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Functional studies of candidate genes contributing to type 1 diabetes in the NOD mouse
Umeå University, Faculty of Medicine, Medical Biosciences. Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics. (Dan Holmberg)
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
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.

Place, publisher, year, edition, pages
Umeå: Medicinsk biovetenskap , 2009. , 81 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1262
Keyword [en]
Type 1 Diabetes, NOD mouse, CTLA-4, Ctex, CD3ζ, apoptosis, Idd6, Lrmp
Research subject
Medical Genetics
Identifiers
URN: urn:nbn:se:umu:diva-22401ISBN: 978-91-7264-778-7 (print)OAI: oai:DiVA.org:umu-22401DiVA: diva2:216268
Public defence
2009-09-04, Hörsal Betula, byggnad 6M, Norrlands Universitetssjukhus, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2009-05-20 Created: 2009-05-07 Last updated: 2009-05-20Bibliographically approved
List of papers
1. Defective induction of CTLA-4 in the NOD mouse is controlled by the NOD allele of Idd3/IL-2 and a novel locus (Ctex) telomeric on chromosome 1
Open this publication in new window or tab >>Defective induction of CTLA-4 in the NOD mouse is controlled by the NOD allele of Idd3/IL-2 and a novel locus (Ctex) telomeric on chromosome 1
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2006 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 55, no 2, 538-544 p.Article in journal (Refereed) Published
Abstract [en]

Cytotoxic T-lymphocyte–associated antigen-4 (CTLA-4), or CD152, is a negative regulator of T-cell activation and has been shown to be associated with autoimmune diseases. Previous work has demonstrated a defect in the expression of this molecule in nonobese diabetic (NOD) mice upon anti-CD3 stimulation in vitro. Using a genetic approach we here demonstrate that a novel locus (Ctex) telomeric on chromosome 1 together with the Idd3 (Il-2) gene confers optimal CTLA-4 expression upon CD3 activation of T-cells. Based on these data, we provide a model for how gene interaction between Idd3 (IL-2), Ctex, and Idd5.1 (Ctla-4) could confer susceptibility to autoimmune diabetes in the NOD mouse. Additionally, we showed that the Ctex and the Idd3 regions do not influence inducible T-cell costimulator (ICOS) protein expression in NOD mice. Instead, as previously shown, higher ICOS levels in NOD mice appear to be controlled by gene(s) in the Idd5.1 region, possibly a polymorphism in the Icos gene itself.

Keyword
Alleles, Animals, Antigens; CD, Antigens; Differentiation/genetics/*metabolism, Cells; Cultured, Chromosomes; Mammalian/*genetics, Diabetes Mellitus/*genetics, Female, Gene Expression Regulation, Genetic Predisposition to Disease, Genotype, Interleukin-2/*genetics, Mice, Mice; Inbred C57BL, Mice; Inbred NOD, Physical Chromosome Mapping, Spleen/cytology, Telomere/*genetics
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:umu:diva-15296 (URN)10.2337/diabetes.55.02.06.db05-1240 (DOI)000235178400037 ()16443792 (PubMedID)2-s2.0-33644753940 (Scopus ID)
Available from: 2008-01-11 Created: 2008-01-11 Last updated: 2017-12-14Bibliographically approved
2. The non-obese diabetic (NOD) mouse allele of Cd3ζ (Cd247) is associated with impaired TCR/CD3 mediated activation of T cells
Open this publication in new window or tab >>The non-obese diabetic (NOD) mouse allele of Cd3ζ (Cd247) is associated with impaired TCR/CD3 mediated activation of T cells
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(English)Manuscript (Other academic)
Identifiers
urn:nbn:se:umu:diva-22399 (URN)
Available from: 2009-05-07 Created: 2009-05-07 Last updated: 2012-01-31Bibliographically 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, 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
4. 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

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