The Controversial Theories of the Unfolded Protein Response and Autophagy as Underlying Mechanisms for the Increase in the Proinflammatory Cytokine IL-23 in Ankylosing Spondylitis.

Brett Johnson

Introduction: Ankylosing Spondylitis (AS), the most severe form of Spondyloarthritis (SpA), causes chronic inflammation most commonly found in the vertebral and sacroiliac joints. AS can be a debilitating disease causing severe back pain, stiffness and new bone growth1. Although AS can affect either sex, any race, and all ages, it is most often seen in Caucasian males between 20-40 years of age.  AS has a high prevalence of 31.9 per 10,000 US citizens, although it remains a relatively unknown disease2. Studies have shown that in nearly 90% of AS patients the HLA-B27 protein is found, however, it is uncertain what role the protein plays in the disease3,4. Other studies give evidence that the pro-inflammatory cytokine IL-23 is over produced in AS patients, although the underlying mechanism causing the increase in the cytokine is not well understood5. The present research looks at current theories to fill in the gaps between the HLA-B27 protein and the increase in cytokine IL-23 to better understand the underlying mechanisms of AS. Methods: A systemic literature search was conducted. The current research was scanned and prevalent theories suggesting the underlying mechanism of AS were found. Data collected from the literature focused on the role of HLA-B27 in the disease and the underlying mechanism which leads to the increase in cytokine IL-23. Results: Two prevalent theories include the unfolded protein response (UPR) and the autophagy theory of AS. Both of these theories suggest that HLA-B27 is misfolded in the endoplasmic reticulum (ER) of macrophages at an exceedingly high rate. The UPR theory suggests that the accumulation of misfolded HLA-B27 protein causes a response that attempts to fix the protein. This response consequently leads to macrophages releasing a high amount of IL-236. Conversely, the autophagy theory suggest that the accumulation of misfolded HLA-B27 damages the ER in macrophages and in an attempt to save the cell from apoptosis the cell destroys the damaged organelles. This process includes the release of IL-23 from macrophages7,8. Conclusion: These findings suggest that the misfolding of the HLA-B27 protein leads to the overexpression of cytokine IL-23. Two prominent theories, UPR and autophagy, suggest different underlying mechanisms which connect the misfolded protein HLA-B27 to IL-23 overexpression. While these two theories present separate plausible mechanisms, further research should be conducted to determine if both the UPR and autophagy contribute to AS. Specifically to determine if the UPR induces autophagy leading to IL-23 overexpression.

  1. de Koning, A., Schoones, J., van der Heijde, D. and van Gaalen, F. (2018). Pathophysiology of axial spondyloarthritis: Consensus and controversies. European Journal of Clinical Investigation, pe.12913.
  2. Dean, L., Jones, G., MacDonald, A., Downham, C., Sturrock, R., Macfarlane, G. (2013). Global prevelance of ankylosing spondylitis. Rheumotology, 53(4), pp 650-657.
  3. DeLay, M., Turner, M., Klenk, E., Smith, J., Sowders, D. and Colbert, R. (2009). HLA-B27 misfolding and the unfolded protein response augment interleukin-23 production and are associated with Th17 activation in transgenic rats. Arthritis & Rheumatism, 60(9), pp.2633-2643.
  4. Zhang, Z., Ciccia, F., Zeng, F. (2017). Functional interaction of endoplasmic reticulum aminopeptidase 2 and HLA-B27 activates the unfolded protein response. Arthritis & Rheumatology, 69(5), pp. 1009-1015.
  5. Benham, H., Rehaume, LM., Hasnain, SZ. (2014). Interleukin-23 mediates the intestinal response to microbial B-1,3-glucan and the development of SA pathology in SKG mice. Arthritis & Rheumatology, 66(7), pp. 1755-1767.
  6. Rezaiemanesh, A., Mahmoudi, M., Amirzargar, A., Vojdanian, M., Jamshidi, A. and Nicknam, M. (2016). Ankylosing spondylitis M-CSF-derived macrophages are undergoing unfolded protein response (UPR) and express higher levels of interleukin-23.Modern Rheumatology, 27(5), pp.862-867.
  7. Ciccia, F., Accardo-Palumbo, A., Rizzo, A., Guggino, G., Raimondo, S., Giardina, A., Cannizzaro, A., Colbert, R., Alessandro, R. and Triolo, G. (2013). Evidence that autophagy, but not the unfolded protein response, regulates the expression of IL-23 in the gut of patients with ankylosing spondylitis and subclinical gut inflammation. Annals of the Rheumatic Diseases, 73(8), pp.1566-1574.
  8. Park, M., Kim, H., Lee, S., Song, J. and Park, Y. (2017). Defective autophagy activity and its association with spinal damage in patients with ankylosing spondylitis. Joint Bone Spine, 84(5), pp.583-587.