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Open Access Research article

Autoantibodies specific for apoptotic U1-70K are superior serological markers for mixed connective tissue disease

Daniëlle Hof1, Kalok Cheung1, Dirk-Jan RAM de Rooij2, Frank H van den Hoogen3, Ger JM Pruijn1, Walther J van Venrooij1 and Jos MH Raats14*

Author Affiliations

1 Department of Biochemistry, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, The Netherlands

2 Department of Rheumatology, Sint Maartenskliniek, Nijmegen, The Netherlands

3 Department of Rheumatology, University Medical Center St Radboud, Nijmegen, The Netherlands

4 ModiQuest BV, Nijmegen, The Netherlands

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Arthritis Res Ther 2005, 7:R302-R309  doi:10.1186/ar1490

Published: 11 January 2005

Abstract

Modifications occurring on autoantigens during cell death have been proposed to have a role in the initiation of autoimmune diseases. Patients suffering from mixed connective tissue disease (MCTD) produce autoantibodies directed to U1 small nuclear ribonucleoprotein (snRNP), and antibodies against a 70 kDa protein component, the U1-70K (70K) protein, are the most prominent. During apoptosis, 70K is cleaved by caspase-3 to a 40 kDa product, which remains associated with the complex. Autoantibodies preferentially recognizing the apoptotic form of 70K have been described previously, and an apoptosis-specific epitope on 70K has been identified. This study shows that 29 of 53 (54%) MCTD sera preferentially recognize the apoptotic form of 70K over intact 70K. Moreover, we show that antibodies directed to an apoptosis-specific epitope on 70K are more specifically associated with MCTD than other anti-70K antibodies, suggesting that apoptotic 70K is a better antigen for the detection of these antibodies in MCTD patients. Longitudinal analysis of 12 MCTD patients showed in several patients that early sera are relatively enriched with antibodies recognizing an apoptosis-specific epitope, and that the levels of these apoptosis-specific antibodies decrease in time. These findings indicate that the early detection of apoptotic 70K is of considerable interest for anti-U1 snRNP-positive patients.

Keywords:
apoptosis; autoantibodies; mixed connective tissue disease; U1 snRNP; U1-70K