Antony Rosen

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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.

Danielle B Ulanet; Nicholas A Flavahan; Livia Casciola-Rosen; Antony Rosen (Profiled Authors: Nicholas Flavahan; Antony Rosen; Livia Casciola-Rosen)

Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Arthritis and rheumatism 2004;50(1):233-41.

OBJECTIVE: 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.

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