Uncovering the Underworld of Axial Spondyloarthritis

Abstract

Axial spondyloarthritis (axial-SpA) is a multifactorial disease characterized by inflammation in sacroiliac joints and spine, bone reabsorption, and aberrant bone deposition, which may lead to ankylosis. Disease pathogenesis depends on genetic, immunological, mechanical, and bioenvironmental factors. HLA-B27 represents the most important genetic factor, although the disease may also develop in its absence. This MHC class I molecule has been deeply studied from a molecular point of view. Different theories, including the arthritogenic peptide, the unfolded protein response, and HLA-B27 homodimers formation, have been proposed to explain its role. From an immunological point of view, a complex interplay between the innate and adaptive immune system is involved in disease onset. Unlike other systemic autoimmune diseases, the innate immune system in axial-SpA has a crucial role marked by abnormal activity of innate immune cells, including γδ T cells, type 3 innate lymphoid cells, neutrophils, and mucosal-associated invariant T cells, at tissue-specific sites prone to the disease. On the other hand, a T cell adaptive response would seem involved in axial-SpA pathogenesis as emphasized by several studies focusing on TCR low clonal heterogeneity and clonal expansions as well as an interindividual sharing of CD4/8 T cell receptors. As a result of this immune dysregulation, several proinflammatory molecules are produced following the activation of tangled intracellular pathways involved in pathomechanisms of axial-SpA. This review aims to expand the current understanding of axial-SpA pathogenesis, pointing out novel molecular mechanisms leading to disease development and to further investigate potential therapeutic targets.

Keywords: axial spondyloarthritis; biological agents; cytokines; innate immunity; personalized medicine.

Figure 1

Axial-SpA may evolve over time, from an early phase without radiologically detectable changes in the pelvic X-ray (nr-axial-SpA) toward a late phase in which structural changes such as sclerosis, erosions, and new bone formation in the sacroiliac joints and in the spine occur (r-axial-SpA).

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”.

Figure 3

Molecular targets and associated signalling pathways. Current therapeutic targets in axial-SpA include TNF-α, IL-17A, and JAKs. TNF-α signals mainly through the NF-κB pathway and could be inhibited by several monoclonal antibodies, anti-TNF-α, and the fusion protein etanercept. IL-17A has a pivotal role in mediating disease pathogenesis and could activate several pathways such as the canonical NF-κB, MAPK, C/EBP pathways and the alternative stabilization of mRNA. Secukinumab and ixekizumab can bind IL-17A with different affinities, inhibiting its downstream actions. The JAK inhibitors upadacitinib, filgotinib, and tofacitinib may act directly by blocking the signal transduction of proinflammatory cytokines including IFN-γ, IL-6, IL-7, IL-12, IL-21, IL-22, IL-23, or indirectly blocking TNF-α and IL-17A/F production following inhibition of upstream stimuli. New targets include the simultaneous inhibition of IL-17A and IL-17F with bimekizumab. Moreover, a potential therapeutic strategy may be represented by GM-CSF inhibition through namilumab. Finally, the PI3K/Akt/mTOR pathway has important immunomodulatory roles, it can elicit RORγT translocation into the nucleus, promoting IL-17A/F production and could be further investigated as a novel target. “Created with BioRender.com”.