Immune & inflammatory pathways in DLE skin are poorly understood1, 2, 3. A bioinformatic approach (LIMMA-DE & WGCNA) analyzed skin biopsy gene expression to gain insight into precise pathogenic mechanisms involved. Genes differing between DLE & healthy individuals were interrogated for cell type specific gene signatures using GSVA validation of I- or T- Scope® analysis of immune or non-immune subsets. Non-immune subsets (fibroblasts, keratinocytes, melanocytes and Langerhans cells) are in WGCNA modules negatively correlated with disease. Genes were functionally characterized using BIG-C® and pathways elucidated using IPA®. DLE has an immune cell signature in WGCNA modules positively correlated with CLASI-A (DCs, myeloid cells, CD4+ & CD8+ Ts, gdTs, NKs, Bs as well as pre- and post-switch PCs as indicated by IgM, IgD, and IgG1 HC genes). The presence of both Ig -κ & -λ as well as VL genes suggests polyclonal activation. Chemokines that mediate lymphocyte organization and/or recruitment into lupus skin are present. Cytokine (TNF, IFNγ, IFNα, CD40L, IL1β, IL2, IL6, IL12, IL17, IL23 & IL27) & signaling (PI3K,NF-κB,NF-AT, and mTOR) pathways as well as proliferation and HDAC activity are evident. IPA® UPR analysis indicated ongoing signaling by TNF, IFNγ, IFNα, CD40L, IL1β, IL2, IL6, IL12, IL17, IL23 and IL27. Statistically significant WGCNA module preservation was observed between all three DLE datasets. Interestingly, connectivity analysis using LINCS/CLUE demonstrated high priority drug targets such as IKZF1/3 (lenlidomide) as well as CC-220, JAK1/2 (ruxolitinib) and HDAC6 (Ricolinostat) may prove to be good options for therapeutic intervention.