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

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.

The relation between congenital heart block and maternal connective-tissue disease was studied by antibody screening of serum samples obtained in connection with 45 cases of isolated congenital complete heart block. Serum was available from 41 mothers (17 who had connective-tissue disease and 24 who were healthy) and 21 children. Thirty-four mothers had antibody to a soluble tissue ribonucleoprotein antigen called Ro(SS-A), which was identified by immunodiffusion. Anti-Ro(SS-A) was found in seven of eight serum samples collected from affected children when they were less than three months old but in none of 13 samples obtained when these children were older. It appears that maternal anti-Ro(SS-A) antibody crosses the placenta and is a marker for risk of congenital complete heart block; its absence from maternal serum suggests that a child is unlikely to be affected. Anti-Ro(SS-A) or a related antibody is probably involved in the pathogenesis of congenital complete heart block.

https://www.nejm.org/doi/pdf/10.1056/NEJM198307283090403?listPDF=true

Connective-tissue disease, antibodies to ribonucleoprotein, and congenital heart block

Autoantibodies in the diagnosis of systemicrheumatic diseases

The RNP and Sm antigens recognized by lupus erythematosus antibodies are located on discrete particles containing single small nuclear RNA's complexed with proteins. The antigens Ro and La are also on ribonucleoproteins. The small RNA's in ribonucleoproteins with Ro are discrete, like those associated with RNP and Sm; in contrast, ribonucleoproteins with La contain a striking highly banded spectrum of small RNA's from uninfected cells as well as virus-associated RNA from adenovirus-infected cells.

https://science.sciencemag.org/content/sci/211/4480/400.full.pdf

Two novel classes of small ribonucleoproteins detected by antibodies associated with lupus erythematosus.

Summary A tissue antigen reactive with sera from SLE patients has been partially characterized. The antigen is a soluble cytoplasmic component which is present in a variety of human tissues and is distinct from known nuclear antigens. It is an acidic macromolecule which has the electrophoretic mobility of an α 1 globulin and is resistant to most proteolytic enzymes including trypsin, pepsin and chymotrypsin. Antigenicity is destroyed by 0.02 M periodate and by 0.001 M parahydroxy mercuribenzoate. Antibodies to this antigen have been found in 40% of unselected LE sera and were absent from a large number of sera from normal persons and from the sera of patients with other connective tissue disorders.

Geoffrey Clark

Papers

Characterization of a Soluble Cytoplasmic Antigen Reactive with Sera from Patients with Systemic Lupus Erythmatosus