. Expression analysis of genes in this chromosomal region highlighted the Lrmp/Jaw1 gene as a prime candidate for Idd6. Lrmp encodes an endoplasmatic reticulum resident protein.

Papers III and IV relate to peripheral tolerance mechanisms. Several T cell populations with regulatory functions have been implicated in type 1 diabetes. In paper III, we analyzed NOD transgenic mice carrying a diverse CD1d-restricted TCR αVa3.2b9), named 24abNOD mice. The number of nonclassical NKT cells was found to be increased in these mice and almost complete protection from diabetes was observed. These results indicate a role for nonclassical NKT cells in the regulation of autoimmune diabetes. In paper IV, we studied the effects of introducing the diverse CD1d-restricted TCR (Va3.2b9) in immunodeficient NOD Rag-/- mice (24abNODRag-/- mice). This resulted in a surprising phenotype with inflammation of the ears and augmented presence of mast cells as well as spleenomegaly and hepatomegaly associated with extended fibrosis and increased numbers of mast cells and eosinophils in the tissues. These observations supported the notion that NKT cells constitute an “intermediary” cell type, not only able to elicit the innate immune system to mount an inflammatory response, but also able to interact with the adaptive immune system affecting the action of effector T cells in an autoimmune situation. In this context the 24abNODRag-/- mice provide an appropriate animal model for studying the interaction of NKT cells with both innate and adaptive components of the immune systemα.

Place, publisher, year, edition, pages
Umeå: Medicinsk biovetenskap , 2005. , 103 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 986
Keyword [en]
Immunology, type 1 diabetes, NOD mouse, susceptibility loci, Idd6, Lrmp, gene, NKT, CD1d, TCR, mast cells
Keyword [sv]
Immunologi
National Category
Immunology in the medical area
Research subject
Medical Genetics
Identifiers
URN: urn:nbn:se:umu:diva-601ISBN: 91-7305-944-7 (print)OAI: oai:DiVA.org:umu-601DiVA: diva2:143937
Public defence
2005-11-04, Betula, 6M, University of Umea, S-901 85 Umea, Umea, 10:00 (English)
Opponent
Supervisors
Available from: 2005-09-27 Created: 2005-09-27 Last updated: 2009-11-11Bibliographically approved
List of papers
1. 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, 1677-1682 p.Article 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
Medical and Health Sciences
Research subject
Immunology
Identifiers
urn:nbn:se:umu:diva-4715 (URN)10.2337/diabetes.52.7.1677 (DOI)12829632 (PubMedID)
Available from: 2005-09-27 Created: 2005-09-27 Last updated: 2017-12-14Bibliographically approved
2. The Idd6 susceptibility locus controls defective expression of the Lrmp gene in non-obese diabetic (NOD) mice
Open this publication in new window or tab >>The Idd6 susceptibility locus controls defective expression of the Lrmp gene in non-obese diabetic (NOD) mice
Manuscript (Other academic)
Identifiers
urn:nbn:se:umu:diva-4716 (URN)
Available from: 2005-09-27 Created: 2005-09-27 Last updated: 2010-01-13Bibliographically approved
3. Prevention of diabetes in nonobese diabetic mice mediated by CD1d-restricted nonclassical NKT cells.
Open this publication in new window or tab >>Prevention of diabetes in nonobese diabetic mice mediated by CD1d-restricted nonclassical NKT cells.
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2004 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 173, no 5, 3112-3118 p.Article in journal (Refereed) Published
Abstract [en]

A role for regulatory lymphocytes has been demonstrated in the pathogenesis of type 1 diabetes in the NOD mouse but the nature of these cells is debated. CD1d-restricted NKT lymphocytes have been implicated in this process. Previous reports of reduced diabetes incidence in NOD mice in which the numbers of NKT cells are artificially increased have been attributed to the enhanced production of IL-4 by these cells and a role for classical NKT cells, using the Valpha14-Jalpha18 rearrangement. We now show that overexpression in NOD mice of CD1d-restricted TCR Valpha3.2(+)Vbeta9(+) NKT cells producing high levels of IFN-gamma but low amounts of IL-4 leads to prevention of type 1 diabetes, demonstrating a role for nonclassical CD1d-restricted NKT cells in the regulation of autoimmune diabetes.

Keyword
Animals, Antigens; CD1/*immunology, Cytokines/immunology/metabolism, Diabetes Mellitus/genetics/immunology/*prevention & control, Gene Transfer Techniques, Killer Cells; Natural/*immunology, Mice, Mice; Inbred NOD, Mice; Transgenic, Receptors; Antigen; T-Cell/genetics/immunology, Spleen/immunology, T-Lymphocyte Subsets/*immunology
Identifiers
urn:nbn:se:umu:diva-15214 (URN)15322171 (PubMedID)
Available from: 2008-01-09 Created: 2008-01-09 Last updated: 2017-12-14Bibliographically approved
4. CD1d-restricted nonclassical NKT cells provoke inflammation with mast cell recruitment in a NOD Rag-/- immunodeficient mouse model
Open this publication in new window or tab >>CD1d-restricted nonclassical NKT cells provoke inflammation with mast cell recruitment in a NOD Rag-/- immunodeficient mouse model
Manuscript (Other academic)
Identifiers
urn:nbn:se:umu:diva-4718 (URN)
Available from: 2005-09-27 Created: 2005-09-27 Last updated: 2010-01-13Bibliographically approved

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