Antinuclear antibodies: clinical correlations and biologic significance

Several trends become evident from the foregoing discussion. As the different ANA antigenic specificities have been identified, they have often been found to be highly conserved polypeptides that subserve very basic cellular functions that are carried out in the nucleus, nucleolus, and ribosomes. The reasons why only 30 or so basic cellular proteins become the targets of an autoimmune response in patients with connective tissue disease at the exclusions of the other 10,000 macromolecules that exist inside cells remain a mystery. However, some insight into this enigma might be provided by the mechanism of molecular mimicry (Table 9). The possibility that highly conserved immunogenic molecules that are expressed by infectious pathogens can trigger an immune response in a genetically predisposed human host that cross-reacts with cellular autoantigens is a well documented phenomenon in disorders such as rheumatic fever. This mechanism is now being mentioned with increasing frequency in discussions pertaining to the pathogenesis of autoimmune connective tissue diseases. Another trend relates to the increasing sensitivity of the newer assays that have been developed to detect ANA. When highly purified or recombinant autoantigens are used in versatile assays such as ELISA, radioimmunoassays, or immunoprecipitation, the frequency with which certain autoantibodies can be detected in patient subgroups can go up significantly. For example, with classical immunodiffusion, anti-Ro/SS-A antibodies can be detected in 25% of unselected patients with SLE, whereas with an ELISA based on affinity purified Ro/SS-A antigen, 50% of patients with SLE are found to have elevated levels of this autoantibody specificity. As is often the case, we pay for increased sensitivity in a laboratory test with decreased specificity. With immunodiffusion, virtually no normal individuals have anti-Ro/SS-A antibodies, but with the ELISA as many as 10% of normals have elevated anti-Ro/SS-A binding levels. Thus, the incremental diagnostic value of this newer anti-Ro/SS-A assay could be questioned. The true clinical value of this new laboratory technology will become more evident when these more sophisticated ANA assays are used together in a panel-like fashion to profile a given patient's autoimmune response at the very onset of his illness. Preliminary work has already begun in this area. This approach, if well standardized, could have significant diagnostic and prognostic value. Another benefit of this newer technology will be the ability to measure antibody binding levels to individual autoepitopes--limited portions of an autoantigen's amino acid sequence that represent single antibody binding sites. It is possible that certain patterns of clinical disease could be linked to autoantibody production against individual autoepitopes rather than whole autoantigenic molecules. This area is only now beginning to be explored.