AUTHOR=Mahyari Eisa , Davin Sean , Ogle Kimberly , Fale-Olsen Emma , Shaut Carley , Martin Tammy M. , Ahuja Jasvinder S. , Suhler Eric , Deodhar Atul , Rosenbaum James T. , Gill Tejpal 

TITLE=Divergent B-cell and cytotoxic TNK cell activation signatures in HLA-B27-associated ankylosing spondylitis and acute anterior uveitis

JOURNAL=Frontiers in Immunology

VOLUME=Volume 16 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1546429

DOI=10.3389/fimmu.2025.1546429

ISSN=1664-3224

ABSTRACT=Ankylosing spondylitis (AS), also known as radiographic axial spondyloarthritis (r-axSpA), is an immune-mediated inflammatory disorder frequently associated with acute anterior uveitis (AAU). Both conditions share a strong association with the genetic risk factor, human leukocyte antigen (HLA)-B27. However, the immunophenotype underlying HLA-B27-associated AS and/or AAU pathophysiology remains known. Using cellular indexing of transcriptomes and epitopes (CITE-Seq) in a well-characterized cohort of 25 subjects—including AS (HLA-B27pos), AS+AAU (HLA-B27pos), AAU (HLA-B27pos), HCs (HLA-B27pos), and HCs (HLA-B27neg); N = 5/group—we identified transcriptomic differences at the single-cell level, along with differentially expressed cell surface markers. Our study elucidates both shared and distinct immune alterations linked to HLA-B27 and disease. Furthermore, we employed sparse decomposition of arrays (SDA) analysis, an unsupervised machine learning method, to examine the high-dimensional transcriptional landscape of our data and identify complex and nonlinear relationships. Our study identified HLA-B27- and disease-specific transcriptomic differences in AS and AAU. The immune profiles of AS+AAU closely resembled those of AS, suggesting AS plays a dominant role in immune dysregulation. SDA analysis further revealed dysregulated B-cell maturation and activation in AS subjects, whereas AAU subjects exhibited an enrichment of cytotoxic effector function in T and NK cells. However, both AS and AAU exhibited myeloid cell activation, a key process in initiating and sustaining inflammation. Additionally, both AS and AAU subjects showed a dampening in homeostatic function, i.e., the balance between identifying and actively eliminating foreign pathogens while preventing an immune response against self-antigens, suggesting that inflammation may arise from immune dysregulation. In conclusion, our results highlight overlapping myeloid effector involvement, along with distinct immunophenotypic responses, such as a decrease in naive B cells in AS subjects and a reduction in the CD8/NK cell population in AAU subjects. These results highlight a distinct set of immune mediators driving AS and AAU pathogenesis. Future studies incorporating HLA-B27-negative AS and AAU patients, along with validation of B-cell and myeloid dysfunction in these diseases, may provide novel biomarkers and therapeutic targets.