Single-Cell RNA-Seq Reveals Cell Type–Specific Molecular and Genetic Associations to Lupus

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with elevated prevalence in women and individuals of Asian, African, and Hispanic ancestry. SLE is a disease in which the immune system attacks its own tissues, causing widespread inflammation and tissue damage in the affected organs. It can affect the joints, skin, brain, lungs, kidneys, and blood vessels.

Historically, flow cytometry and bulk transcriptomic analyses were used to profile the composition and gene expression of circulating immune cells in SLE. However, flow cytometry is biased by its use of a limited set of known markers, whereas bulk transcriptomic profiling does not have sufficient power to detect cell type–specific expression differences.

Medical Scientists at the University of California, San Francisco (San Francisco, CA, USA) and their colleagues used a method called "multiplexed scRNA-seq" (mux-seq), and they assessed more than 1.2 million peripheral blood mononuclear cells (PBMC) isolated from 162 individuals with SLE and 99 unaffected controls, drawn from the California Lupus Epidemiology Study and the Immune Variation project.

The scientists reported that analysis of lymphocyte composition revealed a reduction in naïve CD4+ T cells and an increase in repertoire-restricted GZMH+ CD8+ T cells. Analysis of transcriptomic profiles across eight cell types revealed that classical monocytes expressed the highest levels of both pan–cell type and myeloid-specific type 1 interferon–stimulated genes (ISGs). The expression of ISGs in monocytes was inversely correlated with naïve CD4+ T cell abundance. Cell type–specific expression features accurately predicted case-control status and stratified patients into molecular subtypes.

The investigators integrated genotyping data and using a novel matrix decomposition method, and mapped shared and cell type–specific cis–expression quantitative trait loci (cis-eQTLs) across eight cell types. Cell type–specific cis-eQTLs were enriched for regions of open chromatin specific to the same or related cell types. Joint analysis of cis-eQTLs and genome-wide association study results enabled identification of cell types relevant to immune-mediated diseases, fine-mapping of disease-associated loci, and discovery of novel SLE associations. Interaction analysis identified variants whose effects on gene expression are further modified by interferon activation across patients.

The authors concluded that SLE remains challenging to diagnose and treat. The heterogeneity of disease manifestations and treatment response highlight the need for improved molecular characterization. In a large multiethnic cohort, they demonstrated mux-seq as a systematic approach to characterize cellular composition, identify cell type–specific transcriptomic signatures, and annotate genetic variants associated with SLE. The study was published on April 8, 2022 in the journal Science.

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