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 5

Monocyte ISGhi transcriptional subsets are increased in patients with SLE ACT.

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Monocyte ISGhi transcriptional subsets are increased in patients with SL...
PBMCs from 46 controls and patients with SLE were CD2-depleted, and droplet-based scRNA-Seq was performed using a 10x Genomics platform. (A) UMAP plot representing the 11 clusters of monocytes. The putative identity of each cluster was assigned using gene expression and protein expression from CITE-Seq. (B) Dot plot representing expression values of selected proteins assessed by CITE-Seq and (C) heatmap representing gene expression values of selected genes across each cluster used for cluster annotation. Dot size represents the percentage of cells expressing the marker of interest. Color intensity indicates the mean expression within expressing cells. (D–G) Box plots comparing the proportion of each cluster (mean ± SD) across the disease groups for (D) intermediate, (E) LYZhiIFI6hi, (F) ISGhi, and (G) CD85jhiCD94hi monocytes. Box plots show the interquartile range (box), median (line), and minimum and maximum (whiskers). (H) Gene expression for specific IFN response modules is shown using a dot plot for nonclassical, intermediate, and classical monocytes by disease group. Dot plots compare the proportion of the 3 different DC populations (mean ± SD) identified by UMAP, (I) CLEC9a+ cDC1s, (J) CD1c+ cDC2s, and (K) pDCs. (L) cDC gene expression of HLA antigen presentation components is shown via dot plot by disease group. HLA class I markers are boxed in black, and HLA class II markers are boxed in red. P values were calculated using pairwise Wilcoxon’s rank-sum tests between disease groups with Benjamini-Hochberg correction for multiple comparisons. *P < 0.05, **P < 0.01, and ***P < 0.001. ISG, IFN-stimulated gene.