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The enlarged population of marginal zone/CD1d(high) B lymphocytes in nonobese diabetic mice maps to diabetes susceptibility region Idd11.
Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Medicinsk och klinisk genetik.
Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Medicinsk och klinisk genetik.
Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Medicinsk och klinisk genetik.
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2005 (Engelska)Ingår i: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 174, nr 8, s. 4821-4827Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
2005. Vol. 174, nr 8, s. 4821-4827
Nyckelord [en]
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
Identifikatorer
URN: urn:nbn:se:umu:diva-15262PubMedID: 15814708OAI: oai:DiVA.org:umu-15262DiVA, id: diva2:154934
Tillgänglig från: 2008-01-11 Skapad: 2008-01-11 Senast uppdaterad: 2018-06-09Bibliografiskt granskad
Ingår i avhandling
1. The genetic basis of T and B cell contribution to autoimmune diabetes in NOD mice
Öppna denna publikation i ny flik eller fönster >>The genetic basis of T and B cell contribution to autoimmune diabetes in NOD mice
2006 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Umeå: Medicinsk biovetenskap, 2006. s. 108
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 1015
Nyckelord
Type 1 Diabetes, NOD mouse, CTLA-4, superantigen, T cells, Idd, marginal zone B cells, embryo aggregation chimera, negative selection
Nationell ämneskategori
Immunologi inom det medicinska området
Identifikatorer
urn:nbn:se:umu:diva-728 (URN)91-7264-006-5 (ISBN)
Disputation
2006-03-31, Betula, 6M, Norrlands Universitetssjukhuset,, Umeå, 09:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2006-03-14 Skapad: 2006-03-14 Senast uppdaterad: 2018-01-13Bibliografiskt granskad

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Lundholm, MarieHolmberg, Dan

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