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  • 1.
    Alanentalo, Tomas
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Asayesh, Amir
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Morrison, Harris
    Lorén, Christina E
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    Sharpe, James
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Tomographic molecular imaging and 3D quantification within adult mouse organs.2007In: Nature Methods, ISSN 1548-7091, E-ISSN 1548-7105, Vol. 4, no 1, p. 31-33Article in journal (Refereed)
  • 2.
    Alanentalo, Tomas
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Hörnblad, Andreas
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Mayans, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Nilsson, Anna Karin
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Sharpe, James
    Larefalk, Åsa
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Quantification and 3-D imaging of the insulitis-induced destruction of β-cells in murine type 1 diabetes2010In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 59, no 7, p. 1756-1764Article in journal (Refereed)
    Abstract [en]

    Objective: The aim of this study was to refine the information regarding the quantitative and spatial dynamics of infiltrating lymphocytes and remaining beta-cell volume during the progression of type 1 diabetes in the NOD mouse model of the disease.

    Research design and methods: Using an ex vivo technique, optical projection tomography (OPT), we quantified and assessed the 3D spatial development and progression of insulitis and beta-cell destruction in pancreas from diabetes prone NOD and non-diabetes prone congenic NOD.H-2b mice between 3 and 16 weeks of age.

    Results: Together with results showing the spatial dynamics of the insulitis process we provide data of beta-cell volume distributions down to the level of the individual islets and throughout the pancreas during the development and progression of type 1 diabetes. Our data provide evidence for a compensatory growth potential of the larger insulin(+) islets during the later stages of the disease around the time point for development of clinical diabetes. This is in contrast to smaller islets, which appear less resistant to the autoimmune attack. We also provide new information on the spatial dynamics of the insulitis process itself, including its apparently random distribution at onset, the local variations during its further development, and the formation of structures resembling tertiary lymphoid organs at later phases of insulitis progression.

    Conclusions: Our data provides a powerful tool for phenotypic analysis of genetic and environmental effects on type 1 diabetes etiology as well as for evaluating the potential effect of therapeutic regimes.

  • 3.
    Alanentalo, Tomas
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Lorén, Christina E
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Larefalk, Asa
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Sharpe, James
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    High-resolution three-dimensional imaging of islet-infiltrate interactions based on optical projection tomography assessments of the intact adult mouse pancreas2008In: Journal of Biomedical Optics, ISSN 1083-3668, E-ISSN 1560-2281, Vol. 13, no 5, p. 054070-Article in journal (Refereed)
    Abstract [en]

    A predicament when assessing the mechanisms underlying the pathogenesis of type-1 diabetes (T1D) has been to maintain simultaneous global and regional information on the loss of insulin-cell mass and the progression of insulitis. We present a procedure for high-resolution 3-D analyses of regions of interest (ROIs), defined on the basis of global assessments of the 3-D distribution, size, and shape of molecularly labeled structures within the full volume of the intact mouse pancreas. We apply a refined protocol for optical projection tomography (OPT)-aided whole pancreas imaging in combination with confocal laser scanning microscopy of site-directed pancreatic microbiopsies. As such, the methodology provides a useful tool for detailed cellular and molecular assessments of the autoimmune insulitis in T1D. It is anticipated that the same approach could be applied to other areas of research where 3-D molecular distributions of both global and regional character is required.

  • 4.
    Bergman, Marie-Louise
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Instituto Gulbenkian de Ciencia, Oeiras, Portugal.
    Cilio, Corrado M
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Endocrine Research Unit, Wallenberg Laboratory, Malmö University Hospital MAS, University of Lund, 205 02 Malmö Sweden.
    Penha-Gonçalves, Carlos
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Instituto Gulbenkian de Ciencia, Oeiras, Portugal.
    Lamhamedi-Cherradi, Salah-Eddine
    INSERM U25, Hopital Necker, Paris, France.
    Löfgren, Anna
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Colucci, Francesco
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Lejon, Kristina
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Garchon, Henri-Jean
    INSERM U25, Hopital Necker, Paris, France.
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Instituto Gulbenkian de Ciencia, Oeiras, Portugal.
    CTLA-4-/- mice display T cell-apoptosis resistance resembling that ascribed to autoimmune-prone non-obese diabetic (NOD) mice2001In: Journal of Autoimmunity, ISSN 0896-8411, E-ISSN 1095-9157, Vol. 16, no 2, p. 105-113Article in journal (Refereed)
    Abstract [en]

    The genes conferring susceptibility to autoimmune (insulin-dependent) diabetes mellitus (IDDM) are, in most cases, not defined. Among the loci so far identified as associated with murine IDDM (Idd1-19), only the nature of Idd1 has been assessed. Here we show that thymocytes and peripheral lymphocytes of the non-obese diabetic (NOD) mouse are relatively resistant to apoptosis induced by gamma-irradiation. By linkage analysis of F2 progeny mice, we map this trait to a locus on chromosome 1 containing the Idd5 diabetes susceptibility region. By the use of congenic mice, we confirm the linkage data and map this locus to a 6 cM region on proximal chromosome 1. Ctla4, being localized in this chromosomal region and mediating crucial functions in T cell biology, is a logical candidate gene in the Idd5 susceptibility region. In line with this, we demonstrate that T cells from Ctla4(-/-)deficient mice show a similar resistance to gamma-irradiation-induced apoptosis as observed in the NOD mice. This reinforces the notion that CTLA-4 contributes to the pathogenesis of autoimmune diabetes.

  • 5.
    Bergman, Marie-Louise
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Duarte, Nadia
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Instituto Gulbenkian de Ciencia, Oeiras, Portugal .
    Campino, Susana
    Instituto Gulbenkian de Ciencia, Oeiras, Portugal .
    Lundholm, Marie
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Motta, Vinicius
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Penha-Gonçalves, Carlos
    Instituto Gulbenkian de Ciencia, Oeiras, Portugal.
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Instituto Gulbenkian de Ciencia, Oeiras, Portugal.
    Diabetes protection and restoration of thymocyte apoptosis in NOD Idd6 congenic strains2003In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 52, no 7, p. 1677-1682Article in journal (Refereed)
    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.

  • 6.
    Bergman, Marie-Louise
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Penha-Gonçalves, Carlos
    Gulbenkian Institute for Science, Oeiras, Portugal, PT.
    Lejon, Kristina
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Low rate of proliferation in immature thymocytes of the non-obese diabetic mouse maps to the Idd6 diabetes susceptibility region2001In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 44, no 8, p. 1054-1061Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis: The non-obese diabetic (NOD) mouse spontaneously develops T-cell-dependent autoimmune diabetes. This mouse strain has a number of immune dysfunctions related to T-cell development but so far there are no available data on the proliferation of NOD immature thymocytes. We therefore studied the thymocyte proliferation in the NOD mouse in discrete stages of T-cell development.

    Methods: We depleted thymocytes in vivo and analysed thymocyte proliferation during the thymus recovery from depletion. We used co-segregation analysis and quantitative loci trait analysis to investigate the genetic control of proliferation impairments in NOD thymocytes.

    Results: Immature thymocytes of female NOD mice proliferate with a relatively low rate compared to non-autoimmune C57Bl/6 mice. This aberrant proliferation was most pronounced in CD4 /loCD8+ cells differentiating from the CD4CD8 to the CD4+CD8+ stage. A genetic mapping study using an F2 intercross between the NOD and the C57BL/6 strains showed that a major locus controlling this trait is linked to the insulin-dependent diabetes susceptibility locus Idd6.

    Conclusion/interpretation: Our results suggest that impairment of proliferation of immature thymocytes is one possible mechanism through which the Idd6 locus contributes to the pathogenesis of diabetes.

  • 7. Brauner, Hanna
    et al.
    Elemans, Marjet
    Lemos, Sara
    Broberger, Christian
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Flodström-Tullberg, Malin
    Kärre, Klas
    Höglund, Petter
    Distinct phenotype and function of NK cells in the pancreas of nonobese diabetic mice.2010In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 184, no 5, p. 2272-2280Article in journal (Refereed)
    Abstract [en]

    Little is known about target organ-infiltrating NK cells in type 1 diabetes and other autoimmune diseases. In this study, we identified NK cells with a unique phenotype in the pancreas of NOD mice. Pancreatic NK cells, localized to the endocrine and exocrine parts, were present before T cells during disease development and did not require T cells for their infiltration. Furthermore, NK cells, or NK cell precursors, from the spleen could traffic to the pancreas, where they displayed the pancreatic phenotype. Pancreatic NK cells from other mouse strains shared phenotypic characteristics with pancreatic NK cells from NOD mice, but displayed less surface killer cell lectin-like receptor G1, a marker for mature NK cells that have undergone proliferation, and also did not proliferate to the same extent. A subset of NOD mouse pancreatic NK cells produced IFN-gamma spontaneously, suggesting ongoing effector responses. However, most NOD mouse pancreatic NK cells were hyporesponsive compared with spleen NK cells, as reflected by diminished cytokine secretion and a lower capacity to degranulate. Interestingly, such hyporesponsiveness was not seen in pancreatic NK cells from the nonautoimmune strain C57BL/6, suggesting that this feature is not a general property of pancreatic NK cells. Based on our data, we propose that NK cells are sentinel cells in a normal pancreas. We further speculate that during inflammation, pancreatic NK cells initially mediate proinflammatory effector functions, potentially contributing to organ-specific autoimmunity, but later become hyporesponsive because of exhaustion or regulation.

  • 8. Calado, Dinis Pedro
    et al.
    Paixáo, Tiago
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    Haury, Matthias
    Stochastic monoallelic expression of IL-10 in T cells.2006In: J Immunol, ISSN 0022-1767, Vol. 177, no 8, p. 5358-64Article in journal (Refereed)
  • 9.
    Campino, S
    et al.
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    Bagot, S
    Bergman, M-L
    Almeida, P
    Sepúlveda, N
    Pied, S
    Penha-Goncalves, C
    Holmberg, D
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    Cazenave, P-A
    Genetic control of parasite clearance leads to resistance to Plasmodium berghei ANKA infection and confers immunity.2005In: Genes Immun, ISSN 1466-4879, Vol. 6, no 5, p. 416-21Article in journal (Refereed)
  • 10.
    Carlsson, Anna
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Nylander, P-O
    Hellman, Urban
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Forsman-Semb, Kristina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Holmgren, Gösta
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Holmberg, Monica
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Identification of a susceptibility locus for migraine with and without aura on 6p12.2-p21.1.2002In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 59, no 11, p. 1804-1807Article in journal (Refereed)
    Abstract [en]

    Migraine is the most common type of chronic episodic headache. To find novel susceptibility genes for familial migraine with and without aura, a genomewide screen was performed in a large family from northern Sweden. Evidence of linkage was obtained on chromosome 6p12.2-p21.1, with a maximum two-point lod score of 5.41 for marker D6S452. The patients with migraine shared a common haplotype of 10 Mb between markers D6S1650 and D6S1960.

  • 11.
    Cilio, Corrado M.
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Department of Paediatrics, University of Rome ‘La Sapienza’ Rome, Italy.
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Penha-Goncalves, Carlos
    Colucci, Francesco
    Bergman, Marie-Louise
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    How murine genetics can help to identify susceptibility genes in human disease1998In: Diabetes Metabolism Reviews, ISSN 0742-4221, E-ISSN 1099-0895, Vol. 14, no 2, p. 190-191Article in journal (Refereed)
  • 12. Cisse, Babacar
    et al.
    Caton, Michele L
    Lehner, Manfred
    Maeda, Takahiro
    Scheu, Stefanie
    Locksley, Richard
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    Zweier, Christiane
    den Hollander, Nicolette S
    Kant, Sarina G
    Holter, Wolfgang
    Rauch, Anita
    Zhuang, Yuan
    Reizis, Boris
    Transcription factor E2-2 is an essential and specific regulator of plasmacytoid dendritic cell development.2008In: Cell, ISSN 1097-4172, Vol. 135, no 1, p. 37-48Article in journal (Other academic)
  • 13.
    Colucci, Francesco
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). INSERM U429, Necker Hospital, Paris, France.
    Bergman, Marie-Louise
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Diabetes induction in C57BL/6 mice reconstituted with lymphocytes of nonobese diabetic C57BL/6 mouse embryo aggregation chimeras1998In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 48, no 6, p. 571-576Article in journal (Refereed)
    Abstract [en]

    To determine whether the genetic background of the insulin-producing beta cells of the pancreas contributes to autoimmune diabetes susceptibility, we have used a model of the disease based on transferring spleen cells from nonobese diabetic (NOD) <--> C57BL/6 (B6) embryo aggregation (EA) chimeras into B6 and NOD irradiated mice. Insulitis and diabetes could be induced into both B6 and NOD hosts, albeit with low incidence. Cyclophosphamide (CY) treatment, known to accelerate diabetes in prediabetic NOD mice, was found to increase diabetes incidence up to 50-60% in both B6 and NOD mice reconstituted with chimeric splenocytes, while diabetes did not occur in CY-treated B6 mice reconstituted with B6 splenocytes. We conclude that the genetic make-up of the target organ does not affect the final stage of the pathogenesis of insulin-dependent diabetes mellitus.

  • 14.
    Colucci, Francesco
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Bergman, Marie-Louise
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Penha-Gonçalves, Carlos
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Cilio, Corrado M.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Apoptosis resistance of nonobese diabetic peripheral lymphocytes linked to the Idd5 diabetes susceptibility region1997In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 94, no 16, p. 8670-8674Article in journal (Refereed)
    Abstract [en]

    Defects in lymphocyte apoptosis may lead to autoimmune disorders and contribute to the pathogenesis of type 1 diabetes. Lymphocytes of nonobese diabetic (NOD) mice, an animal model of autoimmune diabetes, have been found resistant to various apoptosis signals, including the alkylating drug cyclophosphamide. Using an F2 intercross between the apoptosis-resistant NOD mouse and the apoptosis-susceptible C57BL/6 mouse, we define a major locus controlling the apoptosis-resistance phenotype and demonstrate its linkage (logarithm of odds score = 3.9) to a group of medial markers on chromosome 1. The newly defined gene cannot be dissociated from Ctla4 and Cd28 and in fact marks a 20-centimorgan region encompassing Idd5, a previously postulated diabetes susceptibility locus. Interestingly, we find that the CTLA-4 (cytotoxic T lymphocyte-associated antigen 4) and the CD28 costimulatory molecules are defectively expressed in NOD mice, suggesting that one or both of these molecules may be involved in the control of apoptosis resistance and, in turn, in diabetes susceptibility.

  • 15.
    Colucci, Francesco
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Cilio, Corrado M.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Department of Pediatrics, University of Rome ‘La Sapienza’ Rome, Italy.
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Penha Gonçalves, Carlos
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Bergman, Marie-Louise
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Programmed cell death in the pathogenesis of murine IDDM: resistance to apoptosis induced in lymphocytes by cyclophosphamide1996In: Journal of Autoimmunity, ISSN 0896-8411, E-ISSN 1095-9157, Vol. 9, no 2, p. 271-276Article in journal (Refereed)
    Abstract [en]

    The non-obese diabetic (NOD) mouse displays several immune related defects, each of which could potentially contribute to the immunopathogenesis of diabetes that spontaneously develops in these mice. The reported resistance of NOD-lymphocytes to several apoptosis-inducing signals constitutes one such factor. Apoptosis plays a key role in the homeostasis of the immune system, as a means of selecting lymphocyte repertoires both in primary lymphoid organs and in the periphery; distortions in the apoptotic machinery may therefore be hypothesized to be implicated in the pathogenesis of autoimmune disorders. We now report that cyclophosphamide constitutes an apoptosis signal to peripheral lymphocytes and we provide evidence that NOD B cells as well as both CD4 and CD8 T cells display resistance to cyclophosphamide-induced apoptosis. These observations support the notion that apoptosis resistance in NOD mice exists at various levels, and suggest that the CY-sensitive lymphoid population, believed to play an important role in inhibiting the disease in diabetes resistant NOD mice (particularly males), may be controlled by mechanisms that are mediated by apoptosis.

  • 16.
    Colucci, Francesco
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Cilio, Corrado M.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Department of Paediatrics, University of Rome ‘La Sapienza’ Rome, Italy.
    Bergqvist, Ingela
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Matsunaga, Takeshi
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Induction of diabetes in NOD‹–›C57BL/6 embryo aggregation chimeras by cyclophosphamide through preferential depletion of C57BL/6 lymphocytes1996In: Journal of Autoimmunity, ISSN 0896-8411, E-ISSN 1095-9157, Vol. 9, no 4, p. 493-499Article in journal (Refereed)
    Abstract [en]

    The majority of embryo aggregation (EA) mouse chimeras between non-obese diabetic (NOD) mice and C57BL/6 (B6) mice show clear signs of insulitis frequently accompanied by beta-cell destruction. Less than 5% of these chimeras, however, spontaneously progress to autoimmune diabetes, an incidence far lower than observed in NOD mice. The resistance in chimeras can be accounted for by the target organ chimerism and/or the immune system chimerism. To investigate the mechanism(s) controlling diabetes resistance in these mice, we studied a total of 92 NOD<-->B6 EA chimeras that showed overt lymphoid chimerism and treated 34 chimeras with cyclophosphamide (CY), a compound known to precipitate an acute form of insulin-dependent diabetes mellitus (IDDM) in pre-diabetic NOD mice, by interfering with regulatory mechanisms. We found that CY-treated EA chimeras displayed an increase in the NOD:B6 lymphocyte ratio and 32% of them developed diabetes that could be adoptively transferred to irradiated NOD or NOD-rag-2-/- mice. These findings suggest that lymphocyte chimerism rather than beta-cell chimerism accounts for diabetes resistance in NOD<-->B6 EA chimeras and that the susceptibility to CY-induced diabetes may be related to the proportion of NOD versus B6 lymphoid cells.

  • 17.
    Duarte, Nadia
    et al.
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    Stenström, Martin
    Campino, Susana
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    Bergman, Marie-Louise
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    Lundholm, Marie
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    Cardell, Susanna L
    Prevention of diabetes in nonobese diabetic mice mediated by CD1d-restricted nonclassical NKT cells.2004In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 173, no 5, p. 3112-3118Article in journal (Refereed)
    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.

  • 18.
    Duarte, Nádia
    et al.
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics. Medicinsk och klinisk genetik. Umeå University, Faculty of Medicine, Medical Biosciences.
    Lundholm, Marie
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics. Medicinsk och klinisk genetik.
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics. Medicinsk och klinisk genetik.
    The Idd6.2 diabetes susceptibility region controls defective expression of the Lrmp gene in nonobese diabetic (NOD) mice2007In: Immunogenetics, ISSN 0093-7711, E-ISSN 1432-1211, Vol. 59, no 5, p. 407-416Article in journal (Refereed)
    Abstract [en]

    The identification of genes mediating susceptibility to type 1 diabetes (T1D) remains a challenging task. Using a positional cloning approach based on the analysis of nonobese diabetic (NOD) mice congenic over the Idd6 diabetes susceptibility region, we found that the NOD allele at this locus mediates lower mRNA expression levels of the lymphoid restricted membrane protein gene (Lrmp/Jaw1). Analysis of thymic populations indicates that Lrmp is expressed mainly in immature thymocytes. The Lrmp gene encodes a type 1 transmembrane protein that localizes to the ER membrane and has homology to the inositol 1,4,5-triphosphate receptor-associated cGMP kinase substrate gene, which negatively regulates intracellular calcium levels. We hypothesize that the observed decrease in expression of the Lrmp gene in NOD mice may constitute a T1D susceptibility factor in the Idd6 region.

  • 19.
    Einarsdottir, Elisabet
    et al.
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    Carlsson, Anna
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    Minde, Jan
    Toolanen, Göran
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Orthopaedics.
    Svensson, Olle
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Orthopaedics.
    Solders, Göran
    Holmgren, Gösta
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    Holmberg, Monica
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    A mutation in the nerve growth factor beta gene (NGFB) causes loss of pain perception.2004In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 13, no 8, p. 799-805Article in journal (Refereed)
    Abstract [en]

    Identification of genes associated with pain insensitivity syndromes can increase the understanding of the pathways involved in pain and contribute to the understanding of how sensory pathways relate to other neurological functions. In this report we describe the mapping and identification of the gene responsible for loss of deep pain perception in a large family from northern Sweden. The loss of pain perception in this family is characterized by impairment in the sensing of deep pain and temperature but with normal mental abilities and with most other neurological responses intact. A severe reduction of unmyelinated nerve fibers and a moderate loss of thin myelinated nerve fibers are observed in the patients. Thus the cases in this study fall into the class of patients with loss of pain perception with underlying peripheral neuropathy. Clinically they best fit into HSAN V. Using a model of recessive inheritance we identified an 8.3 Mb region on chromosome 1p11.2-p13.2 shared by the affected individuals in the family. Analysis of functional candidate genes in the disease critical region revealed a mutation in the coding region of the nerve growth-factor beta (NGFB) gene specific for the disease haplotype. This NGF mutation seems to separate the effects of NGF involved in development of central nervous system functions such as mental abilities, from those involved in peripheral pain pathways. This mutation could therefore potentially provide an important tool to study different roles of NGF, and of pain control.

  • 20.
    Einarsdottir, Elisabet
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics. Medicinsk och klinisk genetik.
    Mayans, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics. Medicinsk och klinisk genetik.
    Ruikka, Karin
    Andersson Escher, Stefan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics. Medicinsk och klinisk genetik.
    Lindgren, Petter
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics. Medicinsk och klinisk genetik.
    Ågren, Åsa
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Näringsforskning.
    Eliasson, Mats
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics. Medicinsk och klinisk genetik.
    Linkage but not association of calpain-10 to type 2 diabetes replicated in northern Sweden2006In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 55, no 6, p. 1879-1883Article in journal (Refereed)
  • 21.
    Einarsdottir, Elisabet
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Söderström, Ingegerd
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Löfgren-Burström, Anna
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Unit for Genome Research, Umeå University.
    Haraldsson, Susann
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Unit for Genome Research, Umeå University.
    Nilsson-Ardnor, Sofie
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Unit for Genome Research, Umeå University.
    Penha-Goncalves, Carlos
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Gulbenkian Institute for Science, Oeiras, Portugal.
    Lind, Lisbet
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics. Unit for Genome Research, Umeå University.
    Holmgren, Gösta
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Holmberg, Monica
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Asplund, Kjell
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Unit for Genome Research.
    The CTLA4 region as a general autoimmunity factor: an extended pedigree provides evidence for synergy with the HLA locus in the etiology of type 1 diabetes mellitus, Hashimoto's thyroiditis and Graves' disease2003In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 11, no 1, p. 81-84Article in journal (Refereed)
    Abstract [en]

    We have identified a large family in the northern part of Sweden with multiple cases of autoimmune diseases, namely type 1 diabetes (T1D), Graves' disease (GD) and Hashimoto's thyroiditis (HT). The family members affected by any of these diseases share a region of 2.4 Mb that comprises among others the CTLA4 gene. We determined that all affected members of the family shared the HLA susceptibility haplotype (DR4-DQA1*0301-DQB1*0302). Analysis of genetic interaction conditioning for HLA haplotype provided strong evidence that the critical region which includes the CTLA4 gene acts together with the HLA locus on the etiology of disease (lodscore 4.20 (theta=0.0). The study of this family allowed us to: (1) reinforce a number of reports on linkage and association of the CTLA4 region to T1D and AITD; (2) demonstrate that a single haplotypic variant in this region constitutes an etiological factor to disease susceptibility in T1D, GD and HT; (3) reveal a strong genetic interaction of the CTLA4 and HLA loci in the genetic architecture of autoimmune disease; (4) emphasise the value of large pedigrees drawn from isolated populations as tools to single out the effect of individual loci in the etiology of complex diseases.

  • 22.
    Eriksson, Björn
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Johansson, Ann-Sofie
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Levan, Göran
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Establishment and characterization of a mouse strain (TLL) that spontaneously develops T-cell lymphomas/leukemia1999In: Experimental Hematology, ISSN 0301-472X, E-ISSN 1873-2399, Vol. 27, no 4, p. 682-688Article in journal (Refereed)
    Abstract [en]

    In this study, a mouse strain (TLL) that spontaneously develops T-cell lymphomas/leukemia with an early onset and high incidence was established and characterized. All tumors analyzed were found to express the alpha,beta T-cell receptor, and the majority of them had a mature, CD3+CD4+CD8- immunophenotype. In a few cases, tumors with a more immature CD3+CD4+CD8+ phenotype were isolated. Expanded phenotyping using a broad panel of lymphocyte differentiation markers confirmed the mature T-cell phenotype of the tumors. Histologic and cell cycle analysis of the tumors revealed an aggressive lymphoblastic malignancy with a very high proliferation rate and widespread engagement of bone marrow and lymphoid as well as nonlymphoid organs. Thus, the TLL mouse strain represents a unique model for the analysis of the oncogenesis and progression of mature T-cell tumors and for the development of therapeutic measures to combat such tumors.

  • 23. Fransen-Pettersson, Nina
    et al.
    Duarte, Nadia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics. nstituto Gulbenkian de Sciencia, Oeiras, 2780–156 Oeiras, Portugal.
    Nilsson, Julia
    Lundholm, Marie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Mayans, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Larefalk, Åsa
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Hannibal, Tine D.
    Hansen, Lisbeth
    Schmidt-Christensen, Anja
    Ivars, Fredrik
    Cardell, Susanna
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Rozell, Bjoern
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics. EMV Immunology, BMC, Lund University, Lund, Sweden; ISIM- Immunology, Faculty of Health and Medical Sciences, Copenhagen University, Copenhagen, Denmark.
    A New Mouse Model That Spontaneously Develops Chronic Liver Inflammation and Fibrosis2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 7, article id e0159850Article in journal (Refereed)
    Abstract [en]

    Here we characterize a new animal model that spontaneously develops chronic inflammation and fibrosis in multiple organs, the non-obese diabetic inflammation and fibrosis (N-IF) mouse. In the liver, the N-IF mouse displays inflammation and fibrosis particularly evident around portal tracts and central veins and accompanied with evidence of abnormal intrahepatic bile ducts. The extensive cellular infiltration consists mainly of macrophages, granulocytes, particularly eosinophils, and mast cells. This inflammatory syndrome is mediated by a transgenic population of natural killer T cells (NKT) induced in an immunodeficient NOD genetic background. The disease is transferrable to immunodeficient recipients, while polyclonal T cells from unaffected syngeneic donors can inhibit the disease phenotype. Because of the fibrotic component, early on-set, spontaneous nature and reproducibility, this novel mouse model provides a unique tool to gain further insight into the underlying mechanisms mediating transformation of chronic inflammation into fibrosis and to evaluate intervention protocols for treating conditions of fibrotic disorders.

  • 24.
    Hillörn, Valter
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Söderström, Ingegerd
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Feld, Sari
    Cilio, Corrado
    Forsgren, Stina
    Hägg, Erik
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Lundkvist, inger
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Aberrant VHGene Utilization in Patients with Established Insulin-Dependent Diabetes Mellitus1997In: Journal of Autoimmunity, ISSN 0896-8411, E-ISSN 1095-9157, Vol. 10, no 2, p. 157-163Article in journal (Refereed)
    Abstract [en]

    We have compared the B-lymphocyte repertoire in seven IDDM patients with 12 healthy controls by examining the variable heavy (VH) gene expression. The VHgene representation in the pool of pokeweed mitogen (PWM) stimulated, immunocompetent B cells and in the pool of naturally activated plasma cells (actual repertoire) was analysed by RNA-RNA in situ hybridization. Differences between IDDM patients and normal controls in the relative expression of several VHgene families were observed. In IDDM patients, the VH3 was significantly underrepresented in the PWM stimulated repertoire. In the actual B cell repertoire the VH5 clones were underrepresented among diabetic patients. Moreover, the altered distribution of VHgene usage between the PWM stimulated repertoire and the actual repertoire observed in normal controls was found to be less pronounced in the IDDM patients. This observation suggests a defect in the V-gene directed cellular selection occurring between resting, immunocompetent B cells and naturally activated plasma cells. The possible implication of the observed aberrations in the B cell selection process for the pathogenesis of autoimmunity is discussed.

  • 25.
    Holmberg, Dan
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Imaging the pancreas: from ex vivo to non-invasive technology.2008In: Diabetologia, ISSN 0012-186X, Vol. 51, no 12, p. 2148-2154Article in journal (Other academic)
  • 26.
    Holmberg, Dan
    et al.
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    Cilio, Corrado M
    Lundholm, Marie
    Motta, Vinicius
    CTLA-4 (CD152) and its involvement in autoimmune disease.2005In: Autoimmunity, ISSN 0891-6934, Vol. 38, no 3, p. 225-33Article in journal (Other academic)
  • 27.
    Holmberg, Dan
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics. EMV, Immunology, BMC, Lund University, SE-221 00 Lund, Sweden.
    Ruikka, Karin
    Department of Medicine, Sunderby Hospital, SE-971 80 Luleå, Sweden.
    Lindgren, Petter
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Eliasson, Mats
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Department of Medicine, Sunderby Hospital, SE-971 80 Luleå, Sweden.
    Mayans, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Association of CD247 (CD3ζ) gene polymorphisms with T1D and AITD in the population of northern Sweden2016In: BMC Medical Genetics, ISSN 1471-2350, E-ISSN 1471-2350, Vol. 17, no 1, article id 70Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: T1D and AITD are autoimmune disorders commonly occurring in the same family and even in the same individual. The genetic contribution to these disorders is complex making uncovering of susceptibility genes very challenging. The general aim of this study was to identify loci and genes contributing to T1D/AITD susceptibility. Our strategy was to perform linkage and association studies in the relatively genetically homogenous population of northern Sweden. We performed a GWLS to find genomic regions linked to T1D/AITD in families from northern Sweden and we performed an association study in the families to test for association between T1D/AITD and variants in previously published candidate genes as well as a novel candidate gene, CD247.

    METHODS: DNA prepared from 459 individuals was used to perform a linkage and an association study. The ABI PRISM Linkage Mapping Set v2.5MD10 was employed for an initial 10-cM GWLS, and additional markers were added for fine mapping. Merlin was used for linkage calculations. For the association analysis, a GoldenGate Custom Panel from Illumina containing 79 SNPs of interest was used and FBAT was used for association calculations.

    RESULTS: Our study revealed linkage to two previously identified chromosomal regions, 4q25 and 6p22, as well as to a novel chromosomal region, 1q23. The association study replicated association to PTPN22, HLA-DRB1, INS, IFIH1, CTLA4 and C12orf30. Evidence in favor of association was also found for SNPs in the novel susceptibility gene CD247.

    CONCLUSIONS: Several risk loci for T1D/AITD identified in published association studies were replicated in a family material, of modest size, from northern Sweden. This provides evidence that these loci confer disease susceptibility in this population and emphasizes that small to intermediate sized family studies in this population can be used in a cost-effective manner for the search of genes involved in complex diseases. The linkage study revealed a chromosomal region in which a novel T1D/AITD susceptibility gene, CD247, is located. The association study showed association between T1D/AITD and several variants in this gene. These results suggests that common susceptibility genes act in concert with variants of CD247 to generate genetic risk for T1D/AITD in this population

  • 28.
    Johansson, Ann-Sofie
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Eriksson, Maria
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Norén-Nyström, Ulrika
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Larefalk, Åsa
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Eriksson, Björn
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Vierimaa, O
    Aittomaki, K
    Pukkala, E
    Launonen, V
    Aaltonen, L A
    Germ line insertions of moloney murine leukemia virus in the TLL mouse causes site-specific differences in lymphoma/leukemia frequency and tumor immunophenotype2006In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 26, no 4B, p. 2873-2878Article in journal (Refereed)
    Abstract [en]

    Background: Moloney murine leukemia virus (Mo-MLV) has proven valuable for studies of the pathogenesis of malignant lymphoma. Inoculation of newborn mice induces T cell lymphoma with 100% incidence. The TLL (T cell lymphoma/leukemia)-strain was previously established and was shown to spontaneously develop T cell lymphoma at high frequency.

    Materials and Methods: Differential screening of cDNA libraries was performed to discover an involvement of Mo-MLV and genomic sequencing was used to identify the chromosomal position of Mo-MLV proviral integration sites. Immunophenotypes of the tumors were established by flow cytometry. Disease frequency curves were created according to the Kaplan-Meier method.

    Results: Two independent Mo-MLV germ line integrations were characterized on chromosomes 2 and 14, giving rise to two substrains of mice denoted TLL-2 and TLL-14. The chromosomal position of the integrated provirus affected the frequency of disease, as well as the immunophenotype of the tumors.

    Conclusion: The data suggest that factors influencing the transcriptional activity of the chromosomal regions, leading to differences in proviral expression, could underlie the observed difference in tumor frequency.

  • 29.
    Johansson, Ann-Sofie
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Norén-Nyström, Ulrika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Larefalk, Åsa
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Lindskog, Magnus
    Fish oil delays lymphoma progression in the TLL mouse2010In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 51, no 11, p. 2092-2097Article in journal (Refereed)
    Abstract [en]

    The objective was to investigate the effects of omega-3 fatty acids, known for their anti-inflammatory effects, on time to lymphoma progression and survival in the TLL mouse, a strain genetically prone to developing aggressive T-cell lymphoma. Compared to mice fed a standard diet, TLL mice fed omega-3 (menhaden fish oil) experienced a significant delay in disease progression and were more likely to remain alive and symptom free during the first 8 months of the study. In contrast, omega-6 supplementation (corn oil) did not significantly affect lymphoma progression. Irrespective of diet, all mice eventually progressed, and 1-year survival was not different between the groups. Immunological analysis demonstrated a significantly altered B-cell compartment and fewer NK cells in healthy C57Black6 mice fed omega-3, compared to controls. In conclusion, a diet rich in omega-3 fatty acids delays lymphoma development in the TLL mouse possibly by mechanisms that include complex effects on immune function.

  • 30.
    Johansson, Ann-Sofie
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics. Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Pawelzik, Sven-Christian
    Department of Medicine, Rheumatology Unit and Karolinska Biomics Centre, Karolinska Institutet, Stockholm, Sweden.
    Larefalk, Åsa
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Jakobsson, Per-Johan
    Department of Medicine, Rheumatology Unit and Karolinska Biomics Centre, Karolinska Institutet, Stockholm, Sweden.
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Lindskog, Magnus
    Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.
    Lymphoblastic T-cell lymphoma in mice is unaffected by Celecoxib as single agent or in combination with cyclophosphamide2009In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 50, no 7, p. 1198-1203Article in journal (Refereed)
    Abstract [en]

    Celecoxib, an inhibitor of cyclooxygenase-2, is a promising novel antitumor agent with pleitropic mechanisms of action. Whereas this drug induces growth arrest and apoptosis of B-lymphoma cells, its effect against aggressive T-cell neoplasms remains to be studied. We therefore evaluated Celecoxib therapy of immunocompetent mice transplanted with lymphoblastic T-cell lymphomas. Oral Celecoxib in clinically relevant and non-toxic doses did not affect the degree of hypersplenism or the number of viable lymphoma cells. The clinical deterioration of Celecoxib-treated mice was not different from untreated controls. The impact of adding Celecoxib (60 mg/kg) to cyclophosphamide (200 mg/kg x 1, i.p.) was assessed but showed no benefit compared to cyclophosphamide alone. Thus, Celecoxib lacks effect against lymphoblastic T-cell lymphoma in mice.

  • 31. Kadri, Nadir
    et al.
    Korpos, Eva
    Gupta, Shashank
    Briet, Claire
    Löfbom, Linda
    Yagita, Hideo
    Lehuen, Agnes
    Boitard, Christian
    Holmberg, Dan
    Department of Disease Biology, Faculty of Life Science, University of Copenhagen.
    Sorokin, Lydia
    Cardell, Susanna L
    CD4(+) type II NKT cells mediate ICOS and programmed death-1-dependent regulation of type 1 diabetes2012In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 188, no 7, p. 3138-3149Article in journal (Refereed)
    Abstract [en]

    Type 1 diabetes (T1D) is a chronic autoimmune disease that results from T cell-mediated destruction of pancreatic β cells. CD1d-restricted NKT lymphocytes have the ability to regulate immunity, including autoimmunity. We previously demonstrated that CD1d-restricted type II NKT cells, which carry diverse TCRs, prevented T1D in the NOD mouse model for the human disease. In this study, we show that CD4(+) 24αβ type II NKT cells, but not CD4/CD8 double-negative NKT cells, were sufficient to downregulate diabetogenic CD4(+) BDC2.5 NOD T cells in adoptive transfer experiments. CD4(+) 24αβ NKT cells exhibited a memory phenotype including high ICOS expression, increased cytokine production, and limited display of NK cell markers, compared with double-negative 24αβ NKT cells. Blocking of ICOS or the programmed death-1/programmed death ligand 1 pathway was shown to abolish the regulation that occurred in the pancreas draining lymph nodes. To our knowledge, these results provide for the first time cellular and molecular information on how type II CD1d-restricted NKT cells regulate T1D.

  • 32. Kalis, Martins
    et al.
    Bolmeson, Caroline
    Esguerra, Jonathan LS
    Gupta, Shashank
    Edlund, Anna
    Tormo-Badia, Neivis
    Speidel, Dina
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Mayans, Sofia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Khoo, Nelson KS
    Wendt, Anna
    Eliasson, Lena
    Cilio, Corrado M
    Beta-cell specific deletion of dicer1 leads to defective insulin secretion and diabetes mellitus2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 12, p. e29166-Article in journal (Refereed)
    Abstract [en]

    Mature microRNAs (miRNAs), derived through cleavage of pre-miRNAs by the Dicer1 enzyme, regulate protein expression in many cell-types including cells in the pancreatic islets of Langerhans. To investigate the importance of miRNAs in mouse insulin secreting beta-cells, we have generated mice with a beta-cells specific disruption of the Dicer1 gene using the Cre-lox system controlled by the rat insulin promoter (RIP). In contrast to their normoglycaemic control littermates (RIP-Cre(+/-) Dicer1(Delta/wt)), RIP-Cre(+/-) Dicer1(flox/flox) mice (RIP-Cre Dicer1(Delta/Delta)) developed progressive hyperglycaemia and full-blown diabetes mellitus in adulthood that recapitulated the natural history of the spontaneous disease in mice. Reduced insulin gene expression and concomitant reduced insulin secretion preceded the hyperglycaemic state and diabetes development. Immunohistochemical, flow cytometric and ultrastructural analyses revealed altered islet morphology, marked decreased beta-cell mass, reduced numbers of granules within the beta-cells and reduced granule docking in adult RIP-Cre Dicer1(Delta/Delta) mice. beta-cell specific Dicer1 deletion did not appear to disrupt fetal and neonatal beta-cell development as 2-week old RIP-Cre Dicer1(Delta/Delta) mice showed ultrastructurally normal beta-cells and intact insulin secretion. In conclusion, we have demonstrated that a beta-cell specific disruption of the miRNAs network, although allowing for apparently normal beta-cell development, leads to progressive impairment of insulin secretion, glucose homeostasis and diabetes development.

  • 33.
    Korpos, E.
    et al.
    Institute of Physiological Chemistry, University of Muenster, Muenster, Germany.
    Kadri, N.
    Goeteborg University, Goeteborg, Sweden.
    Holmberg, D.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Cardell, S.
    Goeteborg University, Goeteborg, Sweden.
    Sorokin, L.
    Institute of Physiological Chemistry, University of Muenster, Muenster, Germany.
    The Role of the Extracellular Matrix in Leukocyte Infiltration into the Pancreas of Non Obese Diabetic Mice2011In: European Society for Microcirculation (ESM): German Society of Microcirculation and Vascular Biology (GfMVB)Munich, Germany, Berlin: Karger , 2011, Vol. 48, p. 334-334Conference paper (Refereed)
  • 34. Lahermo, P
    et al.
    Liljedahl, Ulrika
    Alnaes, Grethe
    Axelsson, Tomas
    Brookes, Anthony J
    Ellonen, Pekka
    Groop, Per-Henrik
    Halldén, Christer
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    Holmberg, Kristina
    Keinänen, Mauri
    Kepp, Katrin
    Kere, Juha
    Kiviluoma, P
    Kristensen, Vessela
    Lindgren, Cecilia
    Odeberg, Jacob
    Osterman, Pia
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Parkkonen, Maija
    Saarela, Janna
    Sterner, Maria
    Strömqvist, Linda
    Talas, Ulvi
    Wessman, Maija
    Palotie, Aarno
    Syvänen, Ann-Christine
    A quality assessment survey of SNP genotyping laboratories2006In: Human mutation, ISSN 1098-1004, Vol. 27, no 7, p. 711-714Article in journal (Refereed)
  • 35.
    Leijon, Kristina
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Freitas, A
    Unite d'lmmunobiologie, lnsritut Pasteur, Paris, France.
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Analysis of VH gene utilisation in the non-obese diabetic mouse1993In: Autoimmunity, ISSN 0891-6934, E-ISSN 1607-842X, Vol. 15, no 1, p. 11-18Article in journal (Refereed)
    Abstract [en]

    The immunoglobulin (Ig) heavy chain variable (VH) gene complexity and the VH gene utilisation pattern of the non-obese diabetic (NOD) mouse were investigated. We found that the NOD mouse displays a VH gene complexity which appears to be identical to that of the C57BL/6 mouse. Thus, Southern hybridisation using probes specific for 9 of the murine VH gene families revealed identical restriction fragment length polymorphism (RFLP) patterns in both mouse strains. As indicated by immunofluorescence analysis using allotype specific monoclonal antibodies the NOD mice were also found to carry the IgCH-1b allele. Collectively, these data suggest that the NOD mice carry an IgVH locus identical to that carried by C57BL/6. In contrast to the apparent identity at the level of germline VH gene repertoires, the pattern of VH gene utilisation differed considerably between these two mouse strains. Thus, in NOD mice the neonatal preference of D-proximal VH genes was found to be more pronounced than in C57BL/6 mice. Moreover, in contrast to adult C57BL/6 mice a D-proximal bias was evident also in adult NOD mice. On the basis of these findings we discuss the possibility that the distorted development of B cell repertoires in the NOD mouse could be directly or indirectly related to the T cell mediated, autoimmune process in the NOD mouse.

  • 36.
    Leijon, Kristina
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Hammarström, Barbro
    SYMBICOM, Box 1451, S-901 24 Umeå, Sweden.
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Non-obese diabetic (NOD) mice display enhanced immune responses and prolonged survival of lymphoid cells1994In: International Immunology, ISSN 0953-8178, E-ISSN 1460-2377, Vol. 6, no 2, p. 339-345Article in journal (Refereed)
    Abstract [en]

    We report that lymphoid cells originating from the non-obese diabetic (NOD) autoimmune prone mouse strain are resistant to several signals known to induce programmed cell death. In vitro culturing of lymphoid cells of splenic or lymph node origin showed that B cells and T cells of both CD4+ and CD8+ phenotypes from NOD mice display extended survival in vitro. By cytofluorimetric analysis, immature CD4+ CD8+ NOD thymocytes were shown to partially resist in vivo treatment with corticosteroids. Finally, immunization with protein antigens induced enhanced and prolonged immune responses in NOD mice compared with normal C57BL/6, BALB/c, and C3H/Tif control mice. We conclude that the NOD mouse displays a defect in the mechanism(s) mediating programmed cell death in T and B lymphocytes. These findings provide a novel explanation for the B cell aberrations observed in the NOD mouse and may have implications for the understanding of the autoimmune pathogenesis in this mouse strain.

  • 37.
    Leijon, Kristina
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Hillörn, Valter
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Bergqvist, Ingela
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Specific destruction of islet transplants in NOD‹–›C57BL/6 and NOD‹–›C3H/Tif embryo aggregation chimeras irrespective of allelic differences in beta-cell antigens1995In: Journal of Autoimmunity, ISSN 0896-8411, E-ISSN 1095-9157, Vol. 8, no 3, p. 347-356Article in journal (Refereed)
    Abstract [en]

    We have tested the hypothesis that allelic differences in the antigens expressed by the beta-cells of the islets of Langerhans influence the development of insulitis in the non-obese diabetic (NOD) mouse. Islets of Langerhans from NOD, C57BL/6 and C3H/Tif mice were transplanted under the kidney capsule of NOD<-->C57BL/6 and NOD<-->C3H/Tif embryo aggregation (EA) chimeras and the infiltration was scored 5-7 weeks later. Mononuclear cell infiltration of pancreatic islets was observed in 60% of the NOD<-->C57BL/6 and in 55% of the NOD<-->C3H/Tif EA chimeras. All transplanted EA chimeras that developed insulitis also displayed mononuclear cell infiltrates in the transplants, irrespective of the origin of the transplanted islets. In contrast, no infiltration of transplants was detected in EA chimeras scoring negative for insulitis. These results demonstrate that the specific destruction of islet transplants does not require the expression of NOD specific antigens by the islets. Moreover, the beta-cell destruction appears not to be restricted to NOD-MHC. The correlation between insulitis and transplant beta-cell destruction suggests the possibility that the development of insulitis is a prerequisite for transplant specific destruction. MHC restricted destruction may, therefore, precede the beta-cell destruction of transplanted islets. The chimerism among the mononuclear cells infiltrating the islet transplants was found to correlate with the overall haematopoetic chimerism in each of the individual EA chimeras. This observation suggests that NOD bone marrow, as well as non-NOD bone marrow, generates cells contributing to the beta-cell destruction process.

  • 38.
    Lundholm, Marie
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Mayans, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics. Univ Copenhagen, Dept Dis Biol, Fac Life Sci, DK-1870 Copenhagen C, Denmark.
    Motta, Vinicius
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics. Univ Toronto, Dept Immunol, Toronto, ON, Canada.
    Löfgren-Burström, Anna
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Danska, Jayne
    Univ Toronto, Dept Immunol, Toronto, ON, Canada.
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics. Univ Copenhagen, Dept Dis Biol, Fac Life Sci, DK-1870 Copenhagen C, Denmark.
    Variation in the Cd3 zeta (Cd247) gene correlates with altered T cell activation and is associated with autoimmune diabetes.2010In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 184, no 10, p. 5537-5544Article in journal (Refereed)
    Abstract [en]

    Tuning of TCR-mediated activation was demonstrated to be critical for lineage fate in T cell development, as well as in the control of autoimmunity. In this study, we identify a novel diabetes susceptibility gene, Idd28, in the NOD mouse and provide evidence that Cd3zeta (Cd247) constitutes a prime candidate gene for this locus. Moreover, we show that the allele of the Cd3zeta gene expressed in NOD and DBA/2 mouse strains confers lower levels of T cell activation compared with the allele expressed by C57BL/6 (B6), BALB/c, and C3H/HeJ mice. These results support a model in which the development of autoimmune diabetes is dependent on a TCR signal mediated by a less-efficient NOD allele of the Cd3zeta gene.

  • 39.
    Lundholm, Marie
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Mayans, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Motta, Vinicius
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Löfgren-Burström, Anna
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    The non-obese diabetic (NOD) mouse allele of Cd3ζ (Cd247) is associated with impaired TCR/CD3 mediated activation of T cellsManuscript (Other academic)
  • 40.
    Lundholm, Marie
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Motta, Vinicius
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Löfgren-Burström, Anna
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Duarte, Nadia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Bergman, Marie-Louise
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Mayans, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    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 12006In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 55, no 2, p. 538-544Article in journal (Refereed)
    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.

  • 41.
    Malmer, Beatrice
    et al.
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Haraldsson, Susann
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    Einarsdottir, Elisabet
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    Lindgren, Petter
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    Homozygosity mapping of familial glioma in Northern Sweden2005In: Acta Oncol, ISSN 0284-186X, Vol. 44, no 2, p. 114-119Article in journal (Refereed)
  • 42.
    Mayans, Sofia
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Lackovic, Kurt
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Lindgren, Petter
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Ruikka, Karin
    Department of Medicine, Sunderby Hospital, Luleå.
    Ågren, Åsa
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Eliasson, Mats
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Department of Medicine, Sunderby Hospital, Luleå.
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics. Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    TCF7L2 polymorphisms are associated with type 2 diabetes in northern Sweden2007In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 15, no 3, p. 342-346Article in journal (Refereed)
    Abstract [en]

    A recent study found association of one microsatellite and five single nucleotide polymorphisms (SNPs) in intron 3 of the TCF7L2 gene with type 2 diabetes (T2D) in the Icelandic, Danish and American populations. The aim of the present study was to investigate if those SNPs were associated to T2D in two (family- and population-based) cohorts from northern Sweden. We genotyped four of the associated SNPs in a case-control cohort consisting of 872 T2D cases and 857 controls matched with respect to age, sex and geographical origin and in a sample of 59 extended families (148 affected and 83 unaffected individuals). Here, we report replication of association between T2D and three SNPs in the case-control (rs7901695, P=0.003; rs7901346, P=0.00002; and rs12255372, P=0.000004) and two SNPs in the family-based (rs7901695, P=0.01 and rs7901346, P=0.04) samples from northern Sweden. This replication strengthens the evidence for involvement of TCF7L2 in T2D.

  • 43.
    Mayans, Sofia
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics. Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Lackovic, Kurt
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Nyholm, Caroline
    Lindgren, Petter
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Ruikka, Karin
    Eliasson, Mats
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Cilio, Corrado M
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    CT60 genotype does not affect CTLA-4 isoform expression despite association to T1D and AITD in northern Sweden2007In: BMC Medical Genetics, ISSN 1471-2350, E-ISSN 1471-2350, Vol. 8, article id 3Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Polymorphisms in and around the CTLA-4 gene have previously been associated to T1D and AITD in several populations. One such single nucleotide polymorphism (SNP), CT60, has been reported to affect the expression level ratio of the soluble (sCTLA-4) to full length CTLA-4 (flCTLA-4) isoforms. The aims of our study were to replicate the association previously published by Ueda et al. of polymorphisms in the CTLA-4 region to T1D and AITD and to determine whether the CT60 polymorphism affects the expression level ratio of sCTLA-4/flCTLA-4 in our population.

    METHODS: Three SNPs were genotyped in 253 cases (104 AITD cases and 149 T1D cases) and 865 ethnically matched controls. Blood from 23 healthy individuals was used to quantify mRNA expression of CTLA-4 isoforms in CD4+ cells using real-time PCR. Serum from 102 cases and 59 healthy individuals was used to determine the level of sCTLA-4 protein.

    RESULTS: Here we show association of the MH30, CT60 and JO31 polymorphisms to T1D and AITD in northern Sweden. We also observed a higher frequency of the CT60 disease susceptible allele in our controls compared to the British, Italian and Dutch populations, which might contribute to the high frequency of T1D in Sweden. In contrast to previously published findings, however, we were unable to find differences in the sCTLA-4/flCTLA-4 expression ratio based on the CT60 genotype in 23 healthy volunteers, also from northern Sweden. Analysis of sCTLA-4 protein levels in serum showed no correlation between sCTLA-4 protein levels and disease status or CT60 genotype.

    CONCLUSION: Association was found between T1D/AITD and all three polymorphisms investigated. However, in contrast to previous investigations, sCTLA-4 RNA and protein expression levels did not differ based on CT60 genotype. Our results do not rule out the CT60 SNP as an important polymorphism in the development of T1D or AITD, but suggest that further investigations are necessary to elucidate the effect of the CTLA-4 region on the development of T1D and AITD.

  • 44.
    Motta, Vinicius
    et al.
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Clinical Microbiology, Immunology/Immunchemistry.
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    The NOD allele of the Idd5 locus on chromosome 1 mediates a non-cell-autonomous defect in negative selection of T cells.2007In: Journal of Autoimmunity, ISSN 0896-8411, E-ISSN 1095-9157, Vol. 28, no 4, p. 216-223Article in journal (Refereed)
    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.

  • 45.
    Nilsson-Ardnor, Sofie
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Janunger, Tomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Wiklund, Per-Gunnar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Lackovic, Kurt
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Nilsson, Anna Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Lindgren, Petter
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Andersson Escher, Stefan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Stegmayr, Birgitta
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Asplund, Kjell
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Genome-wide linkage scan of common stroke in families from northern Sweden.2007In: Stroke, ISSN 0039-2499, E-ISSN 1524-4628, Vol. 38, no 1, p. 34-40Article in journal (Other academic)
  • 46.
    Nilsson-Ardnor, Sofie
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Wiklund, Per-Gunnar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Lindgren, Petter
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Nilsson, Anna Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Janunger, Tomas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Andersson Escher, Stefan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Hallbeck, Björn
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Stegmayr, Birgitta
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Asplund, Kjell
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Linkage of ischemic stroke to the PDE4D region on 5q in a Swedish population.2005In: Stroke, ISSN 0039-2499, E-ISSN 1524-4628, Vol. 36, no 8, p. 1666-1671Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND PURPOSE: Recent Icelandic studies have demonstrated linkage for common forms of stroke to chromosome 5q12 and association between phosphodiesterase4D (PDE4D) and ischemic stroke. Using a candidate region approach, we wanted to test the validity of these findings in a different population from northern Sweden. METHODS: A total of 56 families with 117 affected individuals were included in the linkage study. Genotyping was performed with polymorphic microsatellite markers with an average distance of 4.5 cM on chromosome 5. In the association study, 275 cases of first-ever stroke were included together with 550 matched community controls. Polymorphisms were tested individually for association of PDE4D to stroke. RESULTS: Maximum allele-sharing lod score in favor of linkage was observed at marker locus D5S424 (lod score=2.06; P=0.0010). Conditional logistic regression calculations revealed no significant association of ischemic stroke to the defined at-risk allele in PDE4D (odds ratio, 1.1; 95% confidence interval, 0.84 to 1.45). A protective effect may though be implied for 2 of the polymorphisms analyzed in PDE4D. CONCLUSIONS: Using a candidate region approach in a set of stroke families from northern Sweden, we have replicated linkage of stroke susceptibility to the PDE4D gene region on chromosome 5q. Association studies in an independent nested case-control sample from the same geographically located population suggested that different alleles confer susceptibility/protection to stroke in the Icelandic and the northern Swedish populations.

  • 47.
    Norberg, Anna
    et al.
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Neurology.
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    Holmberg, Monica
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    Exclusion of the juvenile myoclonic epilepsy gene EFHC1 as the cause of migraine on chromosome 6, but association to two rare polymorphisms in MEP1A and RHAG.2006In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 396, no 2, p. 137-142Article in journal (Refereed)
  • 48.
    Nordfjäll, Katarina
    et al.
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology. Patologi.
    Larefalk, Asa
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics. Medicinsk och klinisk genetik.
    Lindgren, Petter
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics. Medicinsk och klinisk genetik.
    Holmberg, Dan
    Medicinsk och klinisk genetik.
    Roos, Göran
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology. Patologi.
    Telomere length and heredity: Indications of paternal inheritance.2005In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 102, no 45, p. 16374-16378Article in journal (Refereed)
  • 49.
    Parsa, Roham
    et al.
    Applied Immunology, Center for Molecular Medicine, Karolinska University Hospital at Solna, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Andresen, Pernilla
    Applied Immunology, Center for Molecular Medicine, Karolinska University Hospital at Solna, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Gillett, Alan
    Neuroimmunology, Center for Molecular Medicine, Karolinska University Hospital at Solna, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Mia, Sohel
    Applied Immunology, Center for Molecular Medicine, Karolinska University Hospital at Solna, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden .
    Zhang, Xing-Mei
    Applied Immunology, Center for Molecular Medicine, Karolinska University Hospital at Solna, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Mayans, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Harris, Robert A.
    Applied Immunology, Center for Molecular Medicine, Karolinska University Hospital at Solna, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Adoptive transfer of immunomodulatory M2 Macrophages prevents type 1 Diabetes in NOD Mice2012In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 61, no 11, p. 2881-2892Article in journal (Refereed)
    Abstract [en]

    Macrophages are multifunctional immune cells that may either drive or modulate disease pathogenesis depending on their activation phenotype. Autoimmune type 1 diabetes (T1D) is a chronic proinflammatory condition characterized by unresolved destruction of pancreatic islets. Adoptive cell transfer of macrophages with immunosuppressive properties represents a novel immunotherapy for treatment of such chronic autoimmune diseases. We used a panel of cytokines and other stimuli to discern the most effective regimen for in vitro induction of immunosuppressive macrophages (M2r) and determined interleukin (IL)-4/IL-10/transforming growth factor-beta (TGF-beta) to be optimal. M2r cells expressed programmed cell death 1 ligand-2, fragment crystallizable region gamma receptor IIlb, IL-10, and TGF-beta, had a potent deactivating effect on proinflammatory lipopolysaccharide/interferon-gamma-stimulated macrophages, and significantly suppressed T-cell proliferation. Clinical therapeutic efficacy was assessed after adoptive transfer in NOD T1D mice, and after a single transfer of M2r macrophages, >80% of treated NOD mice were protected against T1D for at least 3 months, even when transfer was conducted just prior to clinical onset. Fluorescent imaging analyses revealed that adoptively transferred M2r macrophages specifically homed to the inflamed pancreas, promoting 3-cell survival. We suggest that M2r macrophage therapy represents a novel intervention that stops ongoing autoimmune T1D and may have relevance in a clinical setting. Diabetes 61:2881-2892, 2012

  • 50.
    Penha-Gonçalves, Carlos
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Leijon, Kristina
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Persson, Linda
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Type 1 diabetes and the control of dexamethazone-induced apoptosis in mice maps to the same region on chromosome 61995In: Genomics, ISSN 0888-7543, E-ISSN 1089-8646, Vol. 28, no 3, p. 398-404Article in journal (Refereed)
    Abstract [en]

    Quantitative trait loci mapping was used to identify the chromosomal location of genes that contribute to increase the resistance to apoptosis induced in immature CD4+8+ thymocytes. An F2 intercross of the nonobese diabetic (NOD) mouse (displaying an apoptosis-resistance phenotype) and the C57BL/6 mouse (displaying a nonresistance phenotype) was phenotypically analyzed and genotyped for 32 murine microsatellite polymorphisms. Maximum likelihood methods identified a region on the distal part of chromosome 6 that is linked to dexamethazone-induced apoptosis (lod score = 3.46) and accounts for 14% of the phenotypic variation. This chromosomal region contains the diabetes susceptibility locus Idd6, suggesting that the apoptosis-resistance phenotype constitutes a pathogenesis factor in IDDM of NOD mice.

12 1 - 50 of 64
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