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Diabetes protection and restoration of thymocyte apoptosis in NOD Idd6 congenic strains
Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM). Instituto Gulbenkian de Ciencia, Oeiras, Portugal .
Instituto Gulbenkian de Ciencia, Oeiras, Portugal .
Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
Visa övriga samt affilieringar
2003 (Engelska)Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 52, nr 7, s. 1677-1682Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
American Diabetes Association , 2003. Vol. 52, nr 7, s. 1677-1682
Nationell ämneskategori
Immunologi inom det medicinska området Endokrinologi och diabetes
Forskningsämne
immunologi
Identifikatorer
URN: urn:nbn:se:umu:diva-4715DOI: 10.2337/diabetes.52.7.1677ISI: 000183838900013PubMedID: 12829632OAI: oai:DiVA.org:umu-4715DiVA, id: diva2:143933
Tillgänglig från: 2005-09-27 Skapad: 2005-09-27 Senast uppdaterad: 2018-06-09Bibliografiskt granskad
Ingår i avhandling
1. Molecular and cellular mechanisms contributing to the pathogenesis of autoimmune diabetes
Öppna denna publikation i ny flik eller fönster >>Molecular and cellular mechanisms contributing to the pathogenesis of autoimmune diabetes
2005 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Umeå: Medicinsk biovetenskap, 2005. s. 103
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 986
Nyckelord
Immunology, type 1 diabetes, NOD mouse, susceptibility loci, Idd6, Lrmp, gene, NKT, CD1d, TCR, mast cells, Immunologi
Nationell ämneskategori
Immunologi inom det medicinska området
Forskningsämne
medicinsk genetik
Identifikatorer
urn:nbn:se:umu:diva-601 (URN)91-7305-944-7 (ISBN)
Disputation
2005-11-04, Betula, 6M, University of Umea, S-901 85 Umea, Umea, 10:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2005-09-27 Skapad: 2005-09-27 Senast uppdaterad: 2018-01-13Bibliografiskt granskad
2. Functional studies of candidate genes contributing to type 1 diabetes in the NOD mouse
Öppna denna publikation i ny flik eller fönster >>Functional studies of candidate genes contributing to type 1 diabetes in the NOD mouse
2009 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Type 1 Diabetes (T1D) is an autoimmune disorder caused by both genetic and environmental factors. The non-obese diabetic (NOD) mouse is one of the best and most commonly studied animal models for T1D. This mouse strain spontaneously develops diabetes through a process that closely resembles the human pathogenesis. More than 20 insulin dependent susceptibility (Idd) loci have been identified in the NOD mouse, contributing to disease susceptibility; however, the contribution of each of the various factors to disease pathogenesis is largely unknown.

The aim of this thesis was to identify and functionally characterize candidate genes mediating susceptibility to murine T1D.

Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is a negative regulator of T-cell activation and has been shown to be associated with autoimmune diseases. Genetic analyses of the NOD mouse have identified the Ctla-4 gene as a major candidate for the Idd5.1 diabetes susceptibility locus and NOD mice have been found to display an impaired expression of CTLA-4 upon anti-CD3 stimulation in vitro. In Paper I, we showed that a novel locus (Ctex) in the distal part of the chromosome 1 together with the Idd3 (Il-2) locus on chromosome 3, constitute the major factors conferring the observed difference in CTLA-4 expression levels. Moreover, we also demonstrated that the defective expression of CTLA-4 in NOD T-cells can in part be overcome by the addition of exogenous interleukin-2 (IL-2). In Paper II, using congenic mice, we confirmed that the Ctex locus contributes to decreased expression of CTLA-4 observed in NOD mice and restricted the region of interest to a 28.8 Mb region containing the Cd3ζ gene. We also demonstrated a phenotypic correlation between strains carrying the NOD versus C57BL/6 alleles of Cd3ζ, respectively and showed that expression of CD3ζ is impaired in activated NOD CD4+ T cells. The NOD allele of the Cd3ζ region was found to confer impaired T cell activation and the defective CD3 signalling could be surpassed by PMA plus ionomycin stimulation supporting the notion of CD3ζ as a prime candidate gene for Ctex.

NOD lymphocytes display relative resistance to various apoptosis-inducing signals, which have been proposed to contribute to the pathogenesis of diabetes. Resistance to dexamethasone-induced apoptosis in NOD immature thymocytes has been mapped to the Idd6 locus. In Paper III we restricted the Idd6 locus to an 8 cM region on the telomeric end of chromosome 6 using a set of congenic mice. In addition, we could confirm that the Idd6 region controls apoptosis resistance in immature thymocytes and restricted the control of apoptosis resistance to a 3 cM region within the Idd6 locus. In Paper IV, we further restricted the Idd6 locus to a 3 Mb region and excluded the region controlling the resistance to apoptosis as directly mediating susceptibility to diabetes. We also showed that defective expression of the Lrmp/Jaw1 gene, encoding an endoplasmatic reticulum resident protein, is controlled by the Idd6 locus making it the prime candidate for Idd6

Together, these results contribute to the identification and functional characterization of candidate genes that may confer susceptibility to T1D in the NOD mouse. These results offer important insights into the pathophysiological processes underlying this disease.

Ort, förlag, år, upplaga, sidor
Umeå: Medicinsk biovetenskap, 2009. s. 81
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 1262
Nyckelord
Type 1 Diabetes, NOD mouse, CTLA-4, Ctex, CD3ζ, apoptosis, Idd6, Lrmp
Forskningsämne
medicinsk genetik
Identifikatorer
urn:nbn:se:umu:diva-22401 (URN)978-91-7264-778-7 (ISBN)
Disputation
2009-09-04, Hörsal Betula, byggnad 6M, Norrlands Universitetssjukhus, Umeå, 09:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2009-05-20 Skapad: 2009-05-07 Senast uppdaterad: 2009-05-20Bibliografiskt granskad
3. A sub-phenotype approach to dissect the genetic control of murine type 1 diabetes
Öppna denna publikation i ny flik eller fönster >>A sub-phenotype approach to dissect the genetic control of murine type 1 diabetes
2002 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Umeå: Umeå University, 2002. s. 62
Nationell ämneskategori
Endokrinologi och diabetes Cell- och molekylärbiologi
Identifikatorer
urn:nbn:se:umu:diva-148283 (URN)91-7305-257-4 (ISBN)
Disputation
2002-05-02, Lecture Hall "Major Groove", Dept. of Molecular Biology, Umeå, 10:00 (Engelska)
Opponent
Anmärkning

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Tillgänglig från: 2018-05-31 Skapad: 2018-05-31 Senast uppdaterad: 2019-01-21Bibliografiskt granskad

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