Research Fellow Trainee Vanderbilt Univ. Med. Ctr., United States
Disclosure(s):
Gabriel J. Rodriguez-Garcia, PhD: No financial relationships to disclose
Introduction/Rationale: Aortic specimens from patients with large vessel vasculitis (LVV) have shown prominent B cells organizing into arterial tertiary lymphoid structures with germinal centers. We hypothesized that B cells in LVV patients would show transcriptional changes associated with enhanced B cell activation and function.
Methods: To test this hypothesis, CD19+ cells were flow cytometry purified from peripheral blood mononuclear cells (PBMCs) of patients with Takayasu arteritis (TAK) (n=7), giant cell arteritis (GCA) (n=1), or healthy controls (n=4) and single-cell RNA-seq/BCR-seq profiling was performed using the 10X Genomics platform. Pathway analysis was performed using g:Profiler.
Results: Seurat analysis identified n=12 transcriptionally defined clusters, with no major differences in cluster distribution noted between TAK or HC individuals. TAK patients showed upregulated genes relative to healthy donors (FC > 1.5, padj < 0.05) in naïve (n=119 genes), transitional (n=21 genes), activated (n=19 genes), and memory (n=192 genes) B cell subsets. In Memory B cells, upregulated genes were involved in RNA alternative splicing (RBFOX2), mitochondrial function (MT-ND3 and MT-ATP8), protein synthesis (RPS18 and RPL3), T cell co-stimulation (CD86), actin cytoskeleton rearrangement (TAGLN2 and ACTG1), and cell proliferation (DHFR and GAREM1). Pathway analysis on memory B cells identified upregulation of B cell receptor signaling (THEMIS2 and GCSAM). In activated B cells, upregulated genes were involved in endocytosis (RABGAP1L and BMP2K), cell migration (ARHGEF18), and cell proliferation (DLEU2 and IKZF3).
Conclusion: In conclusion, TAK patient B cells exhibit a distinct transcriptional program that might support interactions with autoreactive T cells and contribute to autoimmune disease liability. Future studies will be required to evaluate the functional consequences of these changes with respect to tissue damage in vasculitis.
