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 7

TLR stimulation of healthy Black and White immune cells recapitulates ancestry-associated SLE immunophenotypes.

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TLR stimulation of healthy Black and White immune cells recapitulates an...
One million PBMCs from 10 White and 10 Black healthy controls, devoid of any autoimmune characteristics (ANA–, RF, CCP3 antibody negative, and negative CSQ), were stimulated with R848 (TLR7/8 agonist), CpG (TLR9 agonist), or IFN-α alone or in combination for 7 days and analyzed by flow cytometry. (A) tSNE plots identified 9 different immune cell populations across samples. (B) Representative tSNE plots of healthy White and Black cells following the 9 different stimulation conditions. CD38 expression is shown from red (high expression) to blue (low expression). Cells were counted in culture following 7-day stimulation, and total cell subset numbers were back-calculated using cell frequencies. The total (mean ± SD) (C) T cells, (D) NK cells, (E) B cells, and (F) myeloid cells/mL are shown for the 8 different stimulations by ancestry. (G) B cells were further subdivided by biaxial gating on IgM and CD27 to assess 6 different B cell subsets: 1) class-switched plasmablasts, 2) IgM+ plasmablasts, 3) class-switched memory B cells, 4) IgM+ memory B cells, 5) DN B cells, and 6) naive B cells. The frequency (mean ± SD) of (H) naive B cells, (I) DN B cells, (J) class-switched memory B cells, and (K) class-switched plasmablasts is shown for each condition. Supernatants were collected and assessed via ELISA for (L) total IgG concentrations and (M) IgA concentrations. Statistical significance was determined using a Mann-Whitney U test (P < 0.05), and all FDR q values were used for multiple comparisons.