Distinct Interferon and Intracellular Signaling Signatures in Systemic Lupus Erythematosus and Dermatomyositis by Integrative Transcriptomic and Proteomic Analysis.

OBJECTIVE

Transcript and protein abundance data were measured to compare biologic pathway effects in the peripheral blood of patients diagnosed with systemic lupus erythematosus (SLE) and dermatomyositis (DM) who receive immunosuppressive therapies.

METHODS

Expression data from the peripheral blood of patients with SLE (n = 41) and DM (n = 14) were obtained using one transcriptomic and two proteomic platforms and compared with matched healthy control subjects. Regulatory effects were integrated across the three platforms to assess biologic pathways and downstream signaling, within and across disease cohorts.

RESULTS

Expressions of 973 gene loci were altered overall, with 67 genes shared in SLE and DM, including interferon (IFN) markers ISG15, CXCL10, OAS1, and STAT1, and other markers of cell adhesion, immune signaling, and apoptosis. A total of 24 of 32 (75%) pathways were shared in SLE and DM, including granulocyte adhesion, immune cell migration, acute-phase response, apoptosis, and L1CAM signaling. However, SLE peripheral blood exhibited distinctive activation of Type I IFN through increased ligand-receptor interactions not widely elevated in DM. Blood from patients with DM distinctly showed substantially increased expression of intracellular kinases and associated downstream signaling molecules.

CONCLUSION

Using a multienrichment analytic approach that integrated multiple transcriptomics and proteomics platforms, common underlying immune pathways were identified in SLE and DM. Additionally, two distinctive molecular mechanisms persisted in each condition: IFN signaling was distinctly up-regulated in patients with longstanding SLE, whereas intracellular signaling, particularly kinases, were unique to DM. These shared and distinct findings highlight potential therapeutic opportunities driven by underlying molecular mechanisms.