Ancestry-based differences in the immune phenotype are associated with lupus activity
Samantha Slight-Webb, Kevin Thomas, Miles Smith, Catriona A. Wagner, Susan Macwana, Aleksandra Bylinska, Michele Donato, Mai Dvorak, Sarah E. Chang, Alex Kuo, Peggie Cheung, Laurynas Kalesinskas, Ananthakrishnan Ganesan, Denis Dermadi, Carla J. Guthridge, Wade DeJager, Christian Wright, Mariko H. Foecke, Joan T. Merrill, Eliza Chakravarty, Cristina Arriens, Holden T. Maecker, Purvesh Khatri, Paul J. Utz, Judith A. James, Joel M. Guthridge
Samantha Slight-Webb, Kevin Thomas, Miles Smith, Catriona A. Wagner, Susan Macwana, Aleksandra Bylinska, Michele Donato, Mai Dvorak, Sarah E. Chang, Alex Kuo, Peggie Cheung, Laurynas Kalesinskas, Ananthakrishnan Ganesan, Denis Dermadi, Carla J. Guthridge, Wade DeJager, Christian Wright, Mariko H. Foecke, Joan T. Merrill, Eliza Chakravarty, Cristina Arriens, Holden T. Maecker, Purvesh Khatri, Paul J. Utz, Judith A. James, Joel M. Guthridge
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Resource and Technical Advance Immunology

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

Abstract

Systemic lupus erythematosus (SLE) affects 1 in 537 Black women, which is >2-fold more than White women. Black patients develop the disease at a younger age, have more severe symptoms, and have a greater chance of early mortality. We used a multiomics approach to uncover ancestry-associated immune alterations in patients with SLE and healthy controls that may contribute biologically to disease disparities. Cell composition, signaling, epigenetics, and proteomics were evaluated by mass cytometry; droplet-based single-cell transcriptomics and proteomics; and bead-based multiplex soluble mediator levels in plasma. We observed altered whole blood frequencies and enhanced activity in CD8+ T cells, B cells, monocytes, and DCs in Black patients with more active disease. Epigenetic modifications in CD8+ T cells (H3K27ac) could distinguish disease activity level in Black patients and differentiate Black from White patient samples. TLR3/4/7/8/9-related gene expression was elevated in immune cells from Black patients with SLE, and TLR7/8/9 and IFN-α phospho-signaling and cytokine responses were heightened even in immune cells from healthy Black control patients compared with White individuals. TLR stimulation of healthy immune cells recapitulated the ancestry-associated SLE immunophenotypes. This multiomic resource defines ancestry-associated immune phenotypes that differ between Black and White patients with SLE, which may influence the course and severity of SLE and other diseases.

Authors

Samantha Slight-Webb, Kevin Thomas, Miles Smith, Catriona A. Wagner, Susan Macwana, Aleksandra Bylinska, Michele Donato, Mai Dvorak, Sarah E. Chang, Alex Kuo, Peggie Cheung, Laurynas Kalesinskas, Ananthakrishnan Ganesan, Denis Dermadi, Carla J. Guthridge, Wade DeJager, Christian Wright, Mariko H. Foecke, Joan T. Merrill, Eliza Chakravarty, Cristina Arriens, Holden T. Maecker, Purvesh Khatri, Paul J. Utz, Judith A. James, Joel M. Guthridge

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Figure 3

Changes in the CD8+ T cell epigenetic landscape distinguish Black from White patients and correlate with higher disease activity.

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Changes in the CD8+ T cell epigenetic landscape distinguish Black from W...
PBMCs (n = 53) were used to assess global differences in 40 chromatin modifications in 19 immune cell subsets. (A) Average chromatin marker changes for 1 biological replicate comparing overall changes in cell subsets of patients with SLE versus controls. Heatmap depicts increased levels in red, no change in yellow, and decreased levels in blue. (B) Scatterplot depicting the effect size comparisons of chromatin marks in CD8+ T cells between Black and White patients between 2 biological replicates. Each dot represents the average levels of a chromatin marker. Correlation coefficient and the associated P value are shown. (C and D) Normalized chromatin marker levels of White and Black healthy controls and patients with SLE for (C) H3K18ac and (D) H3K27ac in CD8+ T cells. (E) Receiver operating characteristic (ROC) curves depicting the segregation of CD8+ T cells from Black patients and from White patients using the variance in Mark 4. Curves summarizing the results from both biological replicates are shown, with area under ROC percentages from independent replicates separately listed. Classification specificity (x axis) and sensitivity (y axis) are shown for the ROC curve. (F) Normalized H3K27ac levels in CD8+ T cells from patients with SLE INACT and SLE ACT. Mean ± SD is shown. Wilcoxon’s rank-sum test was used to determine statistical significance, and P values corrected for multiple hypotheses using FDR.