Background/Purpose:

Type I interferon(IFN) appears to contribute to the development of systemic lupus erythematosus (SLE). Overexpression of type I IFN regulated genes has been reported in patients with SLE. Although plasmacytoid dendritic cells (pDCs) is a major source of type I IFN including IFN-a and IFN-b, previous reports showed that IFN-α production by pDCs stimulated with a Toll-like receptor (TLR) 9 agonist or viruses was not increased in SLE compared to healthy controls (HC). In this study, we investigated another endosomal TLR-signaling pathway in SLE and the effect of type I IFN on TLR pathways.

Methods:

Blood samples were obtained from HC and patients with SLE diagnosed according to the systemic lupus international collaborating clinics classification criteria for systemic lupus erythematosus. Peripheral blood mononuclear cells (PBMCs) from SLE patients and HC were stimulated with a TLR9 agonist, CpG-A oligodeoxynucleotides -2216 (CpG-A ODN), or a TLR7 agonist, imiquimod. The proportion of IFN-α producing -pDCs was investigated by intracellular cytokine staining and flowcytometory. PBMCs were pretreated with IFN-α or IFN-β for 24 hours, and then IFN-α and IFN-β production by pDCs was assessed. Localization of TLR7 in cellular compartments in pDCs was investigated with or without pretreatment with IFN-α or IFN-β.

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 the proportion of IFN-α producing pDCs stimulated with CpG-A ODN was negatively correlated with SLEDAI. Exposure to Type I IFN enhanced IFN-α production of TLR7-stimulated pDCs, but reduced that of pDCs activated with CpG-A ODN. TLR7 localization was increased in late endosome/lysosome compartments in pDCs from SLE patients. TLR7 localization was increased in late endosome/lysosome compartments of pDCs treated with either IFN-α or IFN-β both in HC and SLE.

Conclusion:

IFN-α production by pDCs was increased upon stimulation with a TLR7 agonist in SLE patients. We found more TLR7 localization in late endosome/lysosome in lupus pDCs. Because IFN-α production requires TLR trafficking to lysosome-related organelle, enhanced IFN-α production by pDCs was partially due to TLR7 retention in the lysosomes in SLE. We also demonstrated that pretreatment with type I IFN enhanced IFN-α production by a TLR7 agonist-stimulated pDCs. In animal models of lupus, the role of TLR9 pathway in the pathogenesis is unclear but several reports indicated that TLR7 pathway is involved in the progression of autoimmune responses. Our study also indicates the importance of TLR7 pathway in SLE.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/enhanced-ifn-%ce%b1-production-by-plasmacytoid-dendritic-cells-is-associated-with-increased-toll-like-receptor-7-retention-in-the-lysosomes-and-exosure-to-type-i-ifn-in-systemic-lupus-erythematosus/