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II-09 SLE bone marrow contains factors that promote type I interferon activation
  1. Nida Meednu1,
  2. Anna Bird1,
  3. Jennifer Hossler1,
  4. Mariana Kaplan2 and
  5. Jennifer Anolik1
  1. 1Department of Medicine, Division of Allergy, Immunology and Rheumatology, University of Rochester Medical Centre, Rochester, NY, U.S.A
  2. 2Systemic Autoimmunity Branch, Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, U.S.A

Abstract

Background SLE is characterised by the inappropriate activation of type I Interferon (IFN) and increases in apoptosis and NETosis by neutrophils, which in combination with defective apoptotic cell and NET clearance provides an ongoing source of self-antigen. IFN can further propagate the disease process by promoting B cell activation, survival, and differentiation into plasma cells (PC). PC produces autoantibodies that can form immune complexes (IC) to further stimulate IFN production creating a vicious cycle. Important questions that remain unclear are the site and mechanisms of IFN activation. We have recently demonstrated a prominent IFN signature in the bone marrow (BM) of SLE patients that is more pronounced than paired peripheral blood and correlated with higher serum autoantibodies and disease activity. We hypothesise that BM is a key site of IFN activation in SLE and better understanding of signals in the BM that regulate IFN activation may lead to discovery of new treatment targets.

Materials and methods BM supernatant and serum were obtained from SLE patients (n = 11 IFN high, n = 11 IFN low). Plasmacytoid dendritic cells (pDC) were purified from healthy donor blood. To determine if BM supernatant and serum induce IFN production, pDC was cultured with BM supernatant or serum with and without necrotic cell material. Necrotic cell material was generated by repeat freeze-thawed U937 cells. Culture supernatants were collected and IFN was measured by ELISA.

Results We found that BM supernatant from SLE patients with high level of multiple serum autoantibodies was able to induce pDC to produce type I IFN (BM: 12481 ± 259.1, BM + necrotic: 12091 ± 68.50 pg/ml). The serum from the same patient also induced pDC to produce IFN that was greatly enhanced by necrotic cell material (serum: 12244 ± 90, serum + necrotic: 114292 ± 6998 pg/ml). BM supernatant and serum from SLE patients with low level of serum autoantibodies did not induce pDC to produce IFN even in the presence of necrotic cell material. The relationship to the IFN signature and NETosis is under evaluation. Additionally, we are examining ICs as interferonogenic factors in the BM.

Conclusions These data suggest that the BM microenvironment of SLE patient contains factor(s) that promote type I IFN production by pDC that may correlate with the presence of serum autoantibodies. However, the mechanisms of IFN production in the BM appear to be different from that of the serum.

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