Divergent B-cell and cytotoxic TNK cell activation signatures in HLA-B27-associated ankylosing spondylitis and acute anterior uveitis
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....
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Frontiers Media S.A.
2025-03-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1546429/full |
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| author | Eisa Mahyari Sean Davin Kimberly Ogle Emma Fale-Olsen Carley Shaut Tammy M. Martin Jasvinder S. Ahuja Eric Suhler Atul Deodhar James T. Rosenbaum James T. Rosenbaum Tejpal Gill Tejpal Gill |
| author_facet | Eisa Mahyari Sean Davin Kimberly Ogle Emma Fale-Olsen Carley Shaut Tammy M. Martin Jasvinder S. Ahuja Eric Suhler Atul Deodhar James T. Rosenbaum James T. Rosenbaum Tejpal Gill Tejpal Gill |
| author_sort | Eisa Mahyari |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-6845d57483b94482bfd1c2ec718bbec8 |
| institution | DOAJ |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Frontiers Media S.A. |
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| spelling | doaj-art-6845d57483b94482bfd1c2ec718bbec82025-08-20T03:02:10ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-03-011610.3389/fimmu.2025.15464291546429Divergent B-cell and cytotoxic TNK cell activation signatures in HLA-B27-associated ankylosing spondylitis and acute anterior uveitisEisa Mahyari0Sean Davin1Kimberly Ogle2Emma Fale-Olsen3Carley Shaut4Tammy M. Martin5Jasvinder S. Ahuja6Eric Suhler7Atul Deodhar8James T. Rosenbaum9James T. Rosenbaum10Tejpal Gill11Tejpal Gill12Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR, United StatesCasey Eye Institute, Oregon Health and Science University, Portland, OR, United StatesCasey Eye Institute, Oregon Health and Science University, Portland, OR, United StatesCasey Eye Institute, Oregon Health and Science University, Portland, OR, United StatesLaboratory of Immunogenetics, Oregon Health & Science University, Portland, OR, United StatesCasey Eye Institute, Oregon Health and Science University, Portland, OR, United StatesOregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR, United StatesCasey Eye Institute, Oregon Health and Science University, Portland, OR, United StatesDivision of Arthritis and Rheumatic Diseases, Department of Medicine, Oregon Health & Science University, Portland, OR, United StatesLegacy Devers Eye Institute, Portland, OR, United StatesCorvus Pharmaceuticals, Burlingame, CA, United StatesCasey Eye Institute, Oregon Health and Science University, Portland, OR, United StatesDivision of Arthritis and Rheumatic Diseases, Department of Medicine, Oregon Health & Science University, Portland, OR, United StatesAnkylosing 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.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1546429/fullankylosing spondylitisacute anterior uveitisHLA-B27single cell CITE sequencingimmunophenotype |
| spellingShingle | Eisa Mahyari Sean Davin Kimberly Ogle Emma Fale-Olsen Carley Shaut Tammy M. Martin Jasvinder S. Ahuja Eric Suhler Atul Deodhar James T. Rosenbaum James T. Rosenbaum Tejpal Gill Tejpal Gill Divergent B-cell and cytotoxic TNK cell activation signatures in HLA-B27-associated ankylosing spondylitis and acute anterior uveitis Frontiers in Immunology ankylosing spondylitis acute anterior uveitis HLA-B27 single cell CITE sequencing immunophenotype |
| title | Divergent B-cell and cytotoxic TNK cell activation signatures in HLA-B27-associated ankylosing spondylitis and acute anterior uveitis |
| title_full | Divergent B-cell and cytotoxic TNK cell activation signatures in HLA-B27-associated ankylosing spondylitis and acute anterior uveitis |
| title_fullStr | Divergent B-cell and cytotoxic TNK cell activation signatures in HLA-B27-associated ankylosing spondylitis and acute anterior uveitis |
| title_full_unstemmed | Divergent B-cell and cytotoxic TNK cell activation signatures in HLA-B27-associated ankylosing spondylitis and acute anterior uveitis |
| title_short | Divergent B-cell and cytotoxic TNK cell activation signatures in HLA-B27-associated ankylosing spondylitis and acute anterior uveitis |
| title_sort | divergent b cell and cytotoxic tnk cell activation signatures in hla b27 associated ankylosing spondylitis and acute anterior uveitis |
| topic | ankylosing spondylitis acute anterior uveitis HLA-B27 single cell CITE sequencing immunophenotype |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1546429/full |
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