OBJECTIVE: To examine whether autoantibodies recognizing granzyme B (GB)-cleaved autoantigens are associated with ischemic digital loss (IDL) in limited systemic sclerosis (SSc). METHODS: Fifteen of 19 patients with limited SSc and IDL were matched by age, sex, race, and duration of disease to controls with limited SSc but without IDL. The sera were used to immunoblot HeLa cell lysates and chromosome preparations that had been incubated in vitro in the absence or presence of GB. Anticentromere antibodies (ACAs) were assayed by immunofluorescence and immunoprecipitation of in vitro-translated centromere proteins (CENP-B and CENP-C). Immunoprecipitation of GB-cleaved CENPs was also performed. RESULTS: GB-cleaved autoantigens were immunoblotted by 16 of 19 IDL sera (84.2%) compared with 6 of 15 non-IDL sera (40.0%) (odds ratio 8.0, 95% confidence interval 1.6-40.0). This association persisted after adjustment for ACA status. Furthermore, the presence of antibodies to centromere proteins as well as to GB-cleaved antigens was highly specific for IDL, occurring in 12 of 19 IDL patients (63.2%) and in none of 15 controls (P < 0.0001). An identical 60-kd GB-generated fragment was recognized by 5 of 16 IDL sera (31.3%) and was demonstrated to arise through GB-mediated cleavage of CENP-C. GB-cleaved CENP-C fragments were recognized preferentially over the intact CENP-C molecule by antibodies from patients with IDL. CONCLUSION: The striking recognition of GB-generated autoantigen fragments by sera from patients with limited SSc and IDL constitutes the first in vivo evidence that antibodies against GB-generated centromeric peptide fragments identify a distinct clinical subset.
OBJECTIVE: To examine whether autoantibodies recognizing granzyme B (GB)-cleaved autoantigens are associated with ischemic digital loss (IDL) in limited systemic sclerosis (SSc). METHODS: Fifteen of 19 patients with limited SSc and IDL were matched by age, sex, race, and duration of disease to controls with limited SSc but without IDL. The sera were used to immunoblot HeLa cell lysates and chromosome preparations that had been incubated in vitro in the absence or presence of GB. Anticentromere antibodies (ACAs) were assayed by immunofluorescence and immunoprecipitation of in vitro-translated centromere proteins (CENP-B and CENP-C). Immunoprecipitation of GB-cleaved CENPs was also performed. RESULTS:GB-cleaved autoantigens were immunoblotted by 16 of 19 IDL sera (84.2%) compared with 6 of 15 non-IDL sera (40.0%) (odds ratio 8.0, 95% confidence interval 1.6-40.0). This association persisted after adjustment for ACA status. Furthermore, the presence of antibodies to centromere proteins as well as to GB-cleaved antigens was highly specific for IDL, occurring in 12 of 19 IDL patients (63.2%) and in none of 15 controls (P < 0.0001). An identical 60-kd GB-generated fragment was recognized by 5 of 16 IDL sera (31.3%) and was demonstrated to arise through GB-mediated cleavage of CENP-C. GB-cleaved CENP-C fragments were recognized preferentially over the intact CENP-C molecule by antibodies from patients with IDL. CONCLUSION: The striking recognition of GB-generated autoantigen fragments by sera from patients with limited SSc and IDL constitutes the first in vivo evidence that antibodies against GB-generated centromeric peptide fragments identify a distinct clinical subset.
Authors: L Casciola-Rosen; A Miagkov; K Nagaraju; F Askin; L Jacobson; A Rosen; D B Drachman Journal: J Neuroimmunol Date: 2008-08-03 Impact factor: 3.478
Authors: A C Gelber; S R Pillemer; B J Baum; F M Wigley; L K Hummers; S Morris; A Rosen; L Casciola-Rosen Journal: Ann Rheum Dis Date: 2006-01-13 Impact factor: 19.103
Authors: M Huang; H Ida; M Kamachi; N Iwanaga; Y Izumi; F Tanaka; K Aratake; K Arima; M Tamai; A Hida; H Nakamura; T Origuchi; A Kawakami; N Ogawa; S Sugai; P J Utz; K Eguchi Journal: Clin Exp Immunol Date: 2005-10 Impact factor: 4.330