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Träfflista för sökning "WFRF:(Cilio C. M.) "

Sökning: WFRF:(Cilio C. M.)

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3.
  • Cervin, C, et al. (författare)
  • Characterization of a naturally occurring mutation (L107I) in the HNF1 alpha (MODY3) gene.
  • 2002
  • Ingår i: Diabetologia. - 0012-186X .- 1432-0428. ; 45:12, s. 1703-8
  • Tidskriftsartikel (refereegranskat)abstract
    • <p><strong>AIMS/HYPOTHESIS:</strong> Maturity onset diabetes of the young type 3 (MODY3) is a monogenic form of diabetes mellitus caused by mutations in the gene encoding for hepatocyte nuclear factor 1 alpha, HNF1 alpha. In this study we have examined the in vivo and in vitro effects of a mutation (L107I) outside the DNA binding and dimerization domains in the N terminal part of the HNF1 alpha gene.</p> <p><strong>METHODS:</strong> Beta-cell function of the affected family members was assessed by an oral glucose tolerance test. Functional tests were carried out to explain the role of the mutation in vitro by transcriptional activity assay, Western blotting, DNA-binding assays and subcellular localization experiments.</p> <p><strong>RESULTS:</strong> Affected family members showed an 86% decreased insulin response to glucose when compared to age-matched healthy control subjects. In vitro the mutation showed a 79% decrease in transcriptional activity as compared to wild type HNF1 alpha in HeLa cells lacking HNF1 alpha. The transcriptional activity was not suppressed when the mutant was co-expressed with wild type HNF1 alpha suggesting that the decreased activity was not mediated by a dominant negative mechanism. The L107I/HNF1alpha protein showed normal nuclear targeting but impaired binding to an HNF1 alpha consensus sequence.</p> <p><strong>CONCLUSION/INTERPRETATION:</strong> Our results suggest that the L107I substitution represents a MODY3 mutation which impairs beta-cell function by a loss-of-function mechanism.</p>
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  • Radenkovic, M., et al. (författare)
  • Altered regulatory T cell phenotype in latent autoimmune diabetes of the adults (LADA)
  • 2016
  • Ingår i: Clinical and Experimental Immunology. - British Society for Immunology. - 0009-9104. ; 186:1, s. 46-56
  • Tidskriftsartikel (refereegranskat)abstract
    • Latent autoimmune diabetes of the adults (LADA) accounts for up to 12% of all patients with diabetes. Initially the disease resembles type 2 diabetes (T2D); however, the typical presence of β cell autoantibodies indicates an autoimmune basis of LADA. While dysfunctional regulatory T cells (Tregs) have been implicated in autoimmune diabetes, these cells have been scarcely studied in LADA. The aim of this study was to investigate the frequency and phenotype of circulating Tregs in LADA patients early during disease progression. Flow cytometric analysis was performed on whole blood and peripheral mononuclear cells (PBMC) from patients diagnosed with LADA prior to insulin deficiency (n = 39) and from healthy volunteers (n = 20). Overall, we found the frequency and activation status of peripheral putative Tregs to be altered in LADA patients compared to healthy controls. While total T cells and CD4+ T cells expressing high levels of CD25 (CD4+CD25hi) were unchanged, the frequency and total numbers of CD4+ T cells expressing an intermediate level of CD25 (CD4+CD25int) were decreased in LADA patients. Interestingly, the expression of the Treg-specific marker forkhead box protein 3 (FoxP3), as well as the activation and memory makers CD69, cytotoxic T lymphocyte associated antigen 4 (CTLA-4), CCR4 and CD45RO were increased in CD4+CD25+ T cells of the patients. Our data depict phenotypical changes in T cells of LADA patients that may reflect a derangement in peripheral immune regulation contributing to the slow process leading to insulin-dependent diabetes in these patients.
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6.
  • Resic-Lindehammer, Sabina, et al. (författare)
  • Temporal trends of HLA genotype frequencies of type 1 diabetes patients in Sweden from 1986 to 2005 suggest altered risk
  • 2008
  • Ingår i: Acta Diabetologica. - 0940-5429 .- 1432-5233. ; 45:4, s. 231-5
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>The aim of this study was to compare the frequency of human leukocyte antigen (HLA) genotypes in 1-18-year-old patients with type 1 diabetes newly diagnosed in 1986-1987 (n = 430), 1996-2000 (n = 342) and in 2003-2005 (n = 171). We tested the hypothesis that the HLA DQ genotype distribution changes over time. Swedish type 1 diabetes patients and controls were typed for HLA using polymerase chain reaction amplification and allele specific probes for DQ A1* and B1* alleles. The most common type 1 diabetes HLA DQA1*-B1*genotype 0501-0201/0301-0302 was 36% (153/430) in 1986-1987 and 37% (127/342) in 1996-2000, but decreased to 19% (33/171) in 2003-2005 (P \ 0.0001). The 0501-0201/0501-0201 genotype increased from 1% in 1986-1987 to 7% in 1996-2000 (P = 0.0047) and to 5% in 2003-2005 (P &gt; 0.05). This study in 1-18-year-old Swedish type 1 diabetes patients supports the notion that there is a temporal change in HLA risk.</p>
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7.
  • Resic-Lindehammer, Sabina, et al. (författare)
  • Temporal trends of HLA genotype frequencies of type 1 diabetes patients in Sweden from 1986 to 2005 suggest altered risk
  • 2008
  • Ingår i: Acta Diabetologica. - 0940-5429 .- 1432-5233. ; 45:4, s. 231-235
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>The aim of this study was to compare the frequency of human leukocyte antigen (HLA) genotypes in 1-18-year-old patients with type 1 diabetes newly diagnosed in 1986-1987 (n = 430), 1996-2000 (n = 342) and in 2003-2005 (n = 171). We tested the hypothesis that the HLA DQ genotype distribution changes over time. Swedish type 1 diabetes patients and controls were typed for HLA using polymerase chain reaction amplification and allele specific probes for DQ A1* and B1* alleles. The most common type 1 diabetes HLA DQA1*-B1*genotype 0501-0201/0301-0302 was 36% (153/430) in 1986-1987 and 37% (127/342) in 1996-2000, but decreased to 19% (33/171) in 2003-2005 (P \ 0.0001). The 0501-0201/0501-0201 genotype increased from 1% in 1986-1987 to 7% in 1996-2000 (P = 0.0047) and to 5% in 2003-2005 (P &gt; 0.05). This study in 1-18-year-old Swedish type 1 diabetes patients supports the notion that there is a temporal change in HLA risk.</p>
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8.
  • Radenkovic, M., et al. (författare)
  • Characterization of resident lymphocytes in human pancreatic islets
  • 2017
  • Ingår i: Clinical and Experimental Immunology. - British Society for Immunology. - 0009-9104. ; 187:3, s. 418-427
  • Tidskriftsartikel (refereegranskat)abstract
    • The current view of type 1 diabetes (T1D) is that it is an immune-mediated disease where lymphocytes infiltrate the pancreatic islets, promote killing of beta cells and cause overt diabetes. Although tissue resident immune cells have been demonstrated in several organs, the composition of lymphocytes in human healthy pancreatic islets have been scarcely studied. Here we aimed to investigate the phenotype of immune cells associated with human islets of non-diabetic organ donors. A flow cytometry analysis of isolated islets from perfused pancreases (n = 38) was employed to identify alpha, beta, T, natural killer (NK) and B cells. Moreover, the expression of insulin and glucagon transcripts was evaluated by RNA sequencing. Up to 80% of the lymphocytes were CD3+ T cells with a remarkable bias towards CD8+ cells. Central memory and effector memory phenotypes dominated within the CD8+ and CD4+ T cells and most CD8+ T cells were positive for CD69 and up to 50–70% for CD103, both markers of resident memory cells. The frequency of B and NK cells was low in most islet preparations (12 and 3% of CD45+ cells, respectively), and the frequency of alpha and beta cells varied between donors and correlated clearly with insulin and glucagon mRNA expression. In conclusion, we demonstrated the predominance of canonical tissue resident memory CD8+ T cells associated with human islets. We believe that these results are important to understand more clearly the immunobiology of human islets and the disease-related phenotypes observed in diabetes.
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9.
  • Radenkovic, M, et al. (författare)
  • Characterization of resident lymphocytes in human pancreatic islets
  • 2017
  • Ingår i: Clinical and Experimental Immunology. - 0009-9104 .- 1365-2249. ; 187:3, s. 418-427
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>The current view of type 1 diabetes (T1D) is that it is an immune-mediated disease where lymphocytes infiltrate the pancreatic islets, promote killing of beta cells and cause overt diabetes. Although tissue resident immune cells have been demonstrated in several organs, the composition of lymphocytes in human healthy pancreatic islets have been scarcely studied. Here we aimed to investigate the phenotype of immune cells associated with human islets of non-diabetic organ donors. A flow cytometry analysis of isolated islets from perfused pancreases (n = 38) was employed to identify alpha, beta, T, natural killer (NK) and B cells. Moreover, the expression of insulin and glucagon transcripts was evaluated by RNA sequencing. Up to 80% of the lymphocytes were CD3(+) T cells with a remarkable bias towards CD8(+) cells. Central memory and effector memory phenotypes dominated within the CD8(+) and CD4(+) T cells and most CD8(+) T cells were positive for CD69 and up to 50-70% for CD103, both markers of resident memory cells. The frequency of B and NK cells was low in most islet preparations (12 and 3% of CD45(+) cells, respectively), and the frequency of alpha and beta cells varied between donors and correlated clearly with insulin and glucagon mRNA expression. In conclusion, we demonstrated the predominance of canonical tissue resident memory CD8(+) T cells associated with human islets. We believe that these results are important to understand more clearly the immunobiology of human islets and the disease-related phenotypes observed in diabetes.</p>
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10.
  • Sitnicka, E, et al. (författare)
  • Complementary signaling through flt3 and interleukin-7 receptor alpha is indispensable for fetal and adult B cell genesis
  • 2003
  • Ingår i: Journal of Experimental Medicine. - Rockefeller University Press. - 0022-1007 .- 1540-9538. ; 198:10, s. 1495-1506
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Extensive studies of mice deficient in one or several cytokine receptors have failed to support an indispensable role of cytokines in development of multiple blood cell lineages. Whereas B1 B cells and Igs are sustained at normal levels throughout life of mice deficient in IL-7, IL-7Ralpha, common cytokine receptor gamma chain, or flt3 ligand (FL), we report here that adult mice double deficient in IL-7Ralpha and FL completely lack visible LNs, conventional IgM(+) B cells, IgA(+) plasma cells, and B1 cells, and consequently produce no Igs. All stages of committed B cell progenitors are undetectable in FL-/- X IL-7Ralpha(-/-) BM that also lacks expression of the B cell commitment factor Pax5 and its direct target genes. Furthermore, in contrast to IL-7Ralpha(-/-) mice, FL-/- X IL-7Ralpha(-/-) mice also lack mature B cells and detectable committed B cell progenitors during fetal development. Thus, signaling through the cytokine tyrosine kinase receptor flt3 and IL-7Ralpha are indispensable for fetal and adult B cell development.</p>
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