ANTINUCLEAR ANTIBODY IN SYSTEMIC SCLEROSIS (SCLERODERMA)
Section snippets
METHODS FOR IDENTIFICATION OF AUTOANTIGENS
Indirect immunofluorescence (IIF) and Ouchterlony double immunodiffusion (DID) were principally used in early studies to identify antigen specificities of ANAs in sera from patients with systemic rheumatic diseases, including SSc. These two ANA detecting tests are still standard methods for clinical purposes. In addition to the conventional assays, several methods recently have been developed, including immunoblots, enzyme-linked immunosorbent assay (ELISA), and immunoprecipitation. These
DNA TOPOISOMERASE I (Scl-70)
Until the autoantigen was identified as DNA topoisomerase I (topo I) with a native molecular weight of approximately 100 kd,36, 72, 114 it was called Scl-70 because the antigen was recognized by sera from certain scleroderma patients and was characterized as a nonhistone basic protein with a molecular weight of 70 kd.22 Subsequently, the antigen has been shown to have a higher molecular weight of 86 kd125 or 95/100 kd.2 These products are immunologically reactive lower molecular weight
RNA POLYMERASE I, II, AND III
The presence of autoantibodies to RNA polymerases (RNAPs) was initially described in 1982.117, 118 More detailed analyses of autoantibodies to RNAPs, however, especially those to RNAP II and RNAP III, have been performed only recently. Independently, the molecular structure and function of RNAPs have been widely studied (for details, see Sentenac113).
CENTROMERE (KINETOCHORE)
Autoantibodies reactive with centromere of mitotic chromosomes were first described in 1980,82 as tissue culture cells introduced as substrate in IIF test for ANA. The centromere is a constricted region where two sister chromatids of replicated chromosome are tightly paired. The kinetochore is a specialized trilaminar structure located at the surface of the chromosome in centromere and attached by the spindle microtubules at mitosis.
CLINICAL SUBSETS IDENTIFIED BY THREE MAJOR ANTINUCLEAR ANTIBODIES
In 1979 and 1980, serum antibodies to topo I and centromere were identified.22, 81 The specificity of these antibodies for SSc and their clinical associations with clinical subsets within the SSc disease spectrum soon were recognized (Table 2). Because ACAs and anti-topo I antibodies identify two distinct subsets, clinicians have attached great importance to these two antibodies. These two antibodies, however, are present in no more than a half of overall SSc patients, although almost all
NUCLEOLAR ANTIGENS
Autoantibody systems against nucleolar components that are specific to SSc or a subset of SSc have been described (Table 2). Major antinucleolar antibody systems, including fibrillarin, Th/To and PM-Scl, are described below.
MECHANISMS OF ANTINUCLEAR ANTIBODY PRODUCTION AND ITS ROLE IN SYSTEMIC SCLEROSIS
The role of ANA in the pathogenesis or pathophysiology of SSc remains obscure. Currently, there are few data to suggest that ANA are pathogenic or contribute to tissue damage in SSc patients. As this review demonstrates, however, ANA production is highly specific and restricted to SSc or one of the SSc subsets. Therefore, it is likely that ANA synthesis does not result from nonspecific activation of the immune system; rather, it is strongly associated with the disease pathogenesis.
The
SUMMARY
The presence of autoantibodies to intracellular molecules is the hallmark immunologic finding of SSc. Recent sophisticated methods have contributed to characterization of unidentified antigens of ANA in sera from patients with SSc. Antibodies to RNA polymerases are the third major SSc-specific ANA, in addition to anti-topo I and anticentromere antibodies, and it is now possible to identify over 85% of SSc patients. These antibodies have proved helpful in diagnosis of this disease. An
ACKNOWLEDGMENTS
I am grateful to my colleagues in the Division of Rheumatology, Department of Medicine, Keio University School of Medicine (Tokyo, Japan) for giving advice and critical comments; to Dr. Akira Suwa (Tokyo Metropolitan Otsuka Hospital, Tokyo, Japan) for performing an excellent immunoprecipitation assay in Figure 1; to Drs. Thomas A. Medsger, Jr and Chester V. Oddis (University of Pittsburgh, Pittsburgh, PA) and Virginia D. Steen (Georgetown University Medical Center, Washington, DC) for their
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Address reprint requests to Yutaka Okano, MD, Department of Medicine, Nippon Kokan Hospital, 1-2-1 Kokan-dori, Kawasaki-ku, Kawasaki, 210, Japan
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From the Nippon Kokan Hospital, Kawasaki, Japan