Interleukin-23 pathway at the enthesis: The emerging story of enthesitis in spondyloarthropathy

Charlie Bridgewood, Kassem Sharif, Jonathan Sherlock, Abdulla Watad, Dennis McGonagle*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

Abstract

The inflammatory disorders collectively termed the seronegative spondyloarthropathies (SpA) include ankylosing spondylitis (AS), psoriatic arthritis (PsA), reactive arthritis, the arthritis associated with inflammatory bowel disease including Crohn's disease and ulcerative colitis, the arthritis related to anterior uveitis, and finally, somewhat controversially Behcet's disease. All of these diseases are associated with SNPs in the IL-23R or the interleukin-23 (IL-23) cytokine itself and related downstream signaling JAK pathway genes and the interleukin-17 (IL-17) pathway. In rheumatoid arthritis, the target of the immune response is the synovium but the SpA disorders target the tendon, ligament, and joint capsule skeletal anchorage points that are termed entheses. The discovery that IL-23R–expressing cells were ensconced in healthy murine enthesis, and other extraskeletal anchorage points including the aortic root and the ciliary body of the eye and that systemic overexpression of IL-23 resulted in a severe experimental SpA, confirmed a fundamentally different immunobiology to rheumatoid arthritis. Recently, IL-23R–expressing myeloid cells and various innate and adaptive T cells that produce IL-17 family cytokines have also been described in the human enthesis. Blockade of IL-23 pathway with either anti-p40 or anti-p19 subunits has resulted in some spectacular therapeutic successes in psoriasis and PsA including improvement in enthesitis in the peripheral skeleton but has failed to demonstrate efficacy in AS that is largely a spinal polyenthesitis. Herein, we discuss the known biology of IL-23 at the human enthesis and highlight the remarkable emerging story of this unique skeletal tissue.

Original languageEnglish
Pages (from-to)27-47
Number of pages21
JournalImmunological Reviews
Volume294
Issue number1
DOIs
StatePublished - 1 Mar 2020

Funding

FundersFunder number
Janssen Biotech
Janssen Pharmaceuticals

    Keywords

    • animal models
    • enthesis
    • interleukin-17
    • interleukin-23
    • spondyloarthropathies

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