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- Kokkonen, Heidi, et al.
(författare)
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Up-regulation of cytokines and chemokines predates the onset of rheumatoid arthritis
- 2010
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 62:2, s. 383-391
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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- Lejon, Kristina, 1967-
(författare)
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Två bitar i det stora pusslet
- 2013
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Ingår i: Sticket. - Linköping : Barndiabetesfonden. - 1400-8505. ; 2, s. 4-
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Forskningsöversikt (populärvet., debatt m.m.)
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- Madsen, Rasmus, 1979-, et al.
(författare)
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Altered metabolic signature in Pre-Diabetic NOD Mice
- 2012
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Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 7:4, s. e35445-
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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- Stigbrand, Torgny, et al.
(författare)
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Välkomna till 2013 års Forskningens dag!
- 2013. - 1
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Ingår i: Cancerforskning på nya vägar. - Umeå : Umeå universitet. - 9789174598056 ; , s. 7-14
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Bokkapitel (populärvet., debatt m.m.)
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- Sundström, Mia, 1980-
(författare)
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B cell deviations and type 1 diabetes in the NOD mouse
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Type 1 diabetes (T1D) is a chronic autoimmune disease in which the insulin producing β-cells in the pancreatic islets of Langerhans are selectively attacked by the immune system. The β-cells are destroyed resulting in a reduced or eliminated insulin production, which in turn lead to a high blood glucose level. The non-obese diabetic (NOD) mouse is the most commonly used animal model for human T1D. NOD mice develop diabetes spontaneously through a process that closely resembles the human pathogenesis. In both humans and the NOD mouse, disease is caused by a combination of genetic and environmental factors. In the NOD mouse, more than 30 insulin-dependent diabetes (Idd) loci on 15 chromosomes have been linked to disease susceptibility, however, most of the Idd-regions lack identification of a disease associated gene. B cells are required for T1D development, although the underlying mechanisms are not fully revealed. The aim of this thesis was to dissect B cell-related immune deviations in the NOD mouse, including the underlying genetics of these traits. The TACI receptor binds two ligands, i.e. the cytokines BAFF and APRIL.TACI ligation by APRIL mediates class switch, drives plasma cell differentiation and increases immunoglobulin production. In Paper I, a novel NOD-specific B cell-related trait was identified, i.e. the increased percentage of TACIhigh-expressing splenic B cells, by comparing NOD mice with non-autoimmune disease prone C57BL/6 mice. To investigate if the described TACI trait was controlled by genes linked to any Idd-region, an Idd-focused linkage analysis was performed. The TACI-trait mapped to regions on chromosome 1 and 8, more specifically to the vicinity of the Idd5.4 and Idd22. Interestingly, the linkage to Idd22 was explained by mice ≥61 days of age, suggesting a temporal genetic regulation of TACI expression possibly influenced by the ongoing autoimmune process. In Paper II, 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.C1/Idd22 mice. Moreover, the functional consequence of TACI upregulation was investigated, with the focus on plasma cell development and immunoglobulin production. NOD splenic B cells stimulated with APRIL displayed increased numbers of plasma cells and produced higher amounts of IgG and IgA compared to B cells from C57BL/6 mice. Thus, the TACI upregulation on NOD B cells possibly contribute to a B cell compartment which is more disposed to plasma cell differentiation and isotype switch. NOD mice display enhanced and prolonged immune response towards several antigens, including non-self immunoglobulins. In Paper III, the genetic factor(s) controlling the altered immune response against a BALB/c derived monoclonal antibody were dissected. Significant linkage to the Idd1/Idd24, Idd12, and Idd18.1 regions as well as to a proximal region on chromosome 2 (33.5 Mb) was detected. The linkage to Idd1/24 was verified by analyzing a set of H2-congenic NOD and C57BL/6 mice, and the linked region was narrowed down to ~8 Mb. Candidate gene analysis revealed a significant difference in the transcription of the H2-O/DO molecule. This suggests that multiple mechanisms contribute to the loss of immune response control, including an altered MHC class II peptide loading on NOD B cells. In Paper IV, a novel B cell intrinsic receptor for IgM and IgG was revealed. The receptor appeared to be more abundant in NOD mice compared to C57BL/6 mice, as the level of extramembranous IgG monomers and IgM pentamers on peripheral blood B cells from NOD mice was significantly higher compared to C57BL/6 mice. In addition, analysis of immune complex binding using IgG- or IgM-opsonized bacterial particles revealed a higher degree of binding in NOD mice compared with C57BL/6 mice. The enhanced capture of immunoglobulins and immune complexes could thus contribute to the development of T1D by altering normal B cell functions such as activation and immune complex transportation.
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- Sundström, Mia, 1980-, et al.
(författare)
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The prolonged and enhanced immune response in the non-obese diabetic mouse is dependent on genes in the Idd1/24, Idd12 and Idd18 regions
- 2010
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Ingår i: Journal of Autoimmunity. - : Elsevier BV. - 0896-8411 .- 1095-9157. ; 35:4, s. 375-382
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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