Background ANA+systemic autoimmune rheumatic diseases (SARD), including SLE, have a prolonged pre-clinical phase during which ANAs can be detected in the absence of clinical symptoms. ANAs are also seen in healthy individuals, most of whom will not progress to SARD. The immunological changes that promote development of clinical symptoms in SARD and conversely maintain benign autoimmunity in asymptomatic ANA+ individuals (ANA+NS) remain largely unexplored. To address this question, peripheral blood immune populations were examined in ANA+ individuals, with and without SARD.
Methods ANA+ (IF ≥ 1:160) subjects were classified as ANA+NS (n=61, no SARD criteria), undifferentiated connective tissue disease (UCTD, n=54, SARD criteria but lacking sufficient criteria for a diagnosis), or early SARD (SLE, n=10, SjD, n=7, SSc, n=5). All SARD patients were within 2 years of diagnosis and not taking Disease Modifying Anti-Rheumatic Drugs (hydroxychloroquine allowed) or prednisone. ANA–HC (n=21) were also recruited. Peripheral blood mononuclear cells were isolated and stained with fluorochrome labeled antibodies to identify immune cell populations via flow cytometry. Plasma TGF-ß1 levels were measured by ELISA.
Results We previously showed that ANA+NS and UCTD patients have increased B cell activation and expansion of T follicular helper (Tfh) cells, similar to that seen in SARD. Here we show that T peripheral helper (Tph) cells are also increased in ANA+NS and demonstrate further progressive increases in UCTD and SARD, resulting in a significant increase in SARD relative to ANA+NS. In ANA+NS and UCTD the majority of Tfh and Tph cells had a Th2 phenotype, leading to increased proportions of Tfh2 and Tph2 cells, as compared to ANA-HC. In addition to these increases, SARD patients had significant elevations of Tph17 cells. Increases in Extrafollicular and Type 1 Regulatory T cells were also seen in ANA+NS and UCTD, relative to ANA-HC, with SARD patients demonstrating a trend to normalization of these populations. Similar changes were seen in the levels of TGF-ß1. ANA+ individuals who demonstrated symptomatic progression within the subsequent 2 years (n=12) had significantly increased levels of activated class-switched and double negative memory B cells, plasmablasts, plasma cells, and Tph cells at baseline visit, as compared to those who remained stable over the same period of time.
Conclusion Collectively, our findings suggest active immunoregulation prevents clinical autoimmunity in ANA+NS, and that this is impaired in patients with SARD, resulting in an imbalance between Tregs and pro-inflammatory T helper cell subsets.
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