Background/Purpose: Systemic autoimmune rheumatic diseases (SARD) including Sjogren’s Disease (SjD), Systemic Sclerosis (SSc) and Systemic Lupus Erythematosus (SLE) are characterized by the production of anti-nuclear antibodies (ANA) and are associated with considerable morbidity and/or mortality. ANA production can also be seen in ~20% healthy women, only a small subset of which will eventually progress to a SARD diagnosis. Although pro-inflammatory cytokines including TNFα and IL-6 are only increased in symptomatic patients, some of the cellular immune changes associated with SARD are also seen in ANA⁺ non-symptomatic (ANA⁺ NS) individuals. In order to better understand the immunologic changes that lead to SARD progression, we used flow cytometry to investigate a variety of innate and adaptive immune populations in ANA⁺ NS as compared to healthy controls (HC) and SARD patients.

Methods: Consenting ANA⁺ (IF ≥ 1:160) participants were recruited through the clinic and classified as ANA⁺ NS (n = 38), ANA⁺ with symptoms but lacking sufficient criteria for SARD diagnosis (UCTD, n=42) or early SARD (SLE, n=5, SSc, n=2). SARD diagnosis and classification was assessed according to the 1997 ACR criteria for SLE and the 2013 ACR-EULAR criteria for SSc. All SARD patients were within 2 years of diagnosis and not taking DMARDs (hydroxychloroquine allowed) or prednisone. ANA^– HC (n= 14) were also recruited. Peripheral blood mononuclear cells (PMBCs) were isolated and stained with fluorochrome labeled antibodies to identify immune cell populations via flow cytometry.

Results: Several of the immunologic changes previously reported for SARD patients were also seen in ANA⁺ NS and UCTD. These included: increased proportions of plasma cells and plasmablasts; a trend to increased transitional B cells, activated class-switch memory B cells, activated memory Tfh and Tph cells; and a trend towards decreased proportions class-switched memory B cells. Contrary to initial reports that T regulatory (T_reg) cells are decreased in SARD, these cells were increased in ANA⁺ NS and UCTD groups with similar changes seen for the SARD patients. However, a subset of regulatory cells, CD8 T_reg were markedly decreased in ANA⁺ NS and UCTD patients, suggesting a potential functional role for these cells in regulating autoimmunity. Monocytes and myeloid dendritic cells are increased in SARD patients and have been shown to produce pro-inflammatory cytokines. These populations were also significantly increased in ANA⁺ NS and to a lesser extent in UCTD patients, as compared to HC. In contrast, no changes were seen in the proportion of plasmacytoid dendritic cells in ANA⁺ NS and UCTD patients.

Conclusion: Several of the immune changes in ANA⁺ NS individuals appear to parallel those seen in SARD patients, indicating that there is substantial immune activation even in asymptomatic ANA⁺ individuals. These findings argue that the differences between ANA⁺ NS and SARD patients may result from altered function rather than altered proportions of these populations.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/evidence-for-substantial-immune-activation-in-asymptomatic-ana-positive-individuals/