Abstract
Systemic Lupus Erythematosus (SLE) is a heterogeneous autoimmune disease, which currently lacks specific diagnostic biomarkers. The diversity within the patients obstructs clinical trials but may also reflect differences in underlying pathogenesis. Our objective was to obtain protein profiles to identify potential general biomarkers of SLE and to determine molecular subgroups within SLE for patient stratification. Plasma samples from a cross-sectional study of well-characterized SLE patients (n = 379) and matched population controls (n = 316) were analyzed by antibody suspension bead array targeting 281 proteins. To investigate the differences between SLE and controls, Mann–Whitney U-test with Bonferroni correction, generalized linear modeling and receiver operating characteristics (ROC) analysis were performed. K-means clustering was used to identify molecular SLE subgroups. We identified Interferon regulating factor 5 (IRF5), solute carrier family 22 member 2 (SLC22A2) and S100 calcium binding protein A12 (S100A12) as the three proteins with the largest fold change between SLE patients and controls (SLE/Control = 1.4, 1.4, and 1.2 respectively). The lowest p-values comparing SLE patients and controls were obtained for S100A12, Matrix metalloproteinase-1 (MMP1) and SLC22A2 (padjusted = 3 × 10−9, 3 × 10−6, and 5 × 10−6 respectively). In a set of 15 potential biomarkers differentiating SLE patients and controls, two of the proteins were transcription factors, i.e., IRF5 and SAM pointed domain containing ETS transcription factor (SPDEF). IRF5 was up-regulated while SPDEF was found to be down-regulated in SLE patients. Unsupervised clustering of all investigated proteins identified three molecular subgroups among SLE patients, characterized by (1) high levels of rheumatoid factor-IgM, (2) low IRF5, and (3) high IRF5. IRF5 expressing microparticles were analyzed by flow cytometry in a subset of patients to confirm the presence of IRF5 in plasma and detection of extracellular IRF5 was further confirmed by immunoprecipitation-mass spectrometry (IP-MS). Interestingly IRF5, a known genetic risk factor for SLE, was detected extracellularly and suggested by unsupervised clustering analysis to differentiate between SLE subgroups. Our results imply a set of circulating molecules as markers of possible pathogenic importance in SLE. We believe that these findings could be of relevance for understanding the pathogenesis and diversity of SLE, as well as for selection of patients in clinical trials.
Highlights
Systemic Lupus Erythematosus (SLE) is a heterogeneous systemic autoimmune disorder with a plethora of clinical manifestations
Of the 15 proteins in Table 2, three were found to be decreased, i.e., sterile alpha motif (SAM) pointed domain containing E26 transformationspecific (ETS) transcription factor (SPDEF), Apolipoprotein L6 (APOL6), and Cysteine-rich secretory protein 3 (CRISP3), and twelve were found to be increased in the SLE patients compared to controls
interferon regulatory factor 5 (IRF5), a transcription factor involved in regulation of interferon and cytokine production, showed the largest fold change among the differentially expressed proteins between SLE patients and controls
Summary
Systemic Lupus Erythematosus (SLE) is a heterogeneous systemic autoimmune disorder with a plethora of clinical manifestations. Clinical and immunological criteria, defined by the American College of Rheumatology (ACR) [1], are used to classify the disease for research purposes, but reliable diagnostic biomarkers are lacking. There is a great need for exploring subgrouping and novel diagnostic biomarkers in SLE. The current knowledge of protein functions is far from complete and transcription factors and other nuclear molecules could have unknown functions in the circulation or may, regardless of function, constitute novel biomarkers. The intra- and extracellular functions of a protein might be different and unconventional secretion is possible [12]. Both nuclear and cytoplasmic molecules are relevant to study in the circulation with the aim to identify potential biomarkers and possible pathogenic pathways
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