Background/Purpose: Systemic lupus erythematosus (SLE) is an autoimmune disorder with both genetic and environmental contributions to disease etiology. Patients with different ancestral backgrounds have different clinical presentation and severity, which likely result from variation in immune cell composition or response. Understanding the functional biology of the immune system in SLE patients with variable disease activity is critical to understanding the mechanisms behind disease activity.

Methods:  European American (EA) SLE patients (n=20) and African American (AA) SLE patients (n=14) with elevated (SLEDAI >4) and suppressed (SLEDAI≤4) disease activity were matched to healthy controls. Using single cell proteomics by CyTOF, PBMCs were clustered using 33 markers and cell heterogeneity was visualized using viSNE in Cytobank. PBMCs were stimulated with either T cell receptor (anti-CD3/CD28) or B cell receptor (anti-IgG/IgM (Fab’)2) stimulation and assessed for pERK, pPLCγ2, and p38 in cell subsets by flow cytometry. Plasma cytokine levels were assessed by 51-plex xMAP assays and ELISAs. FlowJo was used for flow cytometry analysis and Mann-Whitney test was used to compare non-normally distributed data. Analyses were performed using GraphPad Prism and TIBCO SpotFire. All SLE patients met at least 4 SLE ACR classification criteria.

Results:  SLE patients were differentiated from healthy controls by elevated frequencies of HLA-DR+CD11c+ monocytes and dendritic cells (p=0.0248) and CD38-CD24-IgD+CD27- naïve B cells (p=0.0326). Compared to SLE-low patients, EA SLE-high disease activity patients had a higher frequency of CD4+ T cells (p=0.0433) and fewer CD56+ NK cells (p=0.0402), which correlated significantly with disease activity (p=0.0305 and p=0.0281, respectively). EA SLE-high disease activity patients also had decreased expression of the inhibitory receptor CD85j on monocytes and B cells (p<0.05), which correlated with elevated Th1, Th2 and Th17-type plasma cytokines (p<0.05). In contrast, AA SLE-high disease activity patients had no differences in NK cell frequencies or CD85j expression, but did have increased frequencies of effector memory CD4+ T cells (p=0.035). Further, CD4+ T cells in AA SLE-high disease activity patients had an activated phenotype with higher frequencies of CCR6+ (p=0.0127), CD25+ (p=0.0181), CD127+(p=0.0253) and CXCR3+ (p=0.0350) CD4+ T cells compared to SLE-low patients. This activated CD4+ T cell phenotype in AA SLE-high disease activity patients correlated with elevated ICAM-1 (p=0.004) and diminished TGF-b (p=0.035) plasma levels compared to AA SLE-low patients. No significant differences in TCR or BCR signaling were observed between patients with high and low disease activity, but pro-inflammatory cytokines were significantly elevated in both EA and AA SLE-hi patients.

Conclusion: Our results support a model where differences in the regulation of monocytes and/or B cells are associated with SLE disease, but elevated cytokine production through activated CD4+ T helper cell pathways may contribute to heightened autoimmune disease activity in both European American and African American SLE patients.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/african-american-and-european-american-sle-patients-with-variable-disease-activity-reveal-distinct-differences-in-cd4-t-cell-and-monocyte-pathways/