Date: Sunday, November 5, 2017
Session Type: ACR Concurrent Abstract Session
Session Time: 4:30PM-6:00PM
Background/Purpose: Cutaneous inflammation is a common and disfiguring manifestation for 70% of patients with systemic lupus erythematosus, yet our understanding of the pathogenesis of cutaneous lupus erythematosus (CLE) has lagged. Type I IFN signatures are elevated in CLE lesions and contribute to pathology. However, the source of type I IFN production and the function of type I IFNs in CLE has not been examined. We thus investigated the sources of type I IFN in CLE and examined the role of keratinocyte-produced IFN kappa to prime for type I IFN responses in keratinocytes.
Methods: 90 biopsy-proven CLE patients were examined for type I IFN expression using Affymetrix ST2.1 microarray. Tissue expression of IFNs was confirmed with immunofluorescence microscopy. Primary keratinocytes were grown from biopsies of non-lesional, non-sun exposed skin from healthy controls and patients meeting >4 ACR SLE criteria with a history of documented CLE. IFN activation was examined using real-time PCR and Western blot. IFN kappa knockout keratinocyte lines were made using CRISPR/cas9-mediated deletion.
Results: Analysis of CLE lesions confirmed heightened type I IFN responses and demonstrated IFNK as one of only two increased type I IFN transcripts in CLE lesions vs. control skin. IFN kappa was expressed predominantly in the basal keratinocyte layer in both healthy skin and lesional CLE, but its expression was increased in CLE lesions and in non-lesional SLE keratinocytes. Importantly, IFN kappa was required for basal type I IFN responses in keratinocytes. Indeed, absence of IFNK resulted in minimal type I IFN gene expression and a delayed response to exogenous type I IFN stimulation. In contrast, IFN kappa overexpression accelerated and amplified responses to exogenous IFN alpha in a IFN kappa dependent manner.
Conclusion: IFN kappa is a key regulator of IFN responses in keratinocytes. In SLE and CLE, keratinocytes are primed by an abundance of IFN kappa to generate robust responses to exogenous type I IFNs, setting up a feed forward loop which promotes exaggerated IFN responses and subsequent activation of the immune system. Thus, IFN kappa may serve as an excellent and specific target for treatment and prevention of cutaneous inflammation in SLE patients.
To cite this abstract in AMA style:Gudjonsson J, Sarkar M, Tsoi A, Berthier CC, Hile G, Liang Y, Liu J, Harms P, Kahlenberg JM. Cutaneous Lupus Is Driven By an Exaggerated Interferon Kappa Loop Which Primes for Interferon Alpha Responses [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/cutaneous-lupus-is-driven-by-an-exaggerated-interferon-kappa-loop-which-primes-for-interferon-alpha-responses/. Accessed June 5, 2020.
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