Transcriptomic analysis reveals immune signatures associated with specific cutaneous manifestations of lupus in systemic lupus erythematosus

Summary: Abstract Body: Systemic lupus erythematosus (SLE) presents with heterogenous cutaneous manifestations. However, the molecular and immunologic pathways driving these manifestations of SLE are poorly understood. Here, we leverage transcriptomics from a well-phenotyped longitudinal cohort of SLE patients to map molecular pathways linked to ten distinct SLE-related rashes. Through whole blood (N = 449) and immune cell-sorted bulk RNA sequencing on CD4+ T cells, CD14+ monocytes, CD19+ B cells, and NK cells (N = 120), we identified blood immune signatures and molecular fingerprints specific to cutaneous subtypes of SLE via differential expression (DESeq2) and pathway enrichment (GSEA) analysis. We conducted these analyses on SLE patients within the cohort with and without each of the ten cutaneous phenotypes. Subacute cutaneous lupus erythematosus (SCLE) (N = 30) exhibited broad upregulation of type I interferon, TNF-α, and IL6-JAK-STAT3 pathways, suggesting JAK and type I inhibition as potential therapies. While type I interferon signaling is prominent in some SLE rash subtypes such as acute cutaneous lupus (N = 228), discoid lupus (N = 63), and livedo reticularis (N = 56), it is unexpectedly absent in other cutaneous manifestations such as mucosal ulcers (N = 195). Pathway and cell-type enrichment analysis revealed unexpected roles for CD14+ monocytes in photosensitivity of SLE and NK cells in alopecia (N = 183), mucosal ulcers (N = 195), and livedo reticularis (N = 56). These findings illuminate the immune heterogeneity of rashes in SLE, highlighting subtype-specific mechanistic targets, and presenting opportunities to identify precision therapies for SLE-associated skin phenotypes. Ernest Y. Lee^{3, 1}, Sarah Patterson⁴, Zachary Cutts¹, Cristina M. Lanata⁴, Maria Dall'Era⁴, Jinoos Yazdany⁴, Lindsey A. Criswell⁵, Anna Haemel³, Patricia Katz⁴, Chun Jimmie Ye⁴, Charles Langelier², Marina Sirota¹ 1. Bakar Computational Health Institute, UCSF, San Francisco, CA, United States. 2. Division of Infectious Diseases, Dept. of Medicine, UCSF, San Francisco, CA, United States. 3. Dept. of Dermatology, UCSF, San Francisco, CA, United States. 4. Division of Rheumatology, Dept. of Medicine, UCSF, San Francisco, CA, United States. 5. NHGRI, National Institutes of Health, Bethesda, MD, United States. Bioinformatics, Computational Biology, and Imaging