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  • 1.
    Banday, Viqar Showkat
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Elevated Systemic Glutamic Acid Level in the Non-Obese Diabetic Mouse is Idd Linked and Induces Beta Cell Apoptosis2017In: Immunology, ISSN 0019-2805, E-ISSN 1365-2567, Vol. 150, no 2, p. 162-171Article in journal (Refereed)
    Abstract [en]

    Although type 1 diabetes (T1D) is a T-cell-mediated disease in the effector stage, the mechanism behind the initial beta cell assault is less understood. Metabolomic differences, including elevated levels of glutamic acid, have been observed in patients with T1D before disease onset, as well as in pre-diabetic non-obese diabetic (NOD) mice. Increased levels of glutamic acid damage both neurons and beta cells, implying that this could contribute to the initial events of T1D pathogenesis. We investigated the underlying genetic factors and consequences of the increased levels of glutamic acid in NOD mice. Serum glutamic acid levels from a (NODxB6) F-2 cohort (n = 182) were measured. By genome-wide and Idd region targeted microsatellite mapping, genetic association was detected for six regions including Idd2, Idd4 and Idd22. In silico analysis of potential enzymes and transporters located in and around the mapped regions that are involved in glutamic acid metabolism consisted of alanine aminotransferase, glutamic-oxaloacetic transaminase, aldehyde dehydrogenase 18 family, alutamyl-prolyl-tRNA synthetase, glutamic acid transporters GLAST and EAAC1. Increased EAAC1 protein expression was observed in lysates from livers of NOD mice compared with B6 mice. Functional consequence of the elevated glutamic acid level in NOD mice was tested by culturing NOD. Rag2(-/-) Langerhans' islets with glutamic acid. Induction of apoptosis of the islets was detected upon glutamic acid challenge using TUNEL assay. Our results support the notion that a dysregulated metabolome could contribute to the initiation of T1D. We suggest that targeting of the increased glutamic acid in pre-diabetic patients could be used as a potential therapy.

  • 2.
    Banday, Viqar Showkat
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Thyagarajan, Radha
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    B cell intrinsic defects lead to enhanced immune response in the NOD miceManuscript (preprint) (Other academic)
  • 3.
    Banday, Viqar Showkat
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Thyagarajan, Radha
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Contribution of both B cell intrinsic alterations as well as non-hematopoietic derived factors in the enhanced immune response of the NOD mouse2017In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 86, no 4, p. 252-252Article in journal (Other academic)
  • 4.
    Banday, Viqar Showkat
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Thyagarajan, Radha
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Contribution of both B-cell intrinsic alterations as well as non-hematopoietic-derived factors in the enhanced immune response of the NOD mouse2017In: Autoimmunity, ISSN 0891-6934, E-ISSN 1607-842X, Vol. 50, no 6, p. 363-369Article in journal (Refereed)
    Abstract [en]

    The underlying cellular and molecular mechanism for the development of Type 1 diabetes is still to be fully revealed. We have previously demonstrated that the NOD mouse, a model for Type 1 diabetes, display a prolonged and enhanced immune response to both self and non-self-antigens. The molecular explanation for this defect however, has not been determined. In this study we immunized NOD and C57BL/6 (B6) with the conventional antigen i.e. hen egg lysozyme (HEL) and analyzed B cell activation, germinal center reaction and antibody clearance. Corroborating our previous observations NOD mice responded robustly to a single immunization of HEL. Immunofluorescence analysis of the spleen revealed an increased number of germinal centers in unimmunized NOD compared to B6. However, post immunization germinal center numbers were similar in NOD and B6. NOD mice showed lower response to BCR stimulation with anti-IgM, in particular at lower concentrations of anti-IgM. Antibody clearance in vivo did not differ between the strains. To determine the cell type that is responsible for the prolonged and enhance immune response, we reconstituted NOD-RAGs with cells from primed donors in different combinations. NOD B cells were required to reproduce the phenotype; however the non-lymphoid compartment of NOD origin also played a role. Based on our results we propose that preexisting GCs in the NOD promote the robust response and alteration in the BCR signaling could promote survival of stimulated cells. Overall, this mechanism could in turn also contribute to the activation and maintenance of autoreactive B cells in the NOD mouse.

  • 5.
    Banday, Viqar Showkat
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Thyagarajan, Radha
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Sundström, Mia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Increased expression of TACI on NOD B cells results in germinal centre reaction anomalies, enhanced plasma cell differentiation and immunoglobulin production2016In: Immunology, ISSN 0019-2805, E-ISSN 1365-2567, Vol. 149, no 3, p. 297-305Article in journal (Refereed)
    Abstract [en]

    B cells have an important pathogenic role in the development of type 1 diabetes in the non-obese diabetic (NOD) mouse. We have previously reported that NOD mice display an increased percentage of TACIhigh-expressing B cells compared with C57BL/6 mice and this trait is linked to chromosomes 1 and 8. In this paper the genetic association of the transmembrane activator, calcium modulator and cyclophilin ligand interactor (TACI) trait was confirmed using double congenic NOD.B6C1/Idd22 mice. TACI ligation by a proliferation-inducing ligand (APRIL) has been shown to influence plasma cell differentiation, immunoglobulin production and isotype switch. Hence, the functional consequence of the up-regulation of TACI on NOD B cells was analysed both in vitro and in vivo. NOD B cells stimulated with APRIL showed an enhanced plasma cell differentiation and class switch to IgG and IgA compared with B cells from C57BL/6 mice. Moreover, flow cytometry analyses revealed that germinal centre B cells in NOD failed to down-regulate TACI. Availability of the TACI ligand B-cell activating factor (BAFF) has been shown to be a limiting factor in the germinal centre reaction. In line with this, upon immunization with 4-hydroxy-3-nitrophenylacetyl hapten-conjugated hen egg lysozyme, NOD mice produced higher titres of low-affinity antibodies compared with C57BL/6 mice. This observation was supported by the detection of increased levels of BAFF in NOD germinal centres after immunization compared with C57BL/6 by immunofluorescence. Our results support the hypothesis that increased TACI expression on NOD B cells contributes to the pathogenesis of type 1 diabetes in the NOD mouse.

  • 6.
    Belz, Gabrielle T
    et al.
    Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Victoria 3050, Australia.
    Behrens, Georg M N
    Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Victoria 3050, Australia.
    Smith, Chris M
    Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Victoria 3050, Australia.
    Miller, Jacques F A P
    Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Victoria 3050, Australia.
    Jones, Claerwen
    Department of Microbiology and Immunology, The University of Melbourne, Victoria 3010, Australia.
    Lejon, Kristina
    Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
    Fathman, C. Garrison
    Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
    Mueller, Scott N
    Department of Microbiology and Immunology, The University of Melbourne, Victoria 3010, Australia.
    Shortman, Ken
    Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Victoria 3050, Australia.
    Carbone, Francis R
    Department of Microbiology and Immunology, The University of Melbourne, Victoria 3010, Australia.
    Heath, William R
    Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Victoria 3050, Australia.
    The CD8alpha+ dendritic cell is responsible for inducing peripheral self-tolerance to tissue-associated antigens.2002In: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 196, no 8, p. 1099-1104Article in journal (Refereed)
    Abstract [en]

    We previously described a mechanism for the maintenance of peripheral self-tolerance. This involves the cross-presentation of tissue-associated antigens by a bone marrow-derived cell type that stimulates the proliferation and ultimate deletion of self-reactive CD8 T cells. This process has been referred to as cross-tolerance. Here, we characterize the elusive cell type responsible for inducing cross-tolerance as a CD8alpha(+) dendritic cell (DC). To achieve this aim, transgenic mice were generated expressing yellow fluorescent protein (YFP) linked to CTL epitopes for ovalbumin and glycoprotein B (gB) of herpes simplex virus under the rat insulin promoter (RIP). Although tracking of YFP was inconclusive, the use of a highly sensitive gB-specific hybridoma that produced beta-galactosidase on encounter with antigen, enabled detection of antigen presentation by cells isolated from the pancreatic lymph node. This showed that a CD11c(+)CD8alpha(+) cell was responsible for cross-tolerance, the same DC subset as previously implicated in cross-priming. These data indicate that CD8alpha(+) DCs play a critical role in both tolerance and immunity to cell-associated antigens, providing a potential mechanism by which cytotoxic T lymphocyte can be immunized to viral antigens while maintaining tolerance to self.

  • 7.
    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.

  • 8.
    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.

  • 9.
    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.

  • 10.
    Brink, Mikael
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Ärlestig, Lisbeth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Rantapää-Dahlqvist, Solbritt M.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    B-Regulatory-, CD19(+)CD20(+) CD24(high)CD38(high) -Cells Are Functionally Impaired In Patients With Rheumatoid Arthritis and Healthy First Degree Relatives Compared With Controls2013In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 65, no Special issue, Supplement 10, p. S393-S394, Meeting Abstract: 917Article in journal (Other academic)
  • 11.
    Brink, Mikael
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Ärlestig, Lisbeth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    B Regulatory Cells are Functionally Impaired in Patients with Rheumatoid Arthritis and in Their First-Degree Relatives Compared with Controls2014In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 79, no 6, p. 450-450Article in journal (Other academic)
  • 12.
    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)
  • 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).
    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.

  • 15.
    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.

  • 16.
    Ekici, Rifat
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Sundström, Mia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Thay, Bernard
    Umeå University, Faculty of Medicine, Department of Odontology, Oral Microbiology.
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Biomedical Laboratory Science.
    Enhanced capture of extramembranous IgM and IgG on B cells in the NOD mouse: implications for immune complex trapping2009In: International Immunology, ISSN 0953-8178, E-ISSN 1460-2377, Vol. 21, no 5, p. 533-541Article in journal (Refereed)
    Abstract [en]

    Binding of various antibody isotypes to B cells through either FcgammaRs or complement receptors has been attributed to play several roles, e.g. in immune complex (IC) transportation and regulation of B cell receptor signaling. We have revealed a novel B cell intrinsic receptor for IgM and IgG which is present in C57BL/6 (B6) mice and is more abundant in non-obese diabetic (NOD) mice. As a consequence, the level of extramembranous IgG monomers and IgM pentamers on peripheral blood B cells from NOD mice was significantly higher compared with B6 mice. The effect of this aberration was that all B cells in peripheral blood of (NOD.IgH(a) x B6(IgH(b)))F(1) mice carried both IgM allotypes on their surface. In addition, analysis of IC binding using IgG- or IgM-opsonized bacterial particles revealed a higher degree of binding in NOD mice compared with B6. We hypothesize that this novel Ig-binding receptor is part of the normal immune system function. The aberrant function in the NOD mouse could contribute to the development of Type 1 diabetes by altering normal B cell functions such as activation, IC transportation and B cell homeostasis.

  • 17.
    Ermann, Joerg
    et al.
    Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
    Szanya, Veronika
    Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
    Ford, Gregory S.
    Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
    Paragas, Violette
    Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
    Garrison Fathman, C.
    Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
    Lejon, Kristina
    UmanGenomics, Umestans Företagspark, Umeå, Sweden.
    CD4+CD25+ T cells facilitate the induction of T cell anergy2001In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 167, no 8, p. 4271-4275Article in journal (Refereed)
    Abstract [en]

    T cell anergy is characterized by the inability of the T cell to produce IL-2 and proliferate. It is reversible by the addition of exogenous IL-2. A similar state of unresponsiveness is observed when the proliferative response of murine CD4+CD25- T cells is suppressed in vitro by coactivated CD4+CD25+ T cells. We have developed a suppression system that uses beads coated with anti-CD3 and anti-CD28 Abs as surrogate APCs to study the interaction of CD4+CD25+ and CD4+CD25- T cells in vitro. CD4+CD25+ T cell-induced suppression, in this model, was not abrogated by blocking the B7-CTLA-4 pathway. When the CD4+CD25- T cells were separated from the CD4+CD25+ suppressor cells after 24 h of coactivation by the Ab-coated beads, the CD4+CD25- T cells were unable to proliferate or to produce IL-2 upon restimulation. The induction of this anergic phenotype in the CD4+CD25- T cells correlated with the up-regulated expression of the gene related to anergy in lymphocytes (GRAIL), a novel anergy-related gene that acts as a negative regulator of IL-2 transcription. This system constitutes a novel mechanism of anergy induction in the presence of costimulation.

  • 18.
    Holmberg, Mats
    et al.
    UmanGenomics AB, Umestan, Umeå, Sweden.
    Lejon, Kristina
    UmanGenomics AB, Umestan, Umeå, Sweden.
    The identification and validation of common disease genes: relevance to the drug development process.2001In: Current opinion in molecular therapeutics (Print), ISSN 1464-8431, E-ISSN 2040-3445, Vol. 3, no 6, p. 533-537Article in journal (Refereed)
    Abstract [en]

    The understanding of the genetic factors contributing to the development of common diseases has presented a great challenge. Recent accomplishments in the field of genetics have now transformed this vision into a reachable goal. The increased knowledge will have great impact on our fundamental understanding of biological processes, as well as how we diagnose and treat common disease. Many obstacles still remain, and a careful choice of strategy will be critical to achieve these goals. One key point will be the validation of generated candidates in an optimized study set-up.

  • 19.
    Kindstedt, Elin
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology.
    Holm, Cecilia Koskinen
    Umeå University, Faculty of Medicine, Department of Odontology.
    Palmqvist, Py
    Umeå University, Faculty of Medicine, Department of Odontology.
    Sjöström, Mats
    Umeå University, Faculty of Medicine, Department of Odontology.
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Lundberg, Pernilla
    Umeå University, Faculty of Medicine, Department of Odontology.
    Innate lymphoid cells are present in gingivitis and periodontitis2019In: Journal of Periodontology, ISSN 0022-3492, E-ISSN 1943-3670, Vol. 90, no 2, p. 200-207Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Innate lymphoid cells (ILCs) are the most recently identified leukocytes of the immune system and these cells are increasingly acknowledged to play important roles in host defence and tissue repair. ILCs are also contributors of inflammatory diseases such as asthma and colitis. We analyzed the presence and relative proportions of the different ILC subsets (ILC1, ILC2 and ILC3) in gingivitis and periodontitis. Further, we investigated if ILCs express receptor activator of nuclear factor kappa-B ligand (RANKL), a cytokine crucial for osteoclast differentiation and bone resorption.

    METHODS: We collected gingivitis and periodontitis soft tissue and characterized ILC subsets including RANKL expression in single-cell suspensions using flow cytometry.

    RESULTS: ILCs were detected both in gingivitis and periodontitis. The majority of ILCs, in both conditions, were ILC1s. Furthermore, RANKL expression was detected on a fraction of the ILC1s.

    CONCLUSIONS: Our discovery of the presence of ILCs both in gingivitis and periodontitis and concomitant expression of RANKL on a fraction of the ILC1 population suggest that these cells may be of importance in periodontal disease. In addition, our findings provide a new insight into the field of oral immunology.

  • 20.
    Kindstedt, Elin
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology.
    Koskinen Holm, Cecilia
    Umeå University, Faculty of Medicine, Department of Odontology.
    Palmqvist, Py
    Umeå University, Faculty of Medicine, Department of Odontology.
    Sjöström, Mats
    Umeå University, Faculty of Medicine, Department of Odontology.
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Lundberg, Pernilla
    Umeå University, Faculty of Medicine, Department of Odontology.
    Discovery of Innate Lymphoid Cells in Gingivitis and PeriodontitisManuscript (preprint) (Other academic)
    Abstract [en]

    AIM: Innate lymphoid cells (ILCs) are the most recently identified leukocytes of the immune system and these cells are increasingly acknowledged to play important roles in host defence and tissue repair. ILCs can also contribute to inflammatory diseases such as asthma and colitis. We analysed the presence and proportions of the different ILC subsets (ILC1, ILC2 and ILC3) in gingivitis and periodontitis. Furthermore, we investigated if ILCs express nuclear factor kappa-B ligand (RANKL), a cytokine crucial for osteoclast differentiation and bone resorption.

    MATERIALS AND METHODS: We collected gingivitis and periodontitis soft tissue and characterised ILC subsets including RANKL expression in single cell suspensions using flow cytometry.

    RESULTS: Although not statistically significant, the total number of ILCs detected was twice as many in periodontitis compared to gingivitis. The majority of ILCs, in both conditions, were ILC1s with a 2.5-fold increase of ILC1s in periodontitis compared to gingivitis. Furthermore, we found RANKL expression exclusively expressed on ILC1s.

    CONCLUSIONS: Our discovery of the presence of ILCs in gingivitis and periodontitis and concomitant expression of RANKL in ILC1 suggest that these cells may be of importance in periodontal disease. In addition, our findings provide new insights into the field of oral immunology. 

  • 21.
    Kokkonen, Heidi
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Söderström, Ingegerd
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Rocklöv, Joacim
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Rantapää Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Up-regulation of cytokines and chemokines predates the onset of rheumatoid arthritis2010In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 62, no 2, p. 383-391Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To identify whether cytokines, cytokine-related factors, and chemokines are up-regulated prior to the development of rheumatoid arthritis (RA).

    METHODS: A nested case-control study was performed in 86 individuals who had donated blood samples before experiencing any symptoms of disease (pre-patients) and 256 matched control subjects (1:3 ratio). In 69 of the pre-patients, blood samples were also obtained at the time of the diagnosis of RA. The plasma levels of 30 cytokines, related factors, and chemokines were measured using a multiplex system.

    RESULTS: The levels of several of the cytokines, cytokine receptors, and chemokines were significantly increased in individuals before disease onset compared with the levels in control subjects; i.e., those representing signs of general immune activation (interleukin-1beta [IL-1beta], IL-2, IL-6, IL-1 receptor antagonist, and tumor necrosis factor), activation of Th1 cells (interferon-gamma, IL-12), Th2 cells (IL-4, eotaxin), Treg cells (IL-10), bone marrow-derived factors (IL-7, granulocyte-macrophage colony-stimulating factor, and granulocyte colony-stimulating factor), as well as chemokines (monocyte chemotactic protein 1 and macrophage inflammatory protein 1alpha). The levels were particularly increased in anti-cyclic citrullinated peptide antibody- and rheumatoid factor-positive individuals, and the concentration of most of these increased further after disease onset. The concentration of IL-17 in individuals before disease onset was significantly higher than that in patients after disease onset. Individuals in whom RA subsequently developed were discriminated from control subjects mainly by the presence of Th1 cells, Th2 cells, and Treg cell-related cytokines, while chemokines, stromal cell-derived cytokines, and angiogenic-related markers separated patients after the development of RA from individuals before the onset of RA.

    CONCLUSION: Individuals in whom RA later developed had significantly increased levels of several cytokines, cytokine-related factors, and chemokines representing the adaptive immune system (Th1, Th2, and Treg cell-related factors); after disease onset, the involvement and activation of the immune system was more general and widespread.

  • 22.
    Kolan, Shrikant
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Boman, Andreas
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Matozaki, Takashi
    Department of Biochemistry and Molecular Biology, Division of Molecular and Cellular Signaling, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan..
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Lack of non-hematopoietic SIRPα signaling disturbs the splenic marginal zone architecture resulting in accumulation and displacement of marginal zone B cells2015In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 460, no 3, p. 645-650Article in journal (Refereed)
    Abstract [en]

    Signal regulatory protein α (SIRPα) is an immunoglobulin super family protein predominantly expressed by myeloid but not lymphoid cells, and its role in lymphocyte homeostasis and function is still to be revealed. We demonstrate that mice bearing a mutant SIRPα lacking the cytoplasmic signaling domain (SIRPα MT) had an increased amount of splenic marginal zone (MZ) B cells compared to wild-type controls. Immunohistochemical analysis revealed an increased localization of MZB cells into B cell follicular areas of the white pulp in SIRPα MT spleens. However, we found no signs of an increased MZB cell activation level in MT mice. The immune response to T-independent antigens in vivo was slightly increased in SIRPα MT mice while sorted MZB from these mice responded normally to LPS in vitro. Bone marrow reconstitution experiments demonstrated that the MZB cell phenotype of SIRPα MT mice was due to lack of SIRPα signaling in non-hematopoietic cells. In contrast, MZ retention of MZ macrophages required hematopoietic SIRPα, while normal distribution of metallophilic macrophages required non-hematopoietic SIRPα signaling. In summary, these data identified SIRPα signaling in non-hematopoietic cells to play an important role in regulating the numbers and positioning MZB cell in the spleen.

  • 23.
    Kolan, Shrikant
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Koskinen Holm, Cecilia
    Umeå University, Faculty of Medicine, Department of Odontology.
    Sulniute, Rima
    Umeå University, Faculty of Medicine, Department of Odontology.
    Lundberg, Pernilla
    Umeå University, Faculty of Medicine, Department of Odontology.
    Matozaki, Takashi
    Department of Biochemistry and Molecular Biology, Division of Molecular and Cellular Signaling, Kobe University Graduate School of Medicine, Kobe, Japan.
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Non-Hematopoietic and Hematopoietic SIRPα Signaling Differently Regulates Murine B Cell Maturation in Bone Marrow and Spleen2015In: PLoS One, Vol. 10, no 7, article id e0134113Article in journal (Refereed)
    Abstract [en]

    B lymphocyte development occurs in the bone marrow, while final differentiation and maturation can occur in both the bone marrow and the spleen. Here we provide evidence that signal regulatory protein α (SIRPα), an Ig-superfamily ITIM-receptor expressed by myeloid but not by lymphoid cells, is involved in regulating B cell maturation. Lack of SIRPα signaling in adult SIRPα-mutant mice resulted in a reduced maturation of B cells in the bone marrow, evident by reduced numbers of semi-mature IgD+IgMhi follicular type-II (F-II) and mature IgD+IgMlofollicular type-I (F-I) B cells, as well as reduced blood B cell numbers. In addition, lack of SIRPα signaling also impaired follicular B cell maturation in the spleen. Maturing BM or splenic B cells of SIRPα-mutant mice were found to express higher levels of the pro-apoptotic protein BIM and apoptosis was increased among these B cells. Bone marrow reconstitution experiments revealed that the B cell maturation defect in bone marrow and blood was due to lack of SIRPα signaling in non-hematopoietic cells, while hematopoietic SIRPα signaling was important for follicular B cell maturation in the spleen. Adding on to our previous findings of a stromal cell defect in SIRPα-mutant mice was the finding that gene expression of receptor activator of nuclear factor-ĸB ligand (RANKL) was significantly lower in cultured bone marrow stromal cells of SIRPα mutant mice. These data suggest a novel and opposite contribution of SIRPα signaling within non-hematopoietic and hematopoietic cells, respectively, to maintain B cell maturation and to prevent apoptosis in the bone marrow and spleen of adult mice.

  • 24.
    Kolan, Shrikant
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    The Integrin Associated Protein CD47 Modulates Murine B cell MaturationManuscript (preprint) (Other academic)
    Abstract [en]

    CD47 is a ubiquitously expressed transmembrane glycoprotein that can function as a ligand for the inhibitory ITIM-receptor signal-regulatory protein α (SIRPα), which is highly expressed by myeloid cells but not lymphoid cells. In secondary lymphoid organs, the interaction between CD47 and SIRPα has been shown to be important in the homeostasis of T lymphocytes and CD8- dendritic cells, but a possible role in regulating B cell homeostasis remain unidentified. In the present study, we show that CD47-/- mice displayed reduced numbers of mature B cells in the bone marrow and in blood, and a reduced fraction of follicular B cells in the spleen. On the contrary, the fraction of marginal zone B cells was increased but normally localized to the splenic MZ. This B cell phenotype was found to be associated with an increasing age. However, we were unable to detect increased levels of autoantibodies in CD47-/- mice. From this investigation, no conclusion can be made whether these effects are B cell-intrinsic or secondary to other cell abnormalities. In conclusion, CD47-/- mice manifested a fairly similar B cell phenotype as we have previously described in SIRPα mutant mice (lacking the SIRPα cytoplasmic domain) and suggest that SIRPα and its ligand CD47 are important for steady-state homeostasis of B cells. 

  • 25.
    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.

  • 26.
    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.

  • 27.
    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.

  • 28.
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Cellular and genetic components in the development of IDDM in NOD mice.1996Doctoral thesis, comprehensive summary (Other academic)
  • 29.
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Immunsystemets fina balansgång2017In: Barndiabetesfondens tidskrift "Sticket", ISSN 1400-8505, Vol. 3, no 3, p. 4-4Article, review/survey (Other (popular science, discussion, etc.))
  • 30.
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Kompetens ingen efterfrågar2004In: Kemivärlden Biotech, Vol. 10, no 21Article, review/survey (Other (popular science, discussion, etc.))
  • 31.
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Två bitar i det stora pusslet2013In: Sticket, ISSN 1400-8505, Vol. 2, p. 4-Article, review/survey (Other (popular science, discussion, etc.))
  • 32.
    Lejon, Kristina
    et al.
    Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, CA 94305, USA.
    Garrison Fathman, C.
    Division of Immunology and Rheumatology, R-S021, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305-5111,USA .
    Isolation of self antigen-reactive cells from inflamed islets of nonobese diabetic mice using CD4high expression as a marker1999In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 163, no 10, p. 5708-5714Article in journal (Refereed)
    Abstract [en]

    The low precursor frequency of Ag-reactive CD4+ T cells has been a barrier to the study of CD4+ T cell responses to conventional Ags as well as CD4+ T cell responses to autoantigens recognized during the course of an autoimmune disease. We have recently reported that all "conventional Ag" reactive CD4+ T cells are contained within the subpopulation expressing high levels of the CD4 molecule, termed CD4high. We have identified a CD4high population in the islets of Langerhans of prediabetic nonobese diabetic (NOD) mice that is extremely potent in transferring disease. As few as 500 CD4high islet-infiltrating CD4+ T cells transferred insulin-dependent diabetes mellitus to CD8 reconstituted NOD-SCID mice within 30 days of transfer. In contrast, CD4high T cells isolated from either NOD spleen or salivary glands did not transfer insulin-dependent diabetes mellitus into similar CD8-reconstituted NOD-SCID recipients. These data indicate that the precursor frequency of NOD islet-reactive, pathogenic CD4+ T cells is much higher in the prediabetic NOD pancreas than in these other organs. The islet-infiltrating CD4high T cells displayed selected memory markers, by cell surface analysis, and displayed a Th 1 phenotype by RNase protection assay, but had a marked decrease in IL-4 mRNA determined by quantitative real time PCR when compared with the less pathogenic CD4normal islet-infiltrating T cells. Use of the CD4high marker to select Ag activated T cells represents a tool to isolate and study pathogenic CD4+ T cells from autoimmune lesions in which the Ag has not been previously defined.

  • 33.
    Lind, Lisbet K
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Stecksén-Blicks, Christina
    Umeå University, Faculty of Medicine, Department of Odontology, Pediatric Dentistry.
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Schmitt-Egenolf, Marcus
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    EDAR mutation in autosomal dominant hypohidrotic ectodermal dysplasia in two Swedish families2006In: BMC Medical Genetics, ISSN 1471-2350, E-ISSN 1471-2350, Vol. 7, p. 80-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Hypohidrotic ectodermal dysplasia (HED) is a genetic disorder characterized by defective development of teeth, hair, nails and eccrine sweat glands. Both autosomal dominant and autosomal recessive forms of HED have previously been linked to mutations in the ectodysplasin 1 anhidrotic receptor (EDAR) protein that plays an important role during embryogenesis.

    METHODS: The coding DNA sequence of the EDAR gene was analyzed in two large Swedish three-generational families with autosomal dominant HED.

    RESULTS: A non-sense C to T mutation in exon 12 was identified in both families. This disease-specific mutation changes an arginine amino acid in position 358 of the EDAR protein into a stop codon (p.Arg358X), thereby truncating the protein. In addition to the causative mutation two polymorphisms, not associated with the HED disorder, were also found in the EDAR gene.

    CONCLUSION: The finding of the p.Arg358X mutation in the Swedish families is the first corroboration of a previously described observation in an American family. Thus, our study strengthens the role of this particular mutation in the aetiology of autosomal dominant HED and confirms the importance of EDAR for the development of HED.

  • 34.
    Madsen, Rasmus
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Banday, Viqar Showkat
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Moritz, Thomas
    Umeå Plant Science Center, Department of Forest Genetics and Plant Physiology, Swedish University of Agriculture Sciences, Umeå, Sweden.
    Trygg, Johan
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Altered metabolic signature in Pre-Diabetic NOD Mice2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 4, p. e35445-Article in journal (Refereed)
    Abstract [en]

    Altered metabolism proceeding seroconversion in children progressing to Type 1 diabetes has previously been demonstrated. We tested the hypothesis that non-obese diabetic (NOD) mice show a similarly altered metabolic profile compared to C57BL/6 mice. Blood samples from NOD and C57BL/6 female mice was collected at 0, 1, 2, 3, 4, 5, 6, 7, 9, 11, 13 and 15 weeks and the metabolite content was analyzed using GC-MS. Based on the data of 89 identified metabolites OPLS-DA analysis was employed to determine the most discriminative metabolites. In silico analysis of potential involved metabolic enzymes was performed using the dbSNP data base. Already at 0 weeks NOD mice displayed a unique metabolic signature compared to C57BL/6. A shift in the metabolism was observed for both strains the first weeks of life, a pattern that stabilized after 5 weeks of age. Multivariate analysis revealed the most discriminative metabolites, which included inosine and glutamic acid. In silico analysis of the genes in the involved metabolic pathways revealed several SNPs in either regulatory or coding regions, some in previously defined insulin dependent diabetes (Idd) regions. Our result shows that NOD mice display an altered metabolic profile that is partly resembling the previously observation made in children progressing to Type 1 diabetes. The level of glutamic acid was one of the most discriminative metabolites in addition to several metabolites in the TCA cycle and nucleic acid components. The in silico analysis indicated that the genes responsible for this reside within previously defined Idd regions.

  • 35.
    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.

  • 36.
    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.

  • 37.
    Persson-Sjögren, Solveig
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Lejon, Kristina
    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.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Expression of the NK-1 receptor on islet cells and invading immune cells in the non-obese diabetic mouse2005In: Journal of Autoimmunity, ISSN 0896-8411, Vol. 24, no 4, p. 269-279Article in journal (Refereed)
    Abstract [en]

    The underlying mechanistic causes of immune cell infiltration in the islets of Langerhans and beta cell failure in the non-obese diabetic (NOD) mouse is still to be completely revealed. Substance P (SP) is a substance known to have pro-inflammatory, endocrine, neuromodulatory and trophic effects, and its preferred receptor, the neurokinin receptor 1 (NK-1 R), is reported to be involved in extravasation of granulocytes and in inflammation and tissue derangement. Therefore, we have investigated the expression of NK-1 R during development of insulitis in the NOD mouse. We show that the magnitude of immunoreactivity scoring NK-1 R expression in the islets was increased in the 12-week-old NOD mouse. Expression of NK-1 R co-localized with expression of glucagon. In line with this expression pattern, we did not detect any effect of SP on glucose-induced insulin release. NK-1 R expression was particularly observed in islet cells in association with the clusters of immune cells. Expression of NK-1 R was also demonstrated in a fraction of the infiltrating B and T lymphocytes, as well as on infiltrating macrophages and dendritic cells. The observations show that the level of NK-1 R expression is increased in 12-week-old NOD mice, being correlated with the occurrence of islet mononuclear infiltration. Our data suggest that SP may act as a chemoattractant, contributing to the pathogenic mononuclear infiltration process in the NOD mouse. On the whole, the observations suggest that SP and the NK-1 R to certain extents are involved in the changes that occur during the development of insulitis in the NOD mouse.

  • 38.
    Rasmuson, Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Pourazar, Jamshid
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Mohamed, Nahla
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Blomberg, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Cytotoxic immune responses in the lungs correlate to disease severity in patients with hantavirus infection2016In: European Journal of Clinical Microbiology and Infectious Diseases, ISSN 0934-9723, E-ISSN 1435-4373, Vol. 35, no 4, p. 713-721Article in journal (Refereed)
    Abstract [en]

    Hantavirus infections may cause severe and sometime life-threatening lung failure. The pathogenesis is not fully known and there is an urgent need for effective treatment. We aimed to investigate the association between pulmonary viral load and immune responses, and their relation to disease severity. Bronchoscopy with sampling of bronchoalveolar lavage (BAL) fluid was performed in 17 patients with acute Puumala hantavirus infection and 16 healthy volunteers acting as controls. Lymphocyte subsets, granzyme concentrations, and viral load were determined by flow cytometry, enzyme-linked immunosorbent assay (ELISA), and quantitative reverse transcription polymerase chain reaction (RT-PCR), respectively. Analyses of BAL fluid revealed significantly higher numbers of activated CD8+ T cells and natural killer (NK) cells, as well as higher concentrations of the cytotoxins granzymes A and B in hantavirus-infected patients, compared to controls. In patients, Puumala hantavirus RNA was detected in 88 % of BAL cell samples and correlated inversely to the T cell response. The magnitude of the pulmonary cytotoxic lymphocyte response correlated to the severity of disease and systemic organ dysfunction, in terms of need for supplemental oxygen treatment, hypotension, and laboratory data indicating renal failure, cardiac dysfunction, vascular leakage, and cell damage. Regulatory T cell numbers were significantly lower in patients compared to controls, and may reflect inadequate immune regulation during hantavirus infection. Hantavirus infection elicits a pronounced cytotoxic lymphocyte response in the lungs. The magnitude of the immune response was associated with disease severity. These results give insights into the pathogenesis and possibilities for new treatments.

  • 39.
    Stigbrand, Torgny
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Välkomna till 2013 års Forskningens dag!2013In: Cancerforskning på nya vägar: en bok från Forskningens dag 2013, Medicinska fakulteten vid Umeå universitet / [ed] Mattias Grundström Mitz och Lena Åminne, Umeå: Umeå universitet , 2013, 1, p. 7-14Chapter in book (Other (popular science, discussion, etc.))
  • 40.
    Sundström, Mia
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Banday, Viqar
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Biomedical Laboratory Science.
    Increased expression of TACI in the NOD mouse results in enhanced plasma cell differentiation and immunoglobulin productionManuscript (preprint) (Other academic)
    Abstract [en]

    B cells have an important pathogenic role in the development of Type 1 diabetes in the NOD mouse. We have previously revealed a novel NOD-specific B cell-related trait, i.e. an increased percentage of TACIhigh-expressing B cells in NOD mice compared with C57BL/6 mice. In the NOD mouse the TACI trait is regulated by genes residing on chromosome 1 and 8, more specifically in the vicinity of the Idd5.4 and Idd22 regions. It has previously been demonstrated that TACI ligation by APRIL influences plasma cell differentiation, immunoglobulin production and isotype switch. In this paper the linkage of the TACI trait to chromosome 1 and 8 was confirmed by analyzing the percentage of TACIhigh-expressing B cells in congenic NOD.B6C1/Idd22 mice. Moreover, the functional concequence of TACI upregulation, with the focus on plasma cell development and immunoglobulin production, was investigated. NOD B cells stimulated with APRIL showed an increased plasma cell differentiation and enhanced IgM, IgG and IgA production compared to B cells from C57BL/6 mice. This supports the hypothesis that increased TACI expression on NOD B cells could contribute to the B cell involvement in the pathogenesis of T1D in the NOD mouse.

  • 41.
    Sundström, Mia
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Idd-linked genetic regulation of TACIhigh expressing B cells in NOD mice2007In: Journal of Autoimmunity, ISSN 0896-8411, E-ISSN 1095-9157, Vol. 29, no 2-3, p. 116-124Article in journal (Refereed)
    Abstract [en]

    In NOD mice, B cells play a key role in the initiation of type 1 diabetes pathogenesis. We have identified a novel NOD-specific B cell-related trait, i.e. the increased percentage of TACI(high)-expressing splenic B cells, by comparing NOD mice with non-autoimmune C57BL/6 mice. Using athymic NOD mice, we determined that this trait was T cell independent. We mapped the loci contributing to the increased proportion of TACI(high) expressing splenic B cells and found that the control of TACI expression was strongly linked to chromosome 1, in a region which includes the insulin-dependent diabetes (Idd) 5 loci. Moreover, another locus potentially involved was detected in the vicinity of Idd22 on chromosome 8. Interestingly, when analyzing age-dependent contribution to the obtained LOD scores we observed that the linkage to chromosome 8 was explained solely by mice > or =61 days of age, suggesting a temporal genetic regulation of TACI expression. In addition, analysis of genetic interaction between chromosome 1 and chromosome 8 indicated that the two loci acted in an additive fashion. Our findings corroborate the notion that B cell deviations contribute to type 1 diabetes development, and suggest a temporal regulation of TACI(high) expression, possibly influenced by the ongoing autoimmune process.

  • 42.
    Sundström, Mia
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    The prolonged and enhanced immune response in the non-obese diabetic mouse is dependent on genes in the Idd1/24, Idd12 and Idd18 regions2010In: Journal of Autoimmunity, ISSN 0896-8411, E-ISSN 1095-9157, Vol. 35, no 4, p. 375-382Article in journal (Refereed)
    Abstract [en]

    In non-obese diabetic (NOD) mice B cells are an absolute requirement for T1D development. NOD mice display various B cell related immune deviations when compared to normal mice such as an enhanced and prolonged immune response towards several antigens, including non-self immunoglobulins. We hypothesized that this trait contributes to diabetes pathogenesis, and investigated the genetic factor(s) governing the altered immune response. A (NODxC57BL/6)F(2) cohort (n = 214) were analyzed for its primary immune response against a BALB/c derived monoclonal antibody, and a genome wide linkage analysis was performed. Significant linkage to the Idd1/Idd24, Idd12 and Idd18.1 regions as well as to a proximal region (marker D2Mit367, 33.5 Mb) on chromosome 2 was detected. We verified the observed linkage by analyzing a set of H2 congenic NOD and C57BL/6 mice and narrowed down the region to 8 Mb. Interaction between Idd1/24 and Idd12, as well as the novel locus on chromosome 2 was observed. However, the action by Idd18.1 was not influenced by any of the other loci. In addition to the known H2 I-Aβ(g7) allelic variant of Idd1 in NOD, candidate gene analysis revealed a significant difference in the transcription of the H2-O/DO molecule. We hypothesize that multiple mechanisms contribute to the loss of immune response control, including that peptide loading on MHC class II in B cells of NOD is altered.

  • 43.
    Söderström, Ingegerd
    et al.
    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).
    Colucci, F.
    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).
    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).
    Establishment and characterization of RAG-2 deficient non-obese diabetic mice1996In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 43, no 5, p. 525-530Article in journal (Refereed)
    Abstract [en]

    The authors have established a new immunodeficient mouse strain on the genetic background of the diabetes prone non-obese diabetic (NOD) mouse. A deletion mutant of the RAG-2 gene was back crossed 10 generations onto the NOD/Bom strain background. The homozygous NODrag-2-/- mice lack functionally mature B and T lymphocytes and do not develop insulitis or diabetes throughout life. In contrast, heterozygous NODrag-2+/- develop both insulitis and diabetes with an incidence similar to the wild type NOD mice. In transfer experiments, spleen cells from diabetic NOD donors were found to transfer disease to NODrag-2-/- recipients similar to what has been previously observed in transfer to irradiated NOD recipients or to immunodeficient NOD-scid/scid mice. While resembling the recently established NOD-scid/scid mice in many respects, the NODrag-2-/- mice represents an advantageous model for reconstitution of the pathogenesis of murine IDDM as it does not produce any endogenous, mature T or B lymphocytes.

  • 44.
    Thyagarajan, Radha
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Banday, Viqar
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Ding, Zhoujie
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Contribution of autoallergy to the pathogenesis in the NOD mice2015In: Autoimmunity, ISSN 0891-6934, E-ISSN 1607-842X, Vol. 48, no 5, p. 298-304Article in journal (Refereed)
    Abstract [en]

    The immunoglobulin isotype IgE is commonly associated with allergy. However, its involvement in autoimmune disease in general, and Type 1 diabetes (T1D) in particular, is still not completely clarified, nonetheless IgE has been observed in patients with T1D. In this article, we aimed to elucidate the contribution of IgE in the pathogenesis of the disease in a spontaneous model for T1D, i.e. the NOD mouse. We observed increased levels of IgE in splenic, lymph node and peripheral blood B cells in the NOD mice compared to the control C57BL/6 (B6) mice. No correlation was found between the IgE levels on B cells and those in the sera of these mice, indicating a B cell intrinsic property mediating IgE capture in NOD. Functionally, the B cells from NOD were similar to B6 in rescuing the IgE-mediated immune response via the low affinity receptor CD23 in a transgenic adoptive transfer system. However, the involvement of IgE in diabetes development was clearly demonstrated, as treatment with anti-IgE antibodies delayed the incidence of the diabetes in the NOD mice compared to the PBS treated group. Pancreas sections from a 13-week-old NOD revealed the presence of tertiary lymphoid structures with T cells, B cells, germinal centers and IgE suggesting the presence of autoantigen specific IgE. Our study provides an insight to the commonly overlooked immunoglobulin IgE and its potential role in autoimmunity.

  • 45.
    Thyagarajan, Radha
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    B Cells and IgE in Type 1 Diabetes2014In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 79, no 6, p. 452-452Article in journal (Other academic)
  • 46.
    Wahlin, Bengt
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Fasth, A. E.
    Karp, Kjell
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Södergren, Anna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Wållberg-Jonsson, Solveig
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Cd8+cd28- t-lymphocytes are associated with subclinical atherosclerosis in patients with rheumatoid arthritis2017In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 76, p. 250-250Article in journal (Other academic)
  • 47.
    Wahlin, Bengt
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Fasth, Andreas
    Karp, Kjell
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology.
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Malmström, Vivianne
    Rahbar, Afsar
    Wållberg-Jonsson, Solveig
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Södergren, Anna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Atherosclerosis in rheumatoid arthritis: associations between anti-cytomegalovirus IgG antibodies, CD4+CD28null T-cells, CD8+CD28null T-cells and intima-media thicknessManuscript (preprint) (Other academic)
1 - 47 of 47
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