Overactivation of the innate immune system together with the impaired downstream pathway of type I interferon-responding genes is a hallmark of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and systemic sclerosis (SSc). To date, limited data on the cross-disease innate gene signature exists among those diseases. We compared therefore an innate gene signature of Toll-like receptors (TLRs), seven key members of the interleukin (IL)1/IL1R family, and CXCL8/IL8 in peripheral blood mononuclear cells from well-defined patients with active stages of RA (n = 36, DAS28 ≥ 3.2), SLE (n = 28, SLEDAI > 6), and SSc (n = 22, revised EUSTAR index > 2.25). Emerging diversity and abundance of the innate signature in RA patients were detected: RA was characterized by the upregulation of TLR3, TLR5, IL1RAP/IL1R3, IL18R1, and SIGIRR/IL1R8 when compared to SSc (Pcorr < 0.02) and of TLR2, TLR5, and SIGIRR/IL1R8 when compared to SLE (Pcorr < 0.02). Applying the association rule analysis, six rules (combinations and expression of genes describing disease) were identified for RA (most frequently included high TLR3 and/or IL1RAP/IL1R3) and three rules for SLE (low IL1RN and IL18R1) and SSc (low TLR5 and IL18R1). This first cross-disease study identified emerging heterogeneity in the innate signature of RA patients with many upregulated innate genes compared to that of SLE and SSc.

Department of Immunology Faculty of Medicine and Dentistry Palacky University Olomouc and University Hospital Olomouc Czech Republic

Department of Internal Medicine 3 Nephrology Rheumatology and Endocrinology Faculty of Medicine and Dentistry Palacky University Olomouc and University Hospital Olomouc Czech Republic

Faculty of Electrical Engineering and Computer Science Department of Computer Science VSB Technical University of Ostrava Ostrava Czech Republic

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