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Abstract
Ankylosing spondylitis (AS) is the prototype of spondyloarthritis which shares complex clinical phenotypes and risk factors, both genetic and environmental with other chronic inflammatory disease, e.g. inflammatory bowel disease. Human leukocyte antigen-B27 has been known to be the major AS-susceptibility gene for more than 40 years and these molecules have distinct quaternary structures and biogenesis; at least three different hypotheses regarding the contributions to pathogenesis have been proposed. Advances in the discovery of novel susceptibility genes have pointed towards important biological pathways likely responsible for AS pathogenesis. As such, strong involvement of interleukin (IL)-23/IL-17 pathway has been hypothesized. The disease is characterized by inflammation and ankylosis, mainly at the cartilage− bone interface and enthesis. Besides the genetic background, environmental triggers such as microorganisms and mechanical stress are emerging as initiating and perpetuating factors for AS. Current concepts regard new bone formation at the enthesis as a pathological response to biomechanical stress and microbial consequences such as dysbiosis in gut inflammation.
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Figure 1.
Synovio-entheseal complex in the pathogenesis of enthesoarthritis. Synovio-entheseal complex consists of two anatomical and functional structures of the enthesis and the synovial membrane. Bone-attached tendon is covered with sesamoid fi-brocartilage extending to periosteal cartilage on its deep surface. Normally, avascular enthesis ends up with reparative process following microtrauma, thus, neoangiogenesis and formation of osteophyte at the enetheses-bone interface evolve. These processes are facilitated by presence of adjuvant molecule of bacterial origin with susceptible genetic condition.
Figure 2.
Conceptual framework of inflammation and osteoproliferation in ankylosing spondylitis. The link between inflammation and new bone formation has been much of a controversy. The recent key role of interleukin (IL)-23 mediated cascade leads to an inflammation driven concept to the disease with new bone formation. From a mechanistic view, inflammation or micro-damage may be linked to new bone formation as a inevitable consequence or serendipitous surprise. Signaling of Wnt and bone morphogenic protein (BMP) may have important roles as essential bridges in the process. DKK-1: dickkopf-1, HLA: human leukocyte antigen, NSAIDs: nonsteroidal antiinflammatory drugs, PGE2: prostaglandin 2, TNF: tumor necrosis factor.
Figure 3.
Interleukin (IL)-23/IL-17 pathway in the pathogenesis of ankylosing spondylitis (AS). Cells of both innate and adaptive immune cells are implicated in the pathogenesis of AS. Dendritic cells (DC) and macrophages in the synovium, facet joint, gut and bone marrow produce IL-23 in response to microbial product, misfolded human leukocyte antigen (HLA)-B27 or the biological signals following mechanical stimulation. GI: gastrointestinal, ILC: innate lymphoid cell, iNKT: invariant natural killer T cell, KIR3DL: killer-cell immunoglobulin-like receptor 3DL, TNF: tumor necrosis factor, RORrt: RAR-related orphan receptor gamma.
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