Ancestry-based differences in the immune phenotype are associated with lupus activity

Area of Science:

• Immunology
• Genetics
• Systemic Lupus Erythematosus Research

Background:

• Systemic lupus erythematosus (SLE) disproportionately impacts Black women, presenting with earlier onset, increased severity, and higher mortality rates compared to White women.
• Existing research indicates significant health disparities in SLE outcomes between racial groups, necessitating a deeper understanding of underlying biological mechanisms.

Purpose of the Study:

• To investigate ancestry-associated immune system alterations in Black and White patients with SLE and healthy controls using a multiomics approach.
• To identify specific immune cell phenotypes, epigenetic modifications, and molecular signaling pathways that contribute to SLE disparities.

Main Methods:

• Employed a multiomics strategy including mass cytometry, single-cell transcriptomics and proteomics, and plasma cytokine analysis.
• Assessed cell composition, signaling, epigenetics (H3K27ac), and proteomics in immune cells and plasma from SLE patients and healthy controls stratified by ancestry.
• Utilized Toll-like receptor (TLR) stimulation assays to validate observed immune responses.

Main Results:

• Observed distinct immune cell alterations, including enhanced activity in CD8+ T cells, B cells, monocytes, and dendritic cells (DCs) in Black patients with active SLE.
• Identified specific epigenetic modifications (H3K27ac) in CD8+ T cells that correlate with disease activity and differentiate between Black and White patients.
• Found elevated TLR gene expression and heightened TLR/IFN-α signaling pathways in immune cells from Black patients with SLE and even in healthy Black controls compared to White individuals.

Conclusions:

• Defined ancestry-associated immune phenotypes in SLE, highlighting differences in immune cell activity, epigenetics, and signaling pathways between Black and White patients.
• These immune variations may biologically contribute to the observed disparities in SLE severity, progression, and outcomes.
• The findings provide a multiomic resource for understanding SLE heterogeneity and developing targeted therapeutic strategies.