Primate Monocytes - CD14, CD16 - Ziegler-Heitbrock

Three Distinct Transcriptional Profiles of Monocytes Associate with Disease Activity in Scleroderma Patients.

Abstract

BACKGROUND/PURPOSE: Patients with diffuse cutaneous systemic sclerosis (dcSSc) display a complex clinical phenotype. Transcriptional profiling of whole blood or tissue from patients are affected by changes in cellular composition that drive gene expression and an inability to detect minority cell populations. Here, we focused on the two main subtypes of circulating monocytes, classical (CM) and non-classical (NCM). METHODS: SSc patients were recruited from the Prospective Registry for Early SSc registry. Clinical data were collected as well as peripheral blood for isolation of CM and NCM. Age-, sex-, and race-matched healthy volunteers were recruited as controls. Bulk macrophages were isolated from skin in a separate cohort. All samples were assayed by RNA-seq. RESULTS: We used an unbiased approach to cluster patients into three groups (A-C) based on their transcriptional signatures of CM relative to controls. Further, each group maintained their characteristic transcriptional signature in NCM. Genes upregulated in Group C demonstrated the highest signature compared to the other groups in skin macrophages. Patients from Group B and C exhibited worse lung function than Group A, although there was no difference in skin disease at baseline. We validated our approach by applying our group classifications to published bulk monocyte RNA-seq data on SSc patients: we found that patients with no skin disease were most likely to be classified as Group A. CONCLUSION: We are the first to show that transcriptional signature of CM and NCM can be used to unbiasedly stratify SSc patients and correlate with disease activity outcome measures.