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The genetic basis of T and B cell contribution to autoimmune diabetes in NOD mice
Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The nonobese diabetic mouse (NOD) is an excellent animal model to study type 1 diabetes. As with some humans, disease in the NOD mouse is effected by a combination of genetic and environmental factors. At least 20 insulin dependent diabetes (Idd) susceptibility loci have been identified so far, both in humans and in the NOD mouse.

In this thesis, the overall aim has been to understand the genetic basis of diabetes in the NOD mouse by assessing immunogically-related phenotypes. As lymphocytes are the main players in the onset and progression to overt diabetes, we searched for physiological abnormalities in T and B cells, which could contribute to the breakdown of tolerance to pancreatic antigens. Ultimately, we postulate that abnormalities in the T or B cell compartments, under the genetic control of a previously defined diabetes susceptibility regions (Idds) could unravel the biological mechanisms underlying diabetes susceptibility and facilitate the identification of etiological polymorphisms involved in the disease.

NOD T cells are defective in upregulating CTLA-4 upon in vitro activation. Previous studies have shown that this defect is, at least in part, controlled by gene(s) in the Idd5 region on chromosome 1. In paper I, we provide evidence that defective upregulation of the CTLA-4 in NOD T cells is not controlled by the Idd5.1 and Idd5.2 regions, but rather by genes linked to the telomeric region of chromosome 1 and to the Idd3 locus, for which the prime candidate gene is Il-2. Interestingly, we could restore some of the defective CTLA-4 expression in NOD T cells by the addition of exogenous IL-2 during T cell activation in vitro. In paper II, we show that NOD thymocytes are resistant to superantigen-mediated negative selection and that this trait is under control of the Idd5.2 region. Interestingly, it appears to operate in a T cell non-autonomous manner. In paper III, we describe a competitive advantage of NOD thymocytes to mature when they co-develop with B6 thymocytes in embryo aggregation chimeras. These results imply that defects exist in the positive/negative selection mechanisms in the NOD thymus. Apart from T cells, B cells also play an important role in the initiation of diabetes in NOD mice, probably as antigen presenting cells. In paper IV, we report that the genetic basis of an enlarged marginal zone (MZ) B cell population observed in the NOD mice is linked to the Idd9/Idd11 region. Together, these findings contribute to the dissection of the molecular mechanisms underlying diabetes pathogenesis, and shed light on the contribution of central and peripheral tolerance mechanisms to this process.

Place, publisher, year, edition, pages
Umeå: Medicinsk biovetenskap , 2006. , 108 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1015
Keyword [en]
Type 1 Diabetes, NOD mouse, CTLA-4, superantigen, T cells, Idd, marginal zone B cells, embryo aggregation chimera, negative selection
National Category
Immunology in the medical area
Identifiers
URN: urn:nbn:se:umu:diva-728ISBN: 91-7264-006-5 (print)OAI: oai:DiVA.org:umu-728DiVA: diva2:144332
Public defence
2006-03-31, Betula, 6M, Norrlands Universitetssjukhuset,, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2006-03-14 Created: 2006-03-14 Last updated: 2009-10-15Bibliographically 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 NOD allele of the Idd5 locus on chromosome 1 mediates a non-cell-autonomous defect in negative selection of T cells.
Open this publication in new window or tab >>The NOD allele of the Idd5 locus on chromosome 1 mediates a non-cell-autonomous defect in negative selection of T cells.
2007 (English)In: Journal of Autoimmunity, ISSN 0896-8411, E-ISSN 1095-9157, Vol. 28, no 4, 216-223 p.Article in journal (Refereed) Published
Abstract [en]

Recent data have suggested that non-obese diabetic (NOD) mice display a defect in negative thymic selection. Using mixed bone marrow chimeras, we demonstrate that the NOD allele of the diabetes susceptibility region 5 (Idd5) locus on chromosome 1, confers defective negative selection in response to endogenous superantigens (SAg) Mtv8 and Mtv9. We generated mixed bone marrow (BM) chimeras in which the donor cells of NOD and C3H or NOD.Idd5(b10) and C3H coexist and are similarly exposed to the Mtv8 and Mtv9 SAg. Under these conditions, SAg-mediated deletion of Vbeta11+ T cells is less efficient in chimeric mice reconstituted with NOD+C3H BM, compared with chimeras reconstituted with NOD.Idd5(b10)+C3H BM. Interestingly, the observed discrepancy was not T cell autonomous but was found to be mediated by a BM derived cellular subset, and under control of a gene(s) in the Idd5 region.

Keyword
Alleles, Animals, Antigens; Viral/genetics/immunology, Bone Marrow/immunology, Chromosomes/*genetics/immunology, Diabetes Mellitus; Type 1/*genetics/immunology, Mice, Mice; Inbred NOD, Quantitative Trait Loci/genetics, Receptors; Antigen; T-Cell; alpha-beta, Species Specificity, Superantigens/genetics/immunology, T-Lymphocytes/immunology, Thymus Gland/immunology, Transplantation Chimera/genetics/immunology
Identifiers
urn:nbn:se:umu:diva-7759 (URN)10.1016/j.jaut.2007.03.001 (DOI)17449224 (PubMedID)
Available from: 2008-01-12 Created: 2008-01-12 Last updated: 2017-12-14Bibliographically approved
3. Preferential maturation of NOD T cells in the competitive environment of NODB6 embryo aggregation chimeric system
Open this publication in new window or tab >>Preferential maturation of NOD T cells in the competitive environment of NODB6 embryo aggregation chimeric system
(English)Manuscript (preprint) (Other academic)
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:umu:diva-4994 (URN)
Available from: 2006-03-14 Created: 2006-03-14 Last updated: 2012-06-29Bibliographically approved
4. The enlarged population of marginal zone/CD1d(high) B lymphocytes in nonobese diabetic mice maps to diabetes susceptibility region Idd11.
Open this publication in new window or tab >>The enlarged population of marginal zone/CD1d(high) B lymphocytes in nonobese diabetic mice maps to diabetes susceptibility region Idd11.
Show others...
2005 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 174, no 8, 4821-4827 p.Article in journal (Refereed) Published
Abstract [en]

The NOD mouse is an important experimental model for human type 1 diabetes. T cells are central to NOD pathogenesis, and their function in the autoimmune process of diabetes has been well studied. In contrast, although recognized as important players in disease induction, the role of B cells is not clearly understood. In this study we characterize different subpopulations of B cells and demonstrate that marginal zone (MZ) B cells are expanded 2- to 3-fold in NOD mice compared with nondiabetic C57BL/6 (B6) mice. The NOD MZ B cells displayed a normal surface marker profile and localized to the MZ region in the NOD spleen. Moreover, the MZ B cell population developed early during the ontogeny of NOD mice. By 3 wk of age, around the time when autoreactive T cells are first activated, a significant MZ B cell population of adult phenotype was found in NOD, but not B6, mice. Using an F2(B6 x NOD) cross in a genome-wide scan, we map the control of this trait to a region on chromosome 4 (logarithm of odds score, 4.4) which includes the Idd11 and Idd9 diabetes susceptibility loci, supporting the hypothesis that this B cell trait is related to the development of diabetes in the NOD mouse.

Keyword
Age Factors, Animals, Antigens; CD1/*metabolism, B-Lymphocyte Subsets/*immunology/pathology, Chromosome Mapping, Diabetes Mellitus; Type 1/*genetics/*immunology/pathology, Female, Humans, Male, Mice, Mice; Inbred C57BL, Mice; Inbred NOD/*genetics/*immunology, Phenotype, Spleen/immunology/pathology, T-Lymphocytes/immunology
Identifiers
urn:nbn:se:umu:diva-15262 (URN)15814708 (PubMedID)
Available from: 2008-01-11 Created: 2008-01-11 Last updated: 2017-12-14Bibliographically approved

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