EditorialThe IL-23/Th 17 pathway in spondyloarthritis: The Royal Road?
Section snippets
The IL-23/Th17 pathway
IL-23 is a dimeric cytokine whose two subunits are p40, which is shared with IL-12, and p19, which is specific to IL-23 [1]. The main sources of IL-23 are monocytes and dendritic cells stimulated by lipopolysaccharides and T-lymphocyte receptor activation. The main function of IL-23, together with IL-6 and TGF-β, consists of directing naive CD4+ T cells toward the Th17 phenotype. Th17 cells express surface receptors for TGF-β and IL-23. They produce several IL-17 isoforms (IL-17A through F),
IL-23 and Th17 in spondyloarthritis
Serum IL-17 levels were higher in patients with AS than in controls in two studies [3], [4] but not in another study [5]. Patients with AS may have similar serum IL-23 levels to those in controls but higher levels in joint fluid than in serum, suggesting local production [3].
Within facet-joint bone marrow specimens from patients with AS, the frequencies of IL-23 (p19)-positive cells [6] and IL-17 positive mononuclear cells [7] were elevated compared to patients with osteoarthritis. Furthermore,
Mechanisms of IL-23/Th17 involvement in spondyloarthritis
IL-23 may have multiple sources in patients with SpA. Pathogen-associated molecular patterns (PAMPs), such as bacterial lipopolysaccharides, flagellin, and peptidoglycan are recognized by cells via toll-like receptors (TLRs) as part of the innate immune response. Via PAMPs, microorganisms can activate monocytes and dendritic cells, thereby inducing IL-23 production [14]. Another mechanism of IL-23 overproduction may involve the behavior of HLA-B27. HLA-B27 folding is slow within the endoplasmic
Options for targeted treatment: proof of concept?
The IL-23/Th17 pathway can be targeted by therapeutic agents in a variety of manners, such as IL-23 blockade by monoclonal antibodies or soluble receptors and IL-23 receptor blockade by monoclonal antibodies. Potential targets include each of the IL-23 subunits (p40 and p19), IL-17A, and the IL-17A receptor. Several biological agents directed against these targets are available or are being developed and evaluated in patients with axial SpA or PsA (Table 2) [19], [20], [21], [22], [23], [24].
Discussion
The road may not be so easy to travel. Although the data discussed above establish a role for the IL-23/Th17 pathway in the development and progression of SpA, other mechanisms are probably involved also. Variations in results across studies, in particular, suggest complexity of the pathogenic factors. Thus, serum IL-17 and IL-23 levels elevation are correlated with disease activity (BASDAI) in one study [4] but serum IL-21 and IL-23 levels failed to correlate with clinical or magnetic
Disclosure of interest
The authors declare that they have no conflicts of interest concerning this article.
References (30)
- et al.
Association of serum interleukin-17 and interleukin-23 levels with disease activity in Chinese patients with ankylosing spondylitis
J Chin Med Assoc
(2012) - et al.
The IL-23/IL-17 axis in psoriatic arthritis
Autoimmun Rev
(2014) - et al.
HLA-B27 misfolding and ankylosing spondylitis
Mol Immunol
(2014) - et al.
Insights into the pathophysiology of ankylosing spondylitis: contributions from animal models
Joint Bone Spine
(2012) - et al.
Efficacy and safety of ustekinumab in patients with active psoriatic arthritis: 1-year results of the phase 3, multicentre, double-blind, placebo-controlled PSUMMIT 1 trial
Lancet
(2013) - et al.
Anti-interleukin-17A monoclonal antibody secukinumab in treatment of ankylosing spondylitis: a randomised, double-blind, placebo-controlled trial
Lancet
(2013) - et al.
Active immunization against IL-23p19 improves experimental arthritis
Vaccine
(2011) - et al.
Recommendations of the French Society for Rheumatology (SFR) on the everyday management of patients with spondyloarthritis
Joint Bone Spine
(2014) - et al.
New bone formation in axial spondyloarthritis
Joint Bone Spine
(2013) - et al.
Interleukin-23: as a drug target for autoimmune inflammatory diseases
Immunology
(2011)
Interleukin17 and type 17 helper T cells
N Engl J Med
IL-23 and IL-17 in ankylosing spondylitis
Rheumatol Int
The interleukin-23/interleukin-17 axis in spondyloarthritis pathogenesis: Th17 and beyond
Arthritis Rheumatol
In situ analysis of interleukin-23- and interleukin-12-positive cells in the spine of patients with ankylosing spondylitis
Arthritis Rheum
Analysis of IL-17(+) cells in facet-joints of patients with spondyloarthritis suggests that the innate immune pathway might be of greater relevance than the Th17-mediated adaptive immune response
Arthritis Res Ther
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2017, Biochemical and Biophysical Research CommunicationsCitation Excerpt :It has been recently shown that the TGF-β and concomitant action of other cytokines such as IL-6 or IL-21 induced Treg versus Th17 differentiation, or Treg/Th17 plasticity [55,56]. Studies found that several key cytokines, including IL-1β, IL-23, IL-6, TGF-β, and tumor necrosis factor alpha (TNF-α), creates a cytokine setting that regulates the extension of human Th17 cells [57,58]. A study by Yang et al. demonstrated that Th17 differentiation was controlled by the combination of TGF-β with IL-21 but not IL-6.
Trafficking of antigens from gut to sacroiliac joints and spine in reactive arthritis and spondyloarthropathies: Mainly through lymphatics?
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