Dysregulated Immune Response to Perturbation from Vaccination in ACPA+ Individuals at Risk for Rheumatoid Arthritis 9277

Abstract Description Rheumatoid Arthritis (RA) is preceded by an “at-risk” phase marked by predictive autoantibodies including anti-citrullinated protein antibodies (ACPA). Previously, we reported that ACPA+ at-risk individuals (ARI) exhibit features of systemic inflammation without inflammatory arthritis. Although active RA patients exhibit diminished responses to influenza vaccination, the adaptive immune response of ARI to vaccination in the context of systemic inflammation, remains unclear. We analyzed PBMC scRNA-seq and influenza strain-specific antibody titers in ARI (n = 25) and ACPA- controls (HC; n = 27) before and 7 days after influenza vaccination. While both groups exhibited a comparable increase in antibody titers, transcriptomic analysis revealed differences in cellular immune responses following vaccination. Notably, in contrast to the significant changes in HC, ARI showed minimal gene expression changes in effector B cells and plasma cells. In CD27+ effector B cells, activation and lineage-defining genes, including ZEB2, ITGAX, and ITPR1, were significantly upregulated in HC but not in ARI. Pathway analysis showed enrichment of TGF-β and PIP3 signaling pathways in HC and antigen presentation pathways in ARI. These findings suggest ARI already exhibit altered cellular immune responses to perturbation, potentially driven by baseline immune dysregulation. Further research is warranted to understand how these differences relate to RA development and other autoimmune features in ARI. Funding Sources This work is funded by Allen Insitute Topic Categories Basic Autoimmunity (BA)