Background Systemic lupus erythematosus (SLE) is an autoimmune disorder with a variable clinical presentation and periods of waxing and waning disease. Heterogeneity in SLE is influenced by genetic and non-genetic susceptibility found in different ethnicities that drive disease expression and severity. The immune pathways that contribute to heightened disease activity in lupus and immune variation by race are critical to understanding SLE disease mechanisms and outcomes.
Methods Peripheral whole blood samples of European or African American healthy controls (n=18) and SLE patients with either high (SLEDAI4) (n=20) or low (SLEDAI <4) (n=20) disease activity were stimulated for 4 min with either interferon-(IFN), PMA and ionomycin, or Toll-like receptor (TLR) ligands for either TLR4, TLR7/8 or TLR9 for phospho-protein analysis, or 24 hours for cytokine analysis of cell culture supernatants. Phenotype and phospho-protein analysis was assessed by CyTOF and cell heterogeneity was analyzed using t-SNE and manual gating. Soluble mediators were assessed using 37-plex xMAP assays and ELISA. All SLE patients met ACR classification criteria.
Results European American SLE patients with high disease activity were differentiated from patients with low disease activity by reduced frequencies of peripheral B cells, specifically naïve B cells (CD27-IgD+CD24 lo) (p=0.0101) and double negative B cells (CD27-IgD-) (p=0.0220), while African American patients with high disease activity had elevated frequencies of memory B cells (CD27 +IgD CD38+) (p<0.05) compared to patients with low disease activity. Several cell subsets had increased expression of activation markers during high disease activity including B cells (p=0.0350) and plasmacytoid dendritic cells (pDCs) (p=0.0435) in European Americans (figure 1A), and neutrophils (p<0.05), pDCs (p=0.005), CD8 +T Cells (p=0.0003) and NKT cells (p=0.0033) in African Americans (figure 1B). Following whole blood stimulation with IFN, African American high disease activity patients were distinguished by reduced ability to activate pSTAT5 in almost all major cell populations (p<0.05), and pSTAT3 in monocytes (p=0.0157), granulocytes (p=0.01) and B cells (p=0.0409) compared to low disease activity patients and controls, possibly due to higher basal levels of activation (figure 1). Further, African American patients with high disease activity had significantly elevated cytokine production at baseline compared to healthy controls and European American SLE patients that translated to a reduced fold change in soluble mediators following stimulation (p<0.01).
Conclusions Our results support a model where race influences heightened SLE disease activity mechanisms with alterations in B cell signaling, and greater dysregulation in phospho-signaling and pro-inflammatory soluble mediators observed in African American patients.
Funding Source(s): NIH (U19AI082714, U19AI082719, U54GM104938, P30GM103510, U01AI101934)
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.