JCI Insight (Aug 2023)

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

Journal volume & issue
Vol. 8, no. 16

Abstract

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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.

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