Publisher Summary Early studies pointed to the directions for subsequent investigations and there has been continuing identification of other circulating autoantibodies, characterization of their respective cellular antigens, and demonstration of the relationship between autoantibodies and clinical syndromes. The antibodies identified in these studies have been used extensively by investigators in molecular and cell biology as powerful probes for understanding the precursor messenger RNA (mRNA) splicing. Autoantibodies designated SS-A or Ro and SS-B or La were identified in patients with Sjogren's syndrome (SS) and SLE, and have been shown to target intracellular proteins that may be involved with regulation of RNA polymerase III function. Investigators in the field had long perceived that these spontaneously occurring auto-antibodies in human disease would turn out to be useful reagents in cell biology. It was also appreciated that it was necessary to characterize the molecular nature of the auto-antigens so that in addition to the immunochemical properties, their structure and function might be determined. One of the purposes of this chapter is to show that the new molecular biology of cellular antigens and auto-antibodies could now be providing insights into comprehending some features of autoimmunity. In addition, there appears to be a need for the synthesis of the wealth of information that has accumulated and an evaluation of what it might signify.

Antinuclear antibodies: diagnostic markers for autoimmune diseases and probes for cell biology

Discrete, stable small RNA molecules are found in the nuclei of cells1 from a wide variety of eukaryotic organisms2. Many of these small nuclear RNA (snRNA) species, which range in size from about 90 to 220 nucleotides, have been well-characterised biochemically3–6, and some sequenced7,8. However, their function has remained obscure. The most abundant snRNA species exist as a closely related set of RNA–protein complexes called small nuclear ribonucleoproteins (snRNPs)9. snRNPs are the antigens recognised by antibodies from some patients with lupus erythematosus (LE), an autoimmune rheumatic disease10,11. Anti-RNP antibodies from lupus sera selectively precipitate snRNP species containing Ula7 and Ulb9 RNAs from mouse Ehrlich ascites cell nuclei, whereas anti-Sm antibodies bind these snRNPs and four others containing U2 (ref. 8), U4, US and U6 (ref. 9) RNAs. Both antibody systems precipitate the same seven prominent nuclear proteins (molecular weight 12,000–32,000). All molecules of the snRNAs U1, U2, U4, U5 and U6 appear to exist in the form of antigenic snRNPs9. The particles sediment at about 10S and each probably contains a single snRNA molecule. Indirect immunofluorescence studies (refs 12, 13, and unpublished observations) using anti-RNP and anti-Sm sera confirm the nuclear (but non-nucleolar) location of the antigenic snRNPs. Here we present several lines of evidence that suggest a direct involvement of snRNPs in the splicing of hnRNA. Most intriguing is the observation that the nucleotide sequence at the 5′ end of U1 RNA exhibits extensive complementarity to those across splice junctions in hnRNA molecules.

Are snRNPs involved in splicing

Purpose:To determine the prevalence of lupus anticoagulant and anticardiolipin in systemic lupus erythematosus (SLE) and in non-SLE disorders, and to evaluate the clinical significance of ...

Antiphospholipid Antibodies: Anticardiolipin and the Lupus Anticoagulant in Systemic Lupus Erythematosus (SLE) and in Non-SLE Disorders

PURPOSE To determine the prevalence of lupus anticoagulant and anticardiolipin in systemic lupus erythematosus (SLE) and in non-SLE disorders, and to evaluate the clinical significance of these autoantibodies as they relate to thromboembolic events, neuropsychiatric disorders, thrombocytopenia, and fetal loss. DATA IDENTIFICATION A computer-assisted search of the literature (MEDLINE, 1966 to 1989) and review of the bibliographies of all identified articles. STUDY SELECTION Series of ten or more subjects were included if the assays used for detecting lupus anticoagulant or anticardiolipin met the specified minimal criteria for validity. DATA EXTRACTION Series were categorized according to antibody type and underlying disease. A systematic appraisal of patient selection methods, study design, and assay methods was done. RESULTS OF DATA ANALYSIS An analysis of 29 published series (comprising over 1000 patients with SLE) yielded an average frequency of 34% for the lupus anticoagulant and 44% for anticardiolipin. Antiphospholipid antibodies are also prevalent in patients with various non-SLE disorders. In patients with SLE, a statistically significant association exists between the presence of either antibody and a history of thrombosis, neurologic disorders, or thrombocytopenia. The available data suggest, but do not firmly support, an association between antiphospholipid antibodies and history of fetal loss in women with SLE. Contrary to prevailing opinion, none of these associations have been shown conclusively in patients with non-SLE disorders. CONCLUSIONS The results of predominantly retrospective series suggest that for certain persons (patients with SLE or closely related disorders) antiphospholipid antibodies may be important risk factors for thrombosis, neurologic disease, thrombocytopenia, and fetal loss. Standardized tests for lupus anticoagulant and anticardiolipin, as well as long-term, prospective clinical studies, are needed to determine the prognostic value of antiphospholipid antibodies.

Antiphospholipid Antibodies: Anticardiolipin and the Lupus Anticoagulant in Systemic Lupus Erythematosus (SLE) and in Non-SLE Disorders: Prevalence and Clinical Significance

Publisher Summary Autoantibodies to nuclear antigens (ANAs) have assumed an important place in the diagnostic armamentarium of the clinician because of distinct profiles of ANAs in different diseases. Profiles of ANAs have, therefore, been extremely useful in differential diagnosis, where the disease does not have classical or full-blown manifestations.. Immune complexes formed in the circulation or in situ mediate tissue injury by the activation of complement and other inflammatory mediators. Not only do these antibodies precipitate their respective antigens but also other proteins or nuclear RNAs that might be associated with them in special ways. The reasons for these special associations of protein antigens with specific sets of nuclear RNAs is unknown, but the possibility that there might be functional relationships in these complexed particles is not unreasonable. The key question that pervades the minds of many investigators in this field is the reason for the appearance of ANAs in certain individuals. It is highly improbable that the phenomenon is a random immune response to nuclear breakdown products, because the types of ANAs in different diseases are strikingly different. Some known environmental agents are drugs, such as hydralazine and procainamide, that together with lower levels of hepatic acetyltransferase enzyme predispose the host to the development of ANAs. Another agent may be the Epstein–Barr virus that is a ubiquitous environmental agent.

Autoantibodies to nuclear antigens (ANA): their immunobiology and medicine.

Saline extracts of rabbit thymus were found to contain many nuclear antigens that reacted with antibodies in the sera of patients with systemic rheumatic diseases. Counterimmunoelectrophoresis (CIE) was used to detect antibodies to nuclear acidic protein (Sm), nuclear ribonucleoprotein (RNP), and antibody to nuclear antigen B, which was reported previously in Sjogren's syndrome. All these nuclear antigens behaved as anions with different mobilities in CIE and could be distinguished from one another by the locations of the precipitin lines. They could also be distinguished by the facts that the nuclear RNP precipitin lines were abolished by digestion with ribonuclease whereas others were unaffected, and that Sm precipitin lines developed later than other precipitin lines. With this technique antibody to nuclear RNP was detected in 46% of patients with systemic lupus erythematosus (SLE) compared to 26% detected by the hemagglutination technique. Similarly the increased sensitivity of the CIE technique was able to show that antibody to B antigen was present in 12% of SLE patients, whereas this antibody was not detectable in the same group of patients by immunodiffusion. This study shows that CIE is a rapid and sensitive technique for detecting precipitating antibodies to a number of nuclear acidic antigens. Methods are described to identify the immunochemical specificities of the precipitin lines by the use of standard reference sera.

Identification of antibodies to nuclear acidic antigens by counterimmunoelectrophoresis

The prevalence of different antinuclear antibodies was examined in systemic lupus erythematosus, rheumatoid arthritis, Sjogren's syndrome, progressive systemic sclerosis, dermatomyositis, discoid lupus erythematosus, and mixed connective tissue disease. Antibody to Sm antigen (a nuclear acidic protein) was found almost exclusively in serums of patients with systemic lupus erythematosus, suggesting that this antibody might be a "marker" antibody for this disease. However, antibodies to native DNA and to nuclear ribonucleoprotein were found in a variety of systemic rheumatic diseases. In systemic lupus erythematosus, antibody to native DNA was present in high titer but in other rheumatic diseases in low titer. Antibody to nuclear ribonucleoprotein occurred in certain other systemic rheumatic diseases besides the mixed connective tissue disease syndrome. These studies showed that there were distinct profiles of antinuclear antibodies in certain systemic rheumatic diseases, characterized by the presence or absence of certain antibodies and by differences in their mean titers.

N Kurata

Papers

Identification of antibodies to nuclear acidic antigens by counterimmunoelectrophoresis

Profiles of antinuclear antibodies in systemic rheumatic diseases