The understanding of patients who are autoantibody positive without autoimmune symptoms is evolving: some of these patients may be in the subclinical stages of diseases such as systemic lupus erythematosus (SLE), while most of the remaining individuals may not develop SLE or other autoimmune diseases throughout their lives. The high incidence of autoimmune reactions suggests that autoantibodies are an integral part of the normal immune response, and there are also data demonstrating that certain autoantibodies have important immunomodulatory functions. Based on these results, researchers have asked the following questions: When does an autoimmune response begin and how does it develop into a typical autoimmune disease? If the transition from a subclinical autoimmune response to a classic clinical disease such as SLE could be predicted, physicians would have the opportunity to implement earlier and more effective treatments, and even achieve a complete cure for the disease. In addition, enhanced research into the mechanisms of selective and continuous monitoring of autoantibodies could help screen for new ways to block or prevent disease transformation. Dr. Olsen et al. from the Division of Rheumatology at Hershey Medical Center published a review of current research advances in the role of SLE-related autoantibodies in asymptomatic patients, in which the authors’ perspective on the role of autoantibodies in disease progression is presented. The review was published in the March 2014 issue of Nat Rev Rheumato. It is a typical autoimmune disease in which a variety of specific autoantibodies can be detected in patients. At this stage, the prognosis of SLE patients has improved significantly, with 5-year survival rates exceeding 90%. However, the onset of SLE in young adults and the irreversible organ damage that results in long-term pain and shortened life expectancy pose a significant medical challenge. In fact, even with the strongest immunosuppressive regimens available, physicians are unable to prevent or reverse the organ damage that occurs early in the course of SLE. This harsh reality has stimulated interest in identifying subclinical disease states in SLE and improving early diagnosis. The presence of autoantibodies is a typical feature of SLE, a clinical syndrome that combines a series of independent, nonspecific clinical symptoms with the presence of antinuclear antibodies (ANAs). ANAs were initially detected using the LE (lupus erythematosus) cell assay, in which the presence of ANAs was confirmed by the finding of phagocytosis of polymorphic nuclei of leukocytes. Subsequently, scientists found that ANAs were detected by indirect ANAs have become almost essential for the diagnosis of SLE. Screening by indirect immunofluorescence revealed that more than 99% of SLE patients will show positive ANAs at some point in their disease course. Recent studies have found that ANAs and other autoantibodies can be detected up to 10 years before the onset of typical clinical symptoms in SLE. These findings are not only found in SLE, but also in studies related to subclinical rheumatoid arthritis (RA) and type 1 diabetes. While these findings may make it easier to diagnose disease early, they raise another issue – the detection of these autoantibodies alone is not sufficient to predict disease: the prevalence of positive ANAs or rheumatoid factor (RF) in the general population exceeds the prevalence of SLE or RA in the population. A study of an undifferentiated population sample found that the prevalence of positive ANAs in the sample that were at least low-titer positive was more than 25%, while the prevalence of SLE in the sample was less than 0.15%. It was found that autoantibodies of types other than ANAs can also be present in asymptomatic individuals. These results suggest that the presence of autoantibodies is not indicative of disease; rather, autoimmune responses may be an important component of the normal immune response. The medical community needs to reconceptualize the role of autoantibodies in health and disease. The purpose of this article is to analyze how the presence of SLE-associated autoantibodies in asymptomatic patients affects an individual’s health and disease status, and to further sort out the triggers for disease progression. Autoantibodies outside of SLE – autoantibodies in healthy individuals Positive ANAs are very common in the general population. Studies from different regions have found that about a quarter of individuals have positive autoantibodies at least at low titers (i.e., titers ≥1:40 by immunofluorescence). Using standard immunofluorescence assays in healthy populations, about 5% of healthy individuals were found to be positive for ANAs at ≥1:160 with predominantly speckled cytosolic staining. Several other studies have found that more than 2% of the population will have titers of ANAs that would otherwise be considered abnormal. In fact, some of the specific components of ANAs may be seen more often in healthy individuals than in patients with autoimmune diseases. One study found that autoantibodies of the spotted type were present in nearly 9% of healthy individuals, compared to 3% of SLE patients who were positive. In this study, 6% of patients with Hashimoto’s thyroiditis were positive for speckled autoantibodies, the second highest rate of positivity after the healthy population and even before SLE. This also suggests that there is an undetected thyroid autoimmune response in at least a significant proportion of individuals with normal clinical presentation. Epidemiologic studies have found that women comprise the majority of the healthy population with positive ANAs ≥1:40, with a particular predominance in women aged 40 to 60 years, with a peak at 40-49 years. Some studies have also found that ultra-high titers of ANAs may be seen only in women. It is known that women account for 80-90% of the total number of patients with SLE, and the fact that ANAs positivity is more common in women confirms the correlation between differences in autoantibody positivity in healthy individuals and differences in disease incidence. The susceptibility of female patients to anti-nuclear autoimmune reactions may contribute to their high incidence of SLE. However, for the majority of women with positive ANAs, SLE may not occur throughout their lifetime, suggesting that anti-nuclear autoimmune responses outside of SLE disease may also provide a beneficial immune response for women. The correlation between positivity and age is less clear than the correlation with sex, and a 2012 study reported a positive correlation between ANAs positivity and increasing age, with the highest rate of ANAs positivity in individuals >70 years of age, but some studies have also shown no correlation between age and ANAs expression. Drug-mediated ANAs positivity occurs mainly in the elderly population, but in the younger population (especially in those <40 years of age), the possibility of progression to connective tissue disease is a concern. Some studies have looked at racial and ethnic differences in the rate of ANAs positivity, which is mildly elevated in non-Hispanic black populations. A higher value of ANAs positivity was found in black Americans compared to other races as measured by enzyme-linked immunosorbent assay (ELISA). Different Types of Autoantibodies In addition to ANAs, many other types of autoantibodies have been found in clinically normal individuals, at least some of whom are in the early stages of autoimmune disease. Retrospective examination of previously stored serum samples has revealed that multiple autoantibodies can be present in SLE patients prior to disease diagnosis. Two independent studies from the United States and Northern Sweden had similar results, both suggesting a progressive autoimmune response. Positive anti-SSA/Ro and anti-SSB/La antibodies were detected between the onset of clinical symptoms (on average 3.4 years before diagnosis), while positive anti-dual-stranded DNA antibodies (anti-dsDNA) appeared at a time that largely coincided with diagnosis (on average 1.2 years before diagnosis). In a cross-sectional demographic study, anti-SSA/Ro antibodies were found in 4% of those positive for ANAs, and anti-SSA/Ro, anti-SSB/La, anti-argonaute-2 antibodies, and anti-U1RNP antibodies were the most common antibodies found in ANAs, accounting for 7% of the total. Overall, these autoantibodies are seen mainly in women. Some autoantibodies, such as anti-SSA/Ro antibodies, are not always associated with positive ANAs, so the rate of positivity for these antibodies may be higher in the overall population. Autoantibodies accumulate and eventually lead patients to develop typical clinical autoimmune diseases, but the mechanism behind this is not clear. More than 100 different autoantibodies are associated with the disease and there are many methods for their detection. Current techniques have made it possible to detect many different types of autoantibodies from a very small number of serum samples. Using these techniques in healthy populations, more autoantibodies can be detected, especially in those positive for ANAs. Risk of disease development The characteristics of autoantibodies are related to their underlying pathological mechanisms. For example, there are differences in organ damage mediated by different autoantibodies directed against DNA. This variability is related to the specificity of the antibodies themselves and, of course, to autoantigenic epitopes. Constant regions of anti-DNA antibodies exhibit antigenic specificity and affect survival in mouse models of lupus nephritis. Anti-SSA/Ro antibodies are similarly heterogeneous and are divided into two subtypes according to Ro52 (52kDa Ro protein) and Ro60 (60kDa Ro protein) epitopes, which are associated with differences in clinical symptoms in SLE patients. However, the value of autoantibody subtypes in predicting whether a patient will develop typical clinical disease is unclear. The target proteins of autoantibodies distributed in the skin (e.g., bridging granule core glycoproteins, integral proteins) are present in healthy human skin at levels lower than those of ANAs. Exposure to ultraviolet light or other bad elements causes skin lesions, which may disrupt the immune balance of autoantigens at the earliest. These assumptions are supported by the phenomenon that patients with polymorphic heliotropic rash can detect temporary positive ANAs. In contrast, in disease-susceptible individuals, the elevated levels of ANAs induced in this way may be persistent, ultimately leading to disease onset. For many years, the diagnosis of SLE has revolved around a set of clinical symptoms and laboratory indicators. The previous diagnostic criteria for SLE were developed in 1982 and revised in 1997. Of these 11 criteria, two were related to autoantibodies: one was positive for ANAs and the other was positive for any of antiphospholipid, anti-dsDNA or anti-Sm antibodies. The latest diagnostic criteria for SLE, proposed by the SLICC working group, still require that the patient's diagnosis meet four indicators, but must include at least one clinical indicator and one immunological indicator. This revised protocol reflects the fact that SLE is a disease that involves both clinical symptoms and serum-specific changes. In clinical practice, physicians often encounter cases who do not meet any of the four criteria for SLE, but do have some evidence of autoimmune disorder. These patients need to be monitored with further follow-up, and sometimes they need to be started on treatment. About thirty years ago, this group of patients was named incomplete lupus (ILE). the diagnosis of ILE patients is broader; for example, patients may lack clinical symptoms but have only two immunologic abnormalities that are thought to predict the onset of SLE, or they may have only the typical manifestations of photosensitivity and a rash. Several studies have found that 15-20% of patients with ILE may progress to classic SLE after 5-10 years, and with the diagnosis of ILE, clinicians will pay more attention to the group of patients who are at high risk of developing SLE, as well as offering the possibility to explore the early stages of disease progression. Until now, however, the high-risk factors for ILE progression to SLE have remained unclear, and this predictive information may be key to targeting treatments that delay early SLE progression or completely reverse the early stages of SLE. One study found that patients with ILE have a higher autoimmune response than the general population and that their first-degree relatives are more likely to have an autoimmune disease. Further stratified analysis revealed that seven antigenic determinant clusters on IgG-type autoantibodies were associated with patients' clinical symptoms, with significantly higher correlates in ILE patients compared to the general population. These antigenic determinant clusters included autoantibodies known autoantigens (including SSA/Ro, SSB/La, Jo-1), collagen (type I, II, III), tissue-specific antigens (tissue transglutaminase, endogenous factors), nuclear antigens (dsDNA, single-stranded DNA [ssDNA]), DNA-binding proteins (Ku), small ribonucleoproteins (snRNPs) and histones. Patients who carry autoantibodies with DNA and snRNP antigen determinants are more likely to meet the diagnostic criteria for SLE. These findings suggest that patients with ILE may have an increased autoimmune response and elevated levels of autoantibodies, some of which may progress to SLE and others may develop tissue-specific autoimmune disease. Autoantibody subtypes Several major subtypes of immunoglobulins (IgA, IgE, IgG, IgM) are associated with the autoimmune response, but not all autoantibodies are involved in the pathogenesis of disease. Most of the autoantibodies involved in disease pathogenesis are of the IgG type, while IgM autoantibodies are associated with a reduction in disease symptoms. For example, IgM-type anti-DNA antibodies are therapeutically beneficial in murine models of lupus and are also associated with a reduced incidence of kidney damage in patients with SLE. IgM-type autoantibodies targeting apoptosis-associated antigens are also protective in SLE patients, and are negatively associated with disease activity, organ damage, and cardiovascular event rates. Autoimmune response-related IgA and IgE autoantibodies may be associated with the onset and progression of lupus nephritis. The presence of autoimmune reactions in healthy human B lymphocytes is widely recognized, and B cells can be activated in vitro and produce pathological autoantibodies, such as anti-dsDNA antibodies. This suggests that B lymphocytes with autoimmune response capacity are normally distributed in healthy individuals, but are simply not activated. Increasingly, studies have identified the induction of autoantibody production by peripheral blood autoimmune B cells as an important part of the progression of subclinical autoimmune diseases. The factors involved in the induction of this process are not clear and may be related to estrogen, smoking, drugs, environment, and viral infections. For example, vitamin D deficiency is thought to be associated with autoimmune dysfunction in healthy individuals, but it is not clear whether this association increases the risk of clinical disease development. It has also been suggested that adjuvants mediate the pathogenesis of SLE and that the onset of SLE may be related to UV exposure, toxins, metabolism of drugs that enhance apoptosis or autophagy, and reactive oxygen species; subsequently, intrinsic and acquired immunity is stimulated and immune cells are activated and proliferate, leading to the production of autoantibodies and upregulation of proinflammatory factors that ultimately promote the autoimmune response and the development of autoimmune disease. It is clear that more individuals experience these immune responses but do not eventually develop SLE, so it is important to further define disease susceptibility factors including gender and genetic risk factors. This will allow us to understand not only the course of autoimmunity, but also to recognize the transitions in the progression of the disease from the subclinical stage to the typical clinical stage. The timing of the onset of SLE-related damage is unpredictable, and disease damage may occur before the disease is formally diagnosed. Patients at risk of developing clinically typical SLE or other autoimmune diseases should be identified early and reliably by physicians, who should also try to avoid false-positive predictions of disease progression. Predictive models developed on the basis of autoantibodies or other factors, if used for analysis of asymptomatic populations, must have a high specificity for the risk of disease progression.