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lüll Selective cleavage of nucleolar autoantigen B23 by granzyme B in differentiated vascular smooth muscle cells: insights into the association of specific autoantibodies with distinct disease phenotypes Ulanet DB; Flavahan NA; Casciola-Rosen L; Rosen AArthritis Rheum 2004[Jan]; 50 (1): 233-41OBJECTIVE: To investigate the association of specific autoantibodies with distinct disease phenotypes. The association of autoantibodies to nucleophosmin/B23 with pulmonary hypertension in scleroderma, and the susceptibility of autoantigens to cleavage by granzyme B (GB), provided a focus for these studies. METHODS: Intact cells were subjected to cytotoxic lymphocyte granule-induced death, and the susceptibility of autoantigens to cleavage by GB was addressed by immunoblotting and/or by a novel immunofluorescence assay. RESULTS: B23 was cleaved efficiently by GB in vitro, but was highly resistant to cleavage by GB during cytotoxic lymphocyte granule-mediated death of many intact cell types. In contrast, this molecule was highly susceptible to GB-mediated proteolysis exclusively in differentiated vascular smooth muscle cells. Topoisomerase I and several other GB substrates did not show this striking change in cleavage susceptibility in different cell types. CONCLUSION: These data demonstrate that the cleavage of B23 by GB in intact cells is dependent upon both cell type and phenotype. The susceptibility of this autoantigen (which is associated with a distinct pulmonary vascular phenotype in scleroderma) to GB-mediated proteolysis selectively in vascular smooth muscle cells suggests that the GB-cleavable conformation of autoantigens may occur selectively in the target tissue, and may play a role in shaping the phenotype-specific autoimmune response.|Autoantigens/genetics/*immunology/metabolism[MESH]|Cell Death[MESH]|Cell Differentiation[MESH]|Cell Nucleolus/*immunology[MESH]|Cytoplasmic Granules/immunology[MESH]|DNA Topoisomerases, Type I/metabolism[MESH]|Granzymes[MESH]|HeLa Cells[MESH]|Humans[MESH]|K562 Cells[MESH]|Muscle, Smooth, Vascular/cytology/*immunology[MESH]|Mutagenesis, Site-Directed[MESH]|Nuclear Proteins/genetics/*immunology/metabolism[MESH]|Nucleophosmin[MESH]|Phenotype[MESH]|Serine Endopeptidases/metabolism/*pharmacology[MESH]|T-Lymphocytes, Cytotoxic/metabolism[MESH] |