ANTINUCLEAR ANTIBODY IN SYSTEMIC SCLEROSIS (SCLERODERMA)

doi:10.1016/S0889-857X(05)70297-0

Rheumatic Disease Clinics of North America

Volume 22, Issue 4, 1 November 1996, Pages 709-735

https://doi.org/10.1016/S0889-857X(05)70297-0 Get rights and content

The presence of antinuclear antibodies (ANAs) is a central feature of systemic sclerosis (SSc) or scleroderma.77, 120 Although the mechanisms of ANA production are incompletely understood, autoimmunity is thought to be involved in SSc etiology and pathogenesis. First, ANAs are almost always (>95%) found in sera from patients with SSc, and the scleroderma-specific autoantibodies are virtually absent in healthy persons. Second, recent sophisticated biologic and cellular studies have disclosed that ANA targets consist of essential intracellular molecules. Third, ANAs also occur in other connective tissue diseases, such as systemic lupus erythematosus (SLE), Sjögren's syndrome, and adult onset polymyositis/dermatomyositis (PM/DM), but the intracellular targets of the ANAs in SSc are different from those in other connective tissue diseases. ANAs in SSc target DNA topoisomerase I (topo I), chromosomal centromere or kinetochore proteins, RNA polymerase (RNAP) I, II, and III, and some nucleolar components (Table 1); thus, these ANAs are often called SSc-specific or SSc marker antibodies. Finally, it has been established that some of these ANAs link to subsets characterized by combinations of clinical manifestations (or syndrome) within the spectrum of SSc.

The presence of SSc-specific ANAs helps physicians establish diagnosis and predict prognosis. Using these ANAs as probes, scientists have also extensively characterized the structure and function of some of the previously unknown intracellular molecules. Recent and ongoing studies, including molecular cloning of these autoantigens and identification of immunogenetic associations with the ANA production, may provide important insights into the mechanisms of autoantibody production and relationship to disease pathogenesis. This article briefly reviews the structure and function of intracellular molecules targeted by SSc-specific ANA and emphasizes their antigenicity, immunogenetic associations, and clinical relationships that accompany the specific autoimmune response.

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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Citation Excerpt :
SSc patients have autoantibodies that bind to various intracellular components, such as DNA topoisomerase I (topo I), centromere, RNA polymerases, U1RNP, U3RNP, Th/To, and histones, though these distinct subsets of autoantibodies do not have a proven pathogenic role [5]. However, the presence of autoantibodies is a central feature of immune activation associated with SSc, because antinuclear antibody (Ab) has been detected in >90% of patients [5]. Recent studies have shown that B cells have various crucial roles in immune response regulation [6–8] than that had been previously appreciated (Fig. 1).
Systemic sclerosis (SSc) is a collagen disease characterized by autoimmunity and excessive extracellular matrix deposition in the skin and visceral organs. Although the pathogenic relationship between systemic autoimmunity and the clinical manifestations of SSc remains unknown, SSc patients show a variety of abnormal immune activation including the production of disease-specific autoantibodies and cytokine production. Many recent studies have demonstrated that immune cells, including T cells, B cells, and macrophages, have a variety of immunological abnormalities in SSc. So far, several groups and our group reported that B cells play a critical role in systemic autoimmunity and disease expression through various functions, such as cytokine production, lymphoid organogenesis, and induction of other immune cell activation in addition to autoantibody production. Recent studies show that B cells from SSc patients demonstrate an up-regulated CD19 expression, a crucial regulator of B cell activation, which induces chronic hyper-reactivity of memory B cells and SSc-specific autoantibody production and also causes fibrosis of several organs. Furthermore, in SSc-model mice, such as tight-skin mice, bleomycin-induced SSc model mice, and DNA topoisomerase I and complete Freund’s adjuvant-induced SSc model mice, have abnormal B cell activation which associates with skin and lung fibrosis. Indeed, B cell depletion therapy using anti-CD20 Ab, Rituximab, is considered to one potential beneficial treatment for patients with SSc. However, there is no direct evidence which can explain how B cells, especially autoantigen-reactive B cells, progress or regulate disease manifestations of SSc. Collectively, B cell abnormalities in SSc is most likely participating in fibrosis and tissue damage of SSc. If the relationship between SSc-specific tissue damage and B cell abnormalities is revealed, these findings lead to novel effective therapy for SSc.
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Autoimmunity is a status that immune mechanisms react against self-structure. The immune mechanisms, including cellular and molecular elements have been developed to immune body against foreign invades. Multiple factors such as genetic and epigenetic background, hormonal status, microbiome, and other factors can cause launching the autoreactive responses, in which the immune tolerance breaks and immune mechanisms are against self-antigens. Apoptosis is one of the important mechanisms in maintaining the tolerance and eliminating the autoreactive lymphocyte clones. Due to survivin roles in apoptosis and proliferation, numerous researches have been paying attention to survivin expression and function in autoreactive lymphocytes and tissue cells, playing important roles in the pathogenesis of autoimmune diseases. New line of evidence has been supporting the role of survivin dysfunction or aberrant expression in deriving autoreactive lymphocytes or some important immune tissues, which may underpin the autoimmune conditions such as Lichen planus (LP), Rheumatoid arthritis (RA), Systemic lupus erythematosus (SLE), Myasthenia gravis (MG), Multiple sclerosis (MS), Systemic sclerosis (SSc), Psoriasis, and Inflammatory bowel disease (IBD). Hence, the purpose of the current paper was to review the survivin role in the etiology and pathogenesis of abovementioned autoimmune diseases.
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Citation Excerpt :
Systemic sclerosis (SSc) is an autoimmune disorder of unknown origin, characterized by excess accumulation of the extracellular matrix (ECM), primarily collagen, in skin and other internal organs, vascular alterations, and production of antinuclear antibodies (ANAs) (LeRoy et al., 1988; Okano, 1996).
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View all citing articles on Scopus

: Address reprint requests to Yutaka Okano, MD, Department of Medicine, Nippon Kokan Hospital, 1-2-1 Kokan-dori, Kawasaki-ku, Kawasaki, 210, Japan

^*: From the Nippon Kokan Hospital, Kawasaki, Japan

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ANTINUCLEAR ANTIBODY IN SYSTEMIC SCLEROSIS (SCLERODERMA)

Section snippets

METHODS FOR IDENTIFICATION OF AUTOANTIGENS

DNA TOPOISOMERASE I (Scl-70)

RNA POLYMERASE I, II, AND III

CENTROMERE (KINETOCHORE)

CLINICAL SUBSETS IDENTIFIED BY THREE MAJOR ANTINUCLEAR ANTIBODIES

NUCLEOLAR ANTIGENS

MECHANISMS OF ANTINUCLEAR ANTIBODY PRODUCTION AND ITS ROLE IN SYSTEMIC SCLEROSIS

SUMMARY

ACKNOWLEDGMENTS

Cell

Lancet

J Biol Chem

Am J Med

J Biol Chem

J Biol Chem

Clin Immunol Immunopathol

Cell

Clin Immunol Immunopathol

J Biol Chem

Hum Immunol

Hum Immunol

J Biol Chem

Exp Cell Res

Anti-Scl-70 antibodies detected by immunoblotting in progressive systemic sclerosis: Specificity and clinical correlations

Ann Rheum Dis

Scl-95/100: Doublet of endothelial marker autoantigens in progressive systemic sclerosis

Clin Exp Immunol

Molecular characterization of an autoantigen of PM-Scl in the polymyositis/scleroderma overlap syndrome: A unique and complete human cDNA encoding an apparent 75-kD acidic protein of the nucleolar complex

J Exp Med

Identification and characterization of mitochondria autoantigens in progressive systemic sclerosis: Identity with the 72,000 dalton autoantigen in primary biliary cirrhosis

J Immunol

cDNA cloning and sequencing of human fibrillarin, a conserved nucleolar protein recognized by autoimmune antisera

Proc Natl Acad Sci U S A

Autoantibodies to fibrillarin in systemic sclerosis (scleroderma): An immunogenetic, serologic, and clinical analysis

Arthritis Rheum

An intact Box C sequence in the U3 snRNA is required for binding of fibrillarin, the protein common to the major family of nucleolar snRNPs

EMBO J

Identification and functional analysis of two U3 binding sites on yeast pre-ribosomal RNA

EMBO J

Anticentromere antibody in primary biliary cirrhosis

Ann Rheum Dis

Cloning and characterization of the cDNA coding for a polymyositis-scleroderma overlap syndrome-related nucleolar 100-kD protein

J Exp Med

A molecular and serologic analysis of the major histocompatibility complex and complement component C4 in systemic sclerosis

Arthritis Rheum

Serological markers in progressive systemic sclerosis: Clinical correlations

Ann Rheum Dis

Frequency and clinical significance of anticentromere and anti–Scl-70 antibodies in an English connective tissue disease population

Rheumatol Int

Anticentromere antibody: An immunological marker of a subset of systemic sclerosis

Br J Dermatol

Specificity of antinuclear antibodies in primary biliary cirrhosis

Ann Rheum Dis

A major human centromere protein located beneath the kinetochore

J Cell Biol

cDNA cloning of human DNA topoisomerase I: Catalytic activity of a 67.6-kDa carboxyl-terminal fragment

Proc Natl Acad Sci U S A

Use of molecular cloning methods to map the distribution of epitopes on topoisomerase I (Scl-70) recognized by sera of scleroderma patients

Arthritis Rheum

Initiation of autoimmunity to the p53 tumor suppressor protein by complexes of p53 and SV40 large T antigen

J Exp Med

DNA-DR typing shows HLA-DRw11 RFLPs are increased in frequency in both progressive systemic sclerosis and CREST variants of scleroderma

Tissue Antigens

Three human chromosomal autoantigens are recognized by sera from patients with anticentromere antibodies

J Clin Invest

Molecular cloning of cDNA for CENP-B, the major human centromere autoantigen

J Cell Biol

How some T cells escape tolerance induction

Nature

Cloning of a complementary DNA coding for the 100-kD antigenic protein of the PM-Scl autoantigen

J Clin Invest

Analysis of the specificity of anti-PM-Scl autoantibodies

Arthritis Rheum

Identification of protein components reactive with anti-PM/Scl autoantibodies

Clin Exp Immunol

Immunogenetic associations of scleroderma-related antinuclear antibodies

Arthritis Rheum

Different antibody patterns and different prognoses in patients with scleroderma with various extent of skin sclerosis