IL18-containing 5-gene signature distinguishes histologically identical dermatomyositis and lupus erythematosus skin lesions
Lam C. Tsoi, Mehrnaz Gharaee-Kermani, Celine C. Berthier, Tori Nault, Grace A. Hile, Shannon N. Estadt, Matthew T. Patrick, Rachael Wasikowski, Allison C. Billi, Lori Lowe, Tamra J. Reed, Johann E. Gudjonsson, J. Michelle Kahlenberg
Lam C. Tsoi, Mehrnaz Gharaee-Kermani, Celine C. Berthier, Tori Nault, Grace A. Hile, Shannon N. Estadt, Matthew T. Patrick, Rachael Wasikowski, Allison C. Billi, Lori Lowe, Tamra J. Reed, Johann E. Gudjonsson, J. Michelle Kahlenberg
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Research Article Dermatology

IL18-containing 5-gene signature distinguishes histologically identical dermatomyositis and lupus erythematosus skin lesions

Abstract

Skin lesions in dermatomyositis (DM) are common, are frequently refractory, and have prognostic significance. Histologically, DM lesions appear similar to cutaneous lupus erythematosus (CLE) lesions and frequently cannot be differentiated. We thus compared the transcriptional profile of DM biopsies with CLE lesions to identify unique features. Type I IFN signaling, including IFN-κ upregulation, was a common pathway in both DM and CLE; however, CLE also exhibited other inflammatory pathways. Notably, DM lesions could be distinguished from CLE by a 5-gene biomarker panel that included IL18 upregulation. Using single-cell RNA-sequencing, we further identified keratinocytes as the main source of increased IL-18 in DM skin. This study identifies a potentially novel molecular signature, with significant clinical implications for differentiating DM from CLE lesions, and highlights the potential role for IL-18 in the pathophysiology of DM skin disease.

Authors

Lam C. Tsoi, Mehrnaz Gharaee-Kermani, Celine C. Berthier, Tori Nault, Grace A. Hile, Shannon N. Estadt, Matthew T. Patrick, Rachael Wasikowski, Allison C. Billi, Lori Lowe, Tamra J. Reed, Johann E. Gudjonsson, J. Michelle Kahlenberg

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Figure 5

DM lesions can be distinguished by a 5-gene score and exhibit increased IL-18 in dermal inflammation.

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DM lesions can be distinguished by a 5-gene score and exhibit increased ...
(A) Box plots of DEGs in DM but not CLE (IL18 and LCE2D) or DEGs in CLE but not DM (CCL7 and CD2). (B) RNA was isolated from 9 DM and 9 CLE lesional samples from the independent validation cohort and subjected to real-time PCR with the indicated primers. Data are presented as the fold change calculated as 2-ΔΔCT of DM versus CLE. Statistical significance was calculated via multiple 2-tailed t tests using false discovery rate to account for multiple comparisons of delta CT values normalized to GAPDH expression. The q values are denoted on the graph as follows: *q < 0.05; **q < 0.01. (C) IHC for IL-18 or isotype control in healthy control (representative of 3 controls), DM (representative of 3 patients), and CLE skin (representative of 4 patients). (D) xCell enrichment score for macrophage-derived transcripts in HC, DM, and CLE lesions. (E) scRNA-Seq analysis of DM lesional and nonlesional skin compared with healthy control and lupus skin. Graph represents gene expression in keratinocytes for percentage of cells expressing the indicated gene (by circle size) and degree of expression (by color).