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  • BMJ  (5)
  • Medicine  (5)
  • 1
    Online Resource
    Online Resource
    The social nature of disability, disease and genetics: a response to Gillam, Persson, Holtug, Draper and Chadwick.
    BMJ ; 1999
    In:  Journal of Medical Ethics Vol. 25, No. 2 ( 1999-04-01), p. 172-175
    Details
    In: Journal of Medical Ethics, BMJ, Vol. 25, No. 2 ( 1999-04-01), p. 172-175
    Type of Medium: Online Resource
    ISSN: 0306-6800
    URL: Article
    DOI: 10.1136/jme.25.2.172
    RVK:
    XA 54920
    Language: English
    Publisher: BMJ
    Publication Date: 1999
    detail.hit.zdb_id: 2026397-1
    SSG: 0
    SSG: 1
    SSG: 5,1
    Location Call Number Limitation Availability
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  • 2
    Online Resource
    Online Resource
    Improving Nature? The Science and Ethics of Genetic Engineering
    BMJ ; 1997
    In:  Journal of Medical Ethics Vol. 23, No. 5 ( 1997-10-01), p. 329-331
    Details
    In: Journal of Medical Ethics, BMJ, Vol. 23, No. 5 ( 1997-10-01), p. 329-331
    Type of Medium: Online Resource
    ISSN: 0306-6800
    URL: Article
    DOI: 10.1136/jme.23.5.329-a
    RVK:
    XA 54920
    Language: English
    Publisher: BMJ
    Publication Date: 1997
    detail.hit.zdb_id: 2026397-1
    SSG: 0
    SSG: 1
    SSG: 5,1
    Location Call Number Limitation Availability
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  • 3
    Online Resource
    Online Resource
    Firing up the nature/nurture controversy: bioethics and genetic determinism
    BMJ ; 2005
    In:  Journal of Medical Ethics Vol. 31, No. 9 ( 2005-09-01), p. 526-530
    Details
    In: Journal of Medical Ethics, BMJ, Vol. 31, No. 9 ( 2005-09-01), p. 526-530
    Type of Medium: Online Resource
    ISSN: 0306-6800
    URL: Article
    DOI: 10.1136/jme.2004.008417
    RVK:
    XA 54920
    Language: English
    Publisher: BMJ
    Publication Date: 2005
    detail.hit.zdb_id: 2026397-1
    SSG: 0
    SSG: 1
    SSG: 5,1
    Location Call Number Limitation Availability
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  • 4
    Online Resource
    Online Resource
    AB0016 ASSOCIATION OF PTPN22 GENETIC VARIANTS WITH DISEASE SUSCEPTIBILITY AND CLINICAL VARIABLES IN PRIMARY SJÖGREN SYNDROME
    BMJ ; 2020
    In:  Annals of the Rheumatic Diseases Vol. 79, No. Suppl 1 ( 2020-06), p. 1311.1-1312
    Details
    In: Annals of the Rheumatic Diseases, BMJ, Vol. 79, No. Suppl 1 ( 2020-06), p. 1311.1-1312
    Abstract: Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease characterized by dysfunction of exocrine glands secondary to lymphocytic infiltration. Lymphoid tyrosine phosphatase (LYP) regulates T and B lymphocyte activation. PTPN22 gene encodes LYP; multiple polymorphic variants have been described as genetic risk factor of autoimmune diseases. Objectives: The aim was to analyze the PTPN22 rs2488457G 〉 C, rs33996649G 〉 A, and rs2476601C 〉 T genetic variants relationship with the development risk of pSS in the western Mexico population. Methods: One hundred and eighty healthy subjects (HS) and 150 pSS patients, classified according to EULAR 2016 criteria, were included. The genetic variants and mRNA expression were determined through PCR-RFLP and qPCR assays. Results: The frequency of heterozygote rs33996649GA genotype was higher in pSS patients than HS [OR=3.143 (1–10.234), p=0.046], and also, rs33996649GA genotype was associated with high SSDAI score (p=0.01). The pSS patients showed 44-fold more mRNA expression in comparison with HS (p=0.002), and mRNA expression correlates with SSDAI (r 2 =0.512, p=0.006). Conclusion: The rs33996649G 〉 A genetic variant of the PTPN22 gene is associated with increased development risk of pSS in the western Mexican population. The expression mRNA correlates with disease activity in pSS. References: [1]Brito-Zerón, P., Baldini, C., Bootsma, H., Bowman, S. J., Jonsson, R., Mariette, X., Ramos-Casals, M. (2016). Sjögren syndrome. Nature Reviews Disease Primers , 2(July), 1–20. https://doi.org/10.1038/nrdp.2016.47 [2]Stanford, S. M., & Bottini, N. (2014). PTPN22: The archetypal non-HLA autoimmunity gene. Nature Reviews Rheumatology , 10 (10), 602–611.https://doi.org/10.1038/nrrheum.2014.109 [3]Chen, Z., Zhang, H., Xia, B., Wang, P., Jiang, T., Song, M., & Wu, J. (2013). Association of PTPN22 gene (rs2488457) polymorphism with ulcerative colitis and high levels of PTPN22 mRNA in ulcerative colitis. International Journal of Colorectal Disease , 28 (10), 1351–1358. https://doi.org/10.1007/s00384-013-1671-3 [4]Machado-Contreras, J. R., Muñoz-Valle, J. F., Cruz, A., Salazar-Camarena, D. C., Marín- Rosales, M., & Palafox-Sánchez, C. A. (2016b). Distribution of PTPN22 polymorphismsin SLE from western Mexico: correlation with mRNA expression and disease activity. Clinical and Experimental Medicine , 16 (3), 399–406. https://doi.org/10.1007/s10238-015-0359-0 Disclosure of Interests: None declared
    Type of Medium: Online Resource
    ISSN: 0003-4967 , 1468-2060
    URL: Article
    DOI: 10.1136/annrheumdis-2020-eular.2173
    RVK:
    XA 10000
    Language: English
    Publisher: BMJ
    Publication Date: 2020
    detail.hit.zdb_id: 1481557-6
    Location Call Number Limitation Availability
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  • 5
    Online Resource
    Online Resource
    OP0325 EFFECT OF CITRULLINATION ON THE PROCESSING AND PRESENTATION OF RHEUMATOID ARTHRITIS AUTOANTIGENS
    BMJ ; 2020
    In:  Annals of the Rheumatic Diseases Vol. 79, No. Suppl 1 ( 2020-06), p. 200.1-200
    Details
    In: Annals of the Rheumatic Diseases, BMJ, Vol. 79, No. Suppl 1 ( 2020-06), p. 200.1-200
    Abstract: Citrullinated proteins are hallmark targets of the autoimmune response in rheumatoid arthritis (RA), 1 but the mechanism by which immune tolerance is broken to these self-proteins is poorly understood. CD4 + T cells are implicated as important drivers of the autoimmune response due to the high-affinity, class-switched nature of anti-citrullinated protein antibodies (ACPAs) present in the majority of RA patients and the prominent genetic contribution of certain HLA-DR alleles to RA susceptibility. 2,3 However, the precise effect of citrullination on MHC class II antigen processing and presentation of autoantigens to CD4 + T cells remains unknown. Objectives: Here we aimed to examine the hypothesis that citrullination impacts the processing and presentation of RA autoantigens via destabilization of protein folding and modification of protease cleavage sites, altering the peptide repertoire presented by antigen-presenting cells (APCs). Methods: Using fibrinogen as a model RA autoantigen, the native and citrullinated forms were digested in vitro by a cocktail of lysosomal cathepsins (cathepsins B, S, and H) for proteolytic mapping, or incubated with monocyte-derived dendritic cells (mo-DCs) in a natural antigen processing assay (NAPA). Peptides generated by digestion with the cathepsin cocktail or presented by HLA-DR molecules on mo-DCs were then isolated and identified by mass spectrometry. Results: We found that the repertoire of peptides generated by each method was altered by citrullination. By proteolytic mapping, we detected both changes in the pattern of cathepsin cleavage and an increased number of peptides in the citrullinated samples. Utilizing NAPA, we observed the creation of newly presented peptides in the citrullinated samples in some cases, and loss of presented peptides in others (Fig. 1). Strikingly, all peptides whose presentation was destroyed by citrullination contained a citrullination site. Together these results suggest that both protease cleavage and selection of peptides by HLA-DR are impacted by citrullination. Conclusion: Citrullination alters the peptide repertoire presented by APCs. Interestingly, no citrullinated peptides were identified by NAPA, suggesting that presentation of citrulline-containing peptides to T cells may not be the primary mechanism by which tolerance is broken to citrullinated antigens. Rather, citrullination-induced destabilization of protein folding and modification of protease cleavage sites, leading to the generation of a new peptide repertoire, could play a role in activating autoreactive T cells. This mechanism could thus drive the loss of immune tolerance to the citrullinated forms of RA autoantigens. References: [1]Schellekens, G. A., Jong, B. A. de, van den Hoogen, F. H., van de Putte, L. B. & Venrooij, W. J. van. Citrulline is an essential constituent of antigenic determinants recognized by rheumatoid arthritis-specific autoantibodies. The Journal of Clinical Investigation 101 , 273–281 (1998). [2]Scherer, H. U., Huizinga, T. W. J., Krönke, G., Schett, G. & Toes, R. E. M. The B cell response to citrullinated antigens in the development of rheumatoid arthritis. Nature Reviews Rheumatology 14 , 157–169 (2018). [3]Gregersen, P. K., Silver, J. & Winchester, R. J. The shared epitope hypothesis. an approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis & Rheumatism 30 , 1205–1213 (1987). Acknowledgments: Rheumatology Research Foundation and the JHU SOM Mass Spectrometry and Proteomics Core Disclosure of Interests: Ashley M. Curran: None declared, Jonathan Crawford: None declared, Erika Darrah Grant/research support from: Pfizer, Celgene, and Bristol-Myers Squibb, Consultant of: Padlock Therapeutics and Celgene
    Type of Medium: Online Resource
    ISSN: 0003-4967 , 1468-2060
    URL: Article
    DOI: 10.1136/annrheumdis-2020-eular.1638
    RVK:
    XA 10000
    Language: English
    Publisher: BMJ
    Publication Date: 2020
    detail.hit.zdb_id: 1481557-6
    Location Call Number Limitation Availability
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