Figure 2.

Interplay of innate and adaptive immune system in axial-SpA pathogenesis. Mast cells are not able to produce IL-17; however, they may capture it from extracellular environments and release it after unknown stimulus. NET-bound-IL17 has been demonstrated useful, along with its capability to induce osteogenic differentiation of MSC. Myeloid cells can produce a large amount of proinflammatory cytokines, which may also act on innate-like lymphocytes and innate lymphoid cells such as MAIT, ILC3, and γδ T cells. Not only these cells, but also the T_RM lymphocytes, may concentrate in axial enthesis following migration from the gut, as suggested by intestinal homing markers such as the α4β7 integrin on their surface (gut–joint axis). T cells play a predominant role among adaptive immunity, with an imbalance between T_H17 and T_REG cells, but also T_H1/22 upregulation. T CD8⁺ cells may be activated after presentation of arthritogenic peptide by HLA-B27. HLA-B27 may also contribute to IL-23/IL17 upregulation due to UPR activation and B27₂ binding of KIR₃DL₂ receptors on the NK/ T_H17 cell surface. This cellular interplay leads to an aberrant production of proinflammatory cytokines such as TNF-α, IL-17, and IL-22, which in turn may dysregulate bone homeostasis along with M2 macrophages. B lymphocytes are traditionally considered less relevant even if antibody production has been demonstrated. MAIT: mucosal-associated invariant T cells; ILC3: innate lymphoid cells 3; MSC: mesenchymal stem cells; UPR: unfolded protein response. “Created with BioRender.com”.