Background/Purpose

Photosensitivity is a common symptom in patients with systemic lupus erythematosus (SLE) and lupus skin lesions often contain plasmacytoid dendritic cells (pDC). The mechanisms linking ultraviolet (UV) light to inflammation and cutaneous flares is not  well understood.  While in vitro experiments have suggested that UV-induced apoptosis exposes lupus-specific nuclear antigens and immune complex mediated inflammation, this has not been shown in vivo.  Here, we asked whether, and under what conditions, UVB-induced inflammation could induce Type I interferon (IFN-I) and the roles of pDCs and also autoantibodies in cutaneous lupus.

Methods

Shaved C57BL/6 (B6), IFNAR KO, BDCA2 DTR, and huFcgR2a transgenic mice were irradiated with narrowband UVB at 100 mJ/cm²/day for 5 consecutive days.  To induce interface dermatitis, shaved and depilated mice were subject  to 15 strokes of tape stripping using medical tape (3M). Serial punch biopsies (6 mm) were obtained at 3, 24, and 72 hrs following UVB exposure or tape stripping. PDCs were detected in enzyme digested skin samples by flow cytometry (CD45+, Ly6C+, PDCA1+, CD11c+, Siglec H+). Skin samples were examined for mRNA expression by QPCR of pro-inflammatory cytokines and Interferon Stimulated Genes (ISG). mRNA fold change was calculated by comparison with  non-irradiated control mice. In experiments with huFcgR2a Tg mice, mice were irradiated as above but injected i.p. at the time of the final UVB exposure with purified immunoglobulin pooled from human lupus patients and the skin was examined by immunofluorescence for the presence of human IgG.

Results

Whereas tape stripping induced a robust ISG response associated with the presence of pDC in the skin, repeated UVB exposure induced a more modest IFN-I skin response with bimodal peaks at 3 and 72 hrs when compared to control mice (p<0.05, n=20).  UVB-irradiated IFNAR KO mice had increased levels of pro-inflammatory cytokines TNFα and IL-6 at (p<0.01 at 3 and 24 hr time points, n=12-13) and had increased levels of inflammation by visual scoring suggesting a protective role for IFN-I. Interestingly, pDCs did not appear to be the source of IFN following UVB as pDC-depleted BDCA2 DTR mice maintained moderate expression of ISGs.  Immunoglobulin from human lupus patients, but not IVIG, localized to the skin at the dermal/epidermal junction following UVB of FcgR2A transgenic and wild-type mice, but FcgR2a signaling was required for cellular uptake and enhanced Type 1 IFN signaling (p<0.05, n=5-9).

Conclusion

In the normal host, repeated doses of UVB induce a protective, pDC-independent Type1 IFN response in the skin that attenuates pro-inflammatory signals and limits tissue damage. In contrast, in situations associated with the presence of autoantibodies as occurs in lupus, the antibodies bind to UVB-exposed antigen, deposit in the skin and require Fcgr2a-mediated uptake to produce enhanced expression of IFN-I.  This novel FcgR2a mouse model of cutaneous lupus establishes the role of UVB in exposing otherwise sequestered nuclear antigens and in facilitating immune-complex mediated skin disease in lupus.

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« Back to 2014 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/ultraviolet-b-generates-type-1-interferon-and-induces-autoantibody-mediated-disease-in-a-mouse-model-of-cutaneous-lupus/