Comparative Immunology of Entheseal Anchorage Sites Between Spine, Hip and Knee Demonstrates up to 70-fold Greater IL-23 Induction from Axial Enthesis Bone: A New Angle on the Failure of IL-23 Blockade in Ankylosing Spondylitis

Mark Harland¹, Paula David², Chi Wong¹, Jake Weddell¹, Abhay Rao³, Almas Khan³, Jake Timothy³, Peter Loughenbury³, Robert Dunsmuir³, Vishal Borse³, Campbell MacEachern³, Antonius Pieter Van der Heuvel⁴, Warner Chen⁴, Tom Macleod¹ and Dennis McGonagle⁵, ¹Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), University of Leeds, Leeds, UK, Leeds, United Kingdom, ²Department of Medicine B, Sheba Medical Center, Tel Hashomer, Israel, Ramat Gan, Israel, ³Leeds Teaching Hospitals NHS Trust, Leeds, UK, Leeds, United Kingdom, ⁴Janssen Research & Development, LLC, a Johnson & Johnson Company, Spring House, PA, USA, Spring House, PA, ⁵National Institute for Health Research (NIHR) Leeds Biomedical Research Centre (BRC), Leeds Teaching Hospitals, Leeds, UK, Leeds, England, United Kingdom

Meeting: ACR Convergence 2024

Keywords: Autoinflammatory diseases, cytokines, immunology, Spondyloarthropathies

Session Information

Date: Saturday, November 16, 2024

Title: SpA Including PsA – Basic Science Poster

Session Type: Poster Session A

Session Time: 10:30AM-12:30PM

Background/Purpose: Both peripheral and axial spondyloarthropathy (SpA), psoriasis and inflammatory bowel disease are strongly linked to IL-23 pathway immunogenetics and immunology. Unexpectedly, IL-23 inhibition lacked efficacy in axial disease, namely Ankylosing Spondylitis (AS). Myeloid cells, which are substantial producers of IL-23, are rich in the red spinal marrow so we hypothesised considerable differences may exist between axial and peripheral sites, where haematopoiesis is less active. Therefore, we performed comparative immune studies of spinal, hip, and knee enthesis peri-entheseal bone (PEB) for IL-23 induction following stimulation.

Methods: Spinous process (n=5), hip capsule (n=4), and knee (n=4) PEB collected during orthopaedic surgery was mechanically digested to extract entheseal immune cells. Cell subsets were phenotyped by flow cytometry and stimulated with LPS and zymosan to assess IL-23-producing capacity. Quantification of cytokine production was achieved by ELISA and LEGENDplex assays.

Results: Despite similar cell populations present across each site, myeloid cells including monocytes and neutrophils were numerically more abundant per gram of tissue in the red marrow of spine and hip PEB but scarce in peripheral yellow marrow PEB, in keeping with the fact the spine and hip are haematopoietically active whereas the knee in adults is not. Following stimulation, spine and hip PEB produced 25-70 fold more IL-23 than knee PEB per gram of tissue (spine = 659.5 pg/g, hip = 1382.1 pg/g, knee = 24.8 pg/g; Figure 1).

Conclusion: his comparative immunology study of adult human entheses demonstrates axial PEB, the key target of AS pathology, produces significantly more IL-23 than knee PEB. The findings from our ex vivo stimulation studies raise the possibility that high-dosing regimens of IL-23 blockers may be needed to treat Ankylosing Spondylitis.

Figure 1: Red marrow PEB has logarithmically more cells and produces more IL_23 per gram of tissue than peripheral yellow marrow PEB. A) Population numbers of cell subsets isolated from red marrow PEB (spine and hip) and peripheral PEB (knee) determined by flow cytometry. B) IL_23 produced by entheseal cells isolated from spine, hip, and knee PEB following 24hr stimulation with LPS (10 ng/ml) + interferon gamma (20ng/ml) or zymosan (10 µg/ml) + interferon gamma (20 ng/ml).

Disclosures: M. Harland: None; P. David: None; C. Wong: None; J. Weddell: None; A. Rao: None; A. Khan: None; J. Timothy: None; P. Loughenbury: None; R. Dunsmuir: None; V. Borse: None; C. MacEachern: None; A. Van der Heuvel: None; W. Chen: None; T. Macleod: None; D. McGonagle: AbbVie, 2, 5, 6, Celgene, 2, 5, 6, Janssen, 2, 5, 6, Merck, 2, 5, 6, Novartis, 2, 5, 6, Pfizer, 2, 5, 6, UCB, 2, 6.

To cite this abstract in AMA style:

Harland M, David P, Wong C, Weddell J, Rao A, Khan A, Timothy J, Loughenbury P, Dunsmuir R, Borse V, MacEachern C, Van der Heuvel A, Chen W, Macleod T, McGonagle D. Comparative Immunology of Entheseal Anchorage Sites Between Spine, Hip and Knee Demonstrates up to 70-fold Greater IL-23 Induction from Axial Enthesis Bone: A New Angle on the Failure of IL-23 Blockade in Ankylosing Spondylitis [abstract]. Arthritis Rheumatol. 2024; 76 (suppl 9). https://acrabstracts.org/abstract/comparative-immunology-of-entheseal-anchorage-sites-between-spine-hip-and-knee-demonstrates-up-to-70-fold-greater-il-23-induction-from-axial-enthesis-bone-a-new-angle-on-the-failure-of-il-23-blockad/. Accessed .

ACR Meeting Abstracts - https://acrabstracts.org/abstract/comparative-immunology-of-entheseal-anchorage-sites-between-spine-hip-and-knee-demonstrates-up-to-70-fold-greater-il-23-induction-from-axial-enthesis-bone-a-new-angle-on-the-failure-of-il-23-blockad/