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 8

Pro-inflammatory cytokines vary in patients with SLE by ancestry and shape the TLR immune response.

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Pro-inflammatory cytokines vary in patients with SLE by ancestry and sha...
Pro-inflammatory soluble mediators were measured by multiplex or ELISA. Significant cytokine differences between Black (n = 21) and White (n = 19) SLE patients included increased (A) SCF, (B) TNF-α, (C) BLyS, (D) IL-13, (E) IL-4, (F) sICAM-1, and (G) IL-1RA in Black patients and increased (H) eotaxin in White patients. Linear regression analyses show (I) SCF and (J) MCP-1 to increase with SLE disease activity (SLEDAI) (n = 40). (K) A heatmap summary of the MFI supernatant levels following 24-hour whole blood stimulation with TLR4/7/8/9 agonists for each disease group is shown. Soluble mediator levels are displayed on a color scale ranging from blue (protein levels below the mean) to red (protein levels greater than the mean) using a column z score. Significant differences between Black and White disease groups are noted. The most significant fold-change differences over unstimulated culture samples were in the IFN pathways, including (L) IFN-γ, (M) IL-18, and (N) IFN-α. TLR-stimulated culture supernatant levels of IFN-γ negatively associated with mean ISG gene expression modules in (O) classical and (P) nonclassical monocytes by linear regression analysis. Statistical significance was determined using a Mann-Whitney U test (P < 0.05), and all FDR q values were used for multiple comparisons. Mean ± SD is shown. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. FI, fluorescence intensity.