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AB0038 Increased interferon-alpha production by plasmacytoid dendritic cells stimulated with a TLR-7 agonist in systemic lupus erythematosus
  1. G Murayama1,2,
  2. N Furusawa2,
  3. A Chiba2,
  4. K Yamaji1,
  5. N Tamura1,
  6. S Miyake2
  1. 1Department of Internal Medicine and Rheumatology
  2. 2Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan

Abstract

Background Type I interferon (IFN) appears to contribute to the development of systemic lupus erythematosus (SLE). IFN-α production is known to be increased in peripheral blood mononuclear cells (PBMCs) from SLE patients. Although plasmacytoid dendritic cells (pDCs) is a major source of IFN-α, previous reports showed that IFN-α production by pDCs stimulated with a TLR-9 agonist was decreased in SLE compared to healthy controls (HC).

Objectives We set out to investigate an other endosomal TLR-signaling pathway in SLE by using TLR-7 agonist stimulation.

Methods Blood samples were obtained from 55 HC and 73 SLE patients, diagnosed according to the systemic lupus international collaborating clinics classification criteria for systemic lupus erythematosus (2012). PBMC from SLE patients and HC were stimulated with a TLR-9 agonist, CpG-A oligodeoxynucleotides (CpG-A ODN)-2216, and a TLR-7 agonist, imiquimod. The proportion of pDCs producing IFN-α was investigated by intracellular cytokine staining and flowcytometory. PBMC were pretreated with IFN-α for 24 hours, and then IFN-α production by pDCs was assessed after imiquimod stimulation.

Results As previously reported, the level of IFN-α production by pDCs stimulated with CpG-A ODN was reduced in SLE compared with HC. However, the proportion of IFN-α producing pDCs stimulated with imiquimod was significantly increased in SLE patients. The percentage of IFN-α producing pDCs stimulated with imiquimod was positively correlated with SLE disease activity index (SLEDAI) score, and that of pDCs stimulated with CpG-A ODN was negatively correlated with SLEDAI. The expression of TLR-7 on pDCs, but not TLR-9, was upregulated in SLE patients compared with HC. Furthermore, pretreatment with IFN-α increased IFN-α production by pDCs upon imiquimod stimulation.

Conclusions IFN-α production by pDCs form SLE patients was increased when stimulated with a TLR-7 agonist, and this was accompanied with upregulated TLR-7 expression in these cells. In murine lupus-models, TLR7-deletion has been shown to reduce autoimmune disease. The enhanced TLR-7 signaling pathway in pDC may play an important role in lupus pathology.

References

  1. Christensen SR, et al. Toll-like receptor 7 and TLR9 dictate autoantibody specificity and have opposing inflammatory and regulatory roles in a murine model of lupus. Immunity. 2006; 25: 417–28.

  2. Sacre K, et al. Hydroxychloroquine is associated with impaired interferon-alpha and tumor necrosis factor-alpha production by plasmacytoid dendritic cells in systemic lupus erythematosus. Arthritis Res Ther. 2012;R155.

  3. Fukui R, et al. Unc93B1 restricts systemic lethal inflammation by orchestrating Toll-like receptor 7 and 9 trafficking. Immunity 2011; 35: 69–81.

References

Disclosure of Interest None declared

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