Abstract
Background: Gene expression studies of peripheral blood mononuclear cells from patients with systemic lupus
erythematosus (SLE) have demonstrated a type I interferon signature and increased expression of inflammatory cytokine
genes. Studies of patients with Aicardi Goutie`res syndrome, commonly cited as a single gene model for SLE, have suggested
that accumulation of non-coding RNAs may drive some of the pathologic gene expression, however, no RNA sequencing
studies of SLE patients have been performed. This study was designed to define altered expression of coding and noncoding
RNAs and to detect globally altered RNA processing in SLE.
Methods: Purified monocytes from eight healthy age/gender matched controls and nine SLE patients (with low-moderate
disease activity and lack of biologic drug use or immune suppressive treatment) were studied using RNA-seq. Quantitative
RT-PCR was used to validate findings. Serum levels of endotoxin were measured by ELISA.
Results: We found that SLE patients had diminished expression of most endogenous retroviruses and small nucleolar RNAs,
but exhibited increased expression of pri-miRNAs. Splicing patterns and polyadenylation were significantly altered. In
addition, SLE monocytes expressed novel transcripts, an effect that was replicated by LPS treatment of control monocytes.
We further identified increased circulating endotoxin in SLE patients.
Conclusions: Monocytes from SLE patients exhibit globally dysregulated gene expression. The transcriptome is not simply
altered by the transcriptional activation of a set of genes, but is qualitatively different in SLE. The identification of novel loci,
inducible by LPS, suggests that chronic microbial translocation could contribute to the immunologic dysregulation in SLE, a
new potential disease mechanism.