Background/Purpose: Type I interferons (IFNs) are elevated in the skin and blood of patients with systemic (SLE) and cutaneous (CLE) lupus erythematosus. Upregulation of type I IFNs in non-lesional keratinocytes promotes myeloid activation and cell death in response to ultraviolet light, an important trigger for skin and systemic disease flares. The reasons for chronic type I IFN upregulation in non-lesional SLE remain under-explored but are important targets for disease flare prevention. Here, we examined upregulation of the protein ORF1p, which occurs with de-repression of LINE-1 elements, in conjunction with markers of STING activation and type I IFN signatures in non-lesional SLE skin biopsies.

Methods: Non-lesional skin biopsies were obtained from the upper thigh of 40 patients with SLE and were examined via bulk RNA sequencing and immunohistochemistry (IHC) for ORF1p and phosphorylated (activated) STING. IHC was scored for number of positively staining cells across the basal epidermis within10 field of view at 20x magnification. Expression of ORF1p was correlated with clinical data of patients. Interferon scores using 138 epidermal specific genes regulated by type I IFN exposure was calculated as previously reported.

Results: Healthy control skin biopsies had very low levels of ORF1p expression with no subject having >1 positive cell per field at 20 X magnification (mean 0.395, SD 0.258). SLE patients, on the other hand, exhibited significantly higher expression of ORF1p (mean 16.018, SD18.510). There was a strong correlation between staining for ORF1p and phospho-STING in the basal epidermis (R2=0.871, p< 0.0001). Type I IFN scores were significantly increased in SLE patients who had an average of >10 cells stained for ORF1p per field (mean of < 10 cells -12.070, SD 76.931; mean of > 10 cells 151.080, SD 158.163; p=0.020). Evaluation of clinical data found a correlation between ORF1p epidermal staining and points on the EULAR/ACR classification criteria for SLE (R=0.55, p=0.002). No differences were noted in ORF1p positivity based on use of hydroxychloroquine, history of skin disease, or CLASI activity.

Conclusion: ORF1p staining is increased in non-lesional skin of SLE patients and correlates strongly with the activation of STING in the epidermis and the presence of an interferon signature in the skin. SLE patients with the most widespread disease exhibit the highest ORF1p expression. Further research is needed to determine if ORF1p upregulation (and the preceding de-repression of LINE1 elements) is a cause or consequence of type I IFN signaling in SLE skin. This understanding will lead to novel therapies to treat type I IFN-driven disease.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/orf1p-expression-correlates-with-sting-activation-and-ifn-signatures-in-sle-nonlesional-skin/