Ankylosing spondylitis: etiology, pathogenesis, and treatments

Abstract

Ankylosing spondylitis (AS), a common type of spondyloarthropathy, is a chronic inflammatory autoimmune disease that mainly affects spine joints, causing severe, chronic pain; additionally, in more advanced cases, it can cause spine fusion. Significant progress in its pathophysiology and treatment has been achieved in the last decade. Immune cells and innate cytokines have been suggested to be crucial in the pathogenesis of AS, especially human leukocyte antigen (HLA)‑B27 and the interleukin‑23/17 axis. However, the pathogenesis of AS remains unclear. The current study reviewed the etiology and pathogenesis of AS, including genome-wide association studies and cytokine pathways. This study also summarized the current pharmaceutical and surgical treatment with a discussion of future potential therapies.

Keywords: Calcium and phosphate metabolic disorders; Pathogenesis.

Fig. 1

Various functions of ER resident and cell surface HLA-B27 dimers. ER resident dimers might lead to ER stress and activate unfolded protein responses. Cell-surface dimers might be produced after the recycling of fully folded HLA-B27 cell surface molecules through the endocytic pathway and be re-expressed as dimers for presentation to receptors, such as KIR and LILR. Elevated propagation and existence of KIR3DL2+ CD4+ T lymphocytes and amplified IL-17 production in AS cases after stimulation with antigen-presenting cells expressing HLA-B27 homodimers were confirmed in earlier studies. These cells have largely been revealed to secrete TNF-α and IFN-γ. IL-17 has been shown to coordinate with TNF-α or IFN-γ in stimulating the release of inflammatory regulators and affecting bone construction to function in the development of AS. (Reprinted with permission of Elsevier, from chen et al.)

Fig. 2

Demonstration of the possible role of HLA-B27 and ERAP1/2 in AS pathogenesis. HLA-B27 can present arthritogenic peptides to CD8+ T lymphocytes, which trigger AS initiation. Peptides enter the ER and are further trimmed by ERAP1 and ERAP2. Unusual peptides will be produced because of incorrect ERAP1 or ERAP2 trimming, leading to HLA-B27 free heavy chains (FHCs) and homodimers through endosomal recycling from the cell membrane and then to NK cell and Th17 cell activation by KIRs, particularly KIR3DL2. Abnormal peptide-HLA-B27 complexes gather in the ER, triggering UPR, ER stress, ER-associated protein degradation (ERAD) and autophagy. (Reprinted with permission of Elsevier, from Zohreh and colleagues)

Fig. 3

IL-23/17 pathway in AS pathogenesis. The interplay of genetic and epigenetic influences, particularly Th17 and Th22 cells, with a few kinds of stress, such as mechanical stress, gut microbiota stress, and environmental triggers, gives rise to the production of pro-inflammatory molecules, including IL-17, IL-22, TNF-α, and IL-23. (Reprinted with permission of Elsevier, from Zohreh and colleagues)

Fig. 4

Immunocytes are involved in the initiation, evolution, and regulation of AS. (Reprinted with permission of Elsevier, from Mohammad and colleagues)

Fig. 5

Drug treatment strategy for ankylosing spondylitis patients