Abstract
Purpose Systemic lupus erythematosus (SLE) is a systemic and multifactorial autoimmune disease, and its diverse clinical manifestations affect molecular diagnosis and drug benefits. Our study was aimed at defining the SLE subtypes based on blood transcriptome data, analyzing functional patterns, and elucidating drug benefits. Methods Three data sets were used in this paper that were collected from the Gene Expression Omnibus (GEO) database, which contained two published data sets of pediatric and adult SLE patients (GSE65391, GSE49454) and public longitudinal data (GSE72754) from a cohort of SLE patients treated with IFN-α Kinoid (IFN-K). Based on disease activity scores and gene expression data, we defined a global SLE signature and merged three clustering algorithms to develop a single-sample subtype classifier (SSC). Systematic analysis of coexpression networks based on modules revealed the molecular mechanism for each subtype. Results We identified 92 genes as a signature of the SLE subtypes and three intrinsic subsets (“IFN-high,” “NE-high,” and “mixed”), which varied in disease severity. We speculated that IFN-high might be due to the overproduction of interferons (IFNs) caused by viral infection, leading to the formation of autoantibodies. NE-high might primarily result from bacterial and fungal infections that stimulated neutrophils (NE) to produce neutrophil extracellular traps (NETs) and induced individual autoimmune responses. The mixed type contained both of these molecular mechanisms and showed an intrinsic connection. Conclusions Our research results indicated that identifying the molecular mechanism associated with different SLE subtypes would benefit the molecular diagnosis and stratified therapy. Moreover, repositioning of IFN-K based on subtypes also revealed an improved therapeutic effect, providing a new direction for disease treatment and drug development.
Highlights
Systemic lupus erythematosus (SLE) is a systemic multifactorial autoimmune disease, with breaches of tolerance in both T cells and B cells
Patients were divided into discovery and test sets, using a ratio of 2 : 1. To obtain reliable genes related to disease activity and better evaluate drug benefits, patients with missing clinical data or who had drugs were changed during the test or SLEDAI [18] scores that remained stable over time were not included in the final analysis
We defined differentially expressed genes (DEGs) in the discovery set by comparing all patient samples with healthy controls
Summary
Systemic lupus erythematosus (SLE) is a systemic multifactorial autoimmune disease, with breaches of tolerance in both T cells and B cells. Pathological T cell-B cell interactions and the production of autoantibodies are hallmark features of SLE [1]. The activation of B and T cell immunity (i.e., the adaptive immune system) requires the support of the innate immune system. A basic family required for recognition by the innate immune system is the Toll-like receptor (TLR) family. TLRs can quickly recognize a series of related molecular patterns found on bacteria, viruses, and fungi. The recognition of these molecular patterns on pathogens can trigger the production of proinflammatory cytokines of patients [2]. Proinflammatory cytokines participate in adaptive immunity and drive T cell activation and can stimulate extramedullary hematopoiesis leading to expansion of innate immune cells. Excessive accumulation of autoantibodies can cause tissue damage in SLE [3]
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