SLE Impacts Long Noncoding RNAs in the Placenta of Pregnant Patients

Results indicate that the irregular expression and possible regulatory function of long noncoding RNAs (lncRNAs) in the placentas of women with systemic lupus erythematosus (SLE) may play a role in the pathogenesis of these pregnancies. Further, SLE-dysregulated lncRNAs may possibly be used as biomarkers for SLE, according to a study published in Arthritis Research & Therapy.¹

“During pregnancy, the loss of immune tolerance to the fetus in SLE may cause numerous maternal and fetal complications, including lupus flare, hypertension, preeclampsia (PE), eclampsia, spontaneous abortion, stillbirth, fetal growth restriction (FGR), neonatal lupus, and neonatal deaths,” investigators explained. “The pregnancy outcomes in mothers with SLE and the well beings of fetuses born to SLE mothers have been improved tremendously over the last five decades due to the development of disease management. However, the mechanism underlying SLE-induced pregnancy complications remains unclear.”

To identify SLE-dysregulated lncRNAs and messenger RNAs (mRNAs) in placentas from patients with SLE, as defined by the American College of Rheumatology classification criteria, and normal full-term (NT) pregnancies (n = 8 patients per group), investigators utilized an RNA sequencing analysis. Biological functions of the dysregulated lncRNAs and mRNAs were evaluated via a bioinformatics analysis. Disease activity was determined via the SLE disease activity index (SLEDAI) and a questionnaire collected both demographic data and clinical manifestations. Medical records were used to obtain laboratory data. Patients were excluded if they had cancer, diabetes mellitus, or were current smokers.

Patients with SLE remained on maintenance medication throughout pregnancy (prednisone ≤ 15 mg daily and hydroxychloroquine 200–400 mg daily). While maternal age and body mass index were comparable between both groups, gestation age and newborn body weight was significantly lower in the SLE cohort when compared with the NT cohort (P < 0.05).

The RNA-seq analysis ultimately identified 52 dysregulated lncRNAs in the placentas of patients with SLE, which included 37 upregulated and 15 downregulated. A total of 130 SLE-dysregulated mRNAs were also identified, including 122 upregulated and 8 down regulated.

According to the bioinformatics analysis, SLE-dysregulated genes were linked to biological functions and gene networks, most notably regulation of type I interferon-mediated signaling pathway, response to steroid hormone, regulation of mitogen-activated protein kinase (MAPK) cascade, complement and coagulation cascades, Th1 and Th2 cell differentiation, and response to hypoxia. While it is unclear what causes these dysregulations of lncRNAs, investigators theorize that it may be due to tissue oxygen levels.

The study was the first to report the lncRNA profiles in the placentas of patients with SLE, supporting the idea that lncRNAs play an important role in the pathogenesis of SLE placentas. However, the small number of patients limited the study. Investigators urge further validation of dysregulated mRNAs and lncRNAs within a larger cohort. Additionally, analysis of the association between differential expression genes (DEGs) expression levels and disease activity was hindered by the narrow SLEDAI score range (0-6).

“This study demonstrates a comprehensive expression profile of lncRNAs and mRNAs in SLE placentas,” investigators concluded. “The findings suggest regulatory functions of lncRNAs and mRNAs, which are implicated in the development and pathogenesis of SLE pregnancy. SLE-dysregulated lncRNAs may potentially serve as biomarkers for SLE.”

Reference:

Li HH, Sai LT, Liu Y, et al. Systemic lupus erythematosus dysregulates the expression of long noncoding RNAs in placentas. Arthritis Res Ther. 2022;24(1):142. Published 2022 Jun 14. doi:10.1186/s13075-022-02825-7