Research Review: Ankylosing Spondylitis Pathogenesis

The authors of this article reviewed data from animals and genetic studies highlighting the importance of Type 17 immune responses. The article comprehensively discusses the multifactorial pathogenesis of ankylosing spondylitis.

Aniruddha V. and Paul B. New developments in our understanding of ankylosing spondylitis pathogenesis. 2020. Immunology, 161, 94–102.

Key points: ankylosing spondylitis pathogenesis

• Ankylosing spondylitis (AS) is an autoimmune inflammatory arthritis that is part of a larger class of spondyloarthropathies.

• Complications of AS include iritis, an increased risk of osteoporosis, cardiovascular disease, and a high risk of spinal compression fractures.

• Physiotherapy is the mainstay of treatment for AS along with pain management with analgesia and nonsteroidal anti-inflammatory drugs.

• The risk of siblings or first-degree relatives of AS patients having AS is higher than that of the general population, and there is a high degree of concordance in twins.

• The HLA-B*27 gene has the strongest genetic association with ankylosing spondylitis, followed by IL-23R and endoplasmic reticulum aminopeptidase (ERAP1).

• The prevalence of ankylosing spondylitis in a population depends on the prevalence of HLA-B*27 in that population.

• Multiple genetic loci have been linked to the pathogenesis of AS. However, only a quarter of the heritability of AS is currently accounted for by the genetic loci linked to the disease of which 20.1% is linked to the HLA-B*27 gene alone.

• The IL-17-IL-23 axis and Type 17 immune responses are of particular relevance to the pathogenesis of AS.

  → IL-17 = interleukin 17.

  → The IL-17 protein consists of 150 amino acids.

  → Accumulated evidences have demonstrated that IL-17 is involved in ankylosing spondylitis, reactive arthritis, psoriatic arthritis, and other forms of spondyloarthritic conditions.1

• There is a strong genetic association between ankylosing spondylitis and IL-23R polymorphisms with functional relevance in T cell immune response, indicating that genetic variations in the IL-23/IL-17 axis may influence the effector function of Th17 cells in patients with AS.2

• Patients with AS have increased levels of circulating IL-17 and IL-23 compared with healthy controls.

• Patients with AS have increased numbers of pathogenic TH17, TH22 cells and IL-17-secreting γδ cells in their peripheral blood and accumulating in their joints.

• Th17 cells are a subset of T helper cells.

  → Th17 cells play a key role in the immune system’s defense against extracellular bacteria and fungi, as well as the development of autoimmune diseases.

• TH22 cells are a subset of human T helper cells that are involved in the pathogenesis of inflammatory diseases.

  → Some studies have found that the frequencies of Th22 cells are elevated in patients with ankylosing spondylitis, thus implicating it in the pathogenesis of AS, and making it a reasonable cellular target for therapeutic intervention.3

• There is a strong association between inflammatory bowel disease (IBD) and AS.

  → First-degree relatives of AS patients are three times more likely to have IBD, and up to 70% of AS patients have subclinical gut inflammation on endoscopic or histological examination.

  → Inflammatory bowel disease is not rare in ankylosing spondylitis, with its prevalence ranging from 6% - 14%.4

• The pathophysiology of AS associated with IBD involves the so-called “gut-synovial axis” hypothesis, which implicates host factors and environmental factors.

• Various environmental (gut bacteria-dysbiosis) and host factors (migration of activated gut-T cells and macrophages) leading to initiation of inflammation in genetically predisposed individuals may act as triggers of inflammatory responses against gut and joints components.5

• Type 17 immune response is vital for the maintenance of mucosal barrier function, and AS patients are known to have elevated IL-23 levels.

  → IL-23 is indicated as the necessary mediator for organ-specific autoimmune diseases.

  → It has been demonstrated that IL-23 can increase and stabilize the Th17 cells in disease models and humans.6

• Genetic studies have demonstrated that interleukin-23 receptor (IL-23R) has a key role in various chronic inflammatory diseases including AS.7

  → The results of these studies have led to the speculation that IL-23R gene is responsible for genetic predisposition to AS.8

References

1. Australo-Anglo-American Spondyloarthritis Consortium (TASC), J. D. Reveille, A. M. Sims et al., “Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci,” Nature Genetics, vol. 42, no. 2, pp. 123–127, 2010.

2. I-Tsu Chyuan, Ji-Yih Chen, "Role of Interleukin- (IL-) 17 in the Pathogenesis and Targeted Therapies in Spondyloarthropathies", Mediators of Inflammation, vol. 2018, Article ID 2403935, 8 pages, 2018. https://doi.org/10.1155/2018/2403935

3. Zhang L, Li YG, Li YH, et al. Increased frequencies of Th22 cells as well as Th17 cells in the peripheral blood of patients with ankylosing spondylitis and rheumatoid arthritis. PLoS One. 2012;7(4):e31000. doi:10.1371/journal.pone.0031000

4. Stolwijk C, van Tubergen A, Castillo-Ortiz JD, Boonen A. Prevalence of extra-articular manifestations in patients with ankylosing spondylitis: a systematic review and meta-analysis. Ann Rheum Dis. 2015;74:65–73.

5. Fragoulis GE, Liava C, Daoussis D, Akriviadis E, Garyfallos A, Dimitroulas T. Inflammatory bowel diseases and spondyloarthropathies: From pathogenesis to treatment. World J Gastroenterol. 2019;25(18):2162-2176. doi:10.3748/wjg.v25.i18.2162

6. Langrish C, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD, McClanahan T, Kastelein RA, Cual DJ. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. The Journal of Experimental Medicine, 2005; 201(2): 233–240

7. Sung IH, Kim TH, Bang SY, m TJ, Lee B, Peddle L, Rahman P, Greenwood CM, Hu P, Inman RD.IL-23R polymorphisms in patients with ankylosing spondylitis in Korea. J Rheumatol, 2009; 36: 1003–1005

8. Rueda B, Orozco G, Raya E, Fernandez-Sueiro JL, Mulero J, Blanco FJ, Vilches C, González-Gay MA, Martin J. The IL23R Arg381Gln non-synonymous polymorphism confers susceptibility to ankylosing spondylitis. Ann Rheum Dis, 2008; 67: 1451–1454