Abstract
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 (P corr < 0.02) and of TLR2, TLR5, and SIGIRR/IL1R8 when compared to SLE (P corr < 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.
Highlights
Rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and systemic sclerosis (SSc) are systemic autoimmune diseases characterized by overactivation of the innate immune system together with impaired downstream pathway of type I interferon- (IFN-) responding genes (IFN signature)
RA differed from controls by the upregulated expression of TLR2, TLR3, TLR5, TLR8, IL1B, IL18, IL18R1, IL1RN, IL1RAP, and SIGIRR/IL1R8 (Pcorr ≤ 0 05; Figure S4A, Table S2A)
In patients treated with anti-TNF-α therapy, a trend to lower TLR5 levels in our RA patients was observed (P = 0 07)
Summary
Rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and systemic sclerosis (SSc) are systemic autoimmune diseases characterized by overactivation of the innate immune system together with impaired downstream pathway of type I interferon- (IFN-) responding genes (IFN signature). The emerging role of the innate immunity in the pathogenesis of RA, SLE, and SSc has been demonstrated, there is no data on the cross-disease innate gene signature as well as its heterogeneity among those diseases yet. Numerous studies on individual innate immunity members in RA, SLE, and SSc showed the crucial role of Toll-like receptors (TLRs) and IL1 family [5, 6]. Notable examples of common innate pathways are (i) the involvement of the adapter protein MyD88 which is required for signal transduction by TLRs and receptors of the IL1 family, (ii) the activation of Journal of Immunology Research RA (n = 36) SLE (n = 28) SSc (n = 22) Female/male. Age (years) mean (min-max) 57.5 (39-80) 40.1 (19-67) 58.0 (38-77). Duration of the disease (years) mean (min-max)
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