Investigation of the Serological Changes that Discriminate Asymptomatic Antinuclear Antibody Positive Individuals from Systemic Autoimmune Rheumatic Disease Patients
The Antinuclear antibody (ANA) associated Systemic Autoimmune Rheumatic Diseases (SARDs) are chronic rheumatic disorders associated with high morbidity. Many patients with these diseases have irreversible tissue damage at disease presentation. Current therapies aim to control symptoms and prevent further damage by lessening the inflammatory immune response through broad and often aggressive immunosuppression, which leaves patients vulnerable to numerous side effects. Although ANAs are a serological hallmark for the ANA-associated SARD, they are also seen in healthy individuals, most of whom will not progress to disease. This not only precludes their use as biomarkers of progression but also indicates that their presence alone is insufficient to induce tissue damage and symptoms. Elucidating the serological differences between ANA-associated SARD patients and asymptomatic ANA+ individuals and the underlying immune mechanism(s) that led to these differences will permit identifying individuals at increased risk of progression and enable the development of better therapeutic targets. Here, we show that although the type, number, and levels of specific auto-antibodies (auto-Abs) remained stable over a 2-year follow-up period in the subset of asymptomatic ANA+ individuals that developed new SARD symptoms, these individuals have elevated levels of anti-Ro52 auto-Ab as compared to those that did not progress. We also demonstrated that SARD patients have very high levels of IgG auto-Abs as compared to ANA+ individuals that lack a SARD diagnosis, that are not detected by current screening techniques, arguing for the introduction of assays with a better dynamic range and discriminatory capacity. Additionally, we found that the IgG of SARD patients has a reduced sialic acid content, as compared to healthy controls and asymptomatic ANA+ individuals, which correlated with an increased ability to induce a pro-inflammatory response by monocyte-derived dendritic cells, serum levels of TNF- and the proportion of circulating T follicular helper 17 cells. These findings enhance our understanding of the underlying immunologic dysregulations that promote the transition from asymptomatic autoimmunity to disease and suggest that therapies that target these pathways may be useful to prevent progression to SARD.
Microarray, Microparticles, Sialic acid, Systemic autoimmune rheumatic diseases, Systemic lupus erythematosus
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