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Ankylosing spondylitis: an autoimmune or autoinflammatory disease?

Abstract

Ankylosing spondylitis (AS) is a chronic inflammatory disorder of unknown aetiology. Unlike other systemic autoimmune diseases, in AS, the innate immune system has a dominant role characterized by aberrant activity of innate and innate-like immune cells, including γδ T cells, group 3 innate lymphoid cells, neutrophils, mucosal-associated invariant T cells and mast cells, at sites predisposed to the disease. The intestine is involved in disease manifestations, as it is at the forefront of the interaction between the mucosal-associated immune cells and the intestinal microbiota. Similarly, biomechanical factors, such as entheseal micro-trauma, might also be involved in the pathogenesis of the articular manifestation of AS, and sentinel immune cells located in the entheses could provide links between local damage, genetic predisposition and the development of chronic inflammation. Although these elements might support the autoinflammatory nature of AS, studies demonstrating the presence of autoantibodies (such as anti-CD74, anti-sclerostin and anti-noggin antibodies) and evidence of activation and clonal expansion of T cell populations support an autoimmune component to the disease. This Review presents the evidence for autoinflammation and the evidence for autoimmunity in AS and, by discussing the pathophysiological factors associated with each, aims to reconcile the two hypotheses.

Key points

  • The pathogenesis of ankylosing spondylitis (AS) is not fully understood, despite advances in understanding some of the underlying mechanisms.

  • Genetic studies and the effects of local tissue factors, such as biomechanical stress and bacterial products, support the importance of a chronic innate immune response in AS.

  • Innate and innate-like immune cells can be found at sites of disease and probably represent the major source of IL-17 production in AS.

  • Immune pathways such as inflammasome activation, autophagy and ubiquitination are involved in both innate and adaptive immunity in AS.

  • The presence of an autoimmune response accompanied by the production of specific autoantibodies is a growing concept in AS.

  • Both autoinflammatory and autoimmune factors participate in the pathogenesis of AS in a probable continuum.

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Fig. 1: Contribution of biomechanical stress to the onset of axial disease in ankylosing spondylitis.
Fig. 2: Immune mechanisms linking intestinal dysbiosis to disease in ankylosing spondylitis.
Fig. 3: Autoimmunity versus autoinflammation in the pathogenesis of ankylosing spondylitis.

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All authors researched data for the article. D.M., R.T., M.A.B. and F.C. provided substantial contributions to discussions of content. All authors wrote the article. D.M., R.T., R.L., M.A.B. and F.C. reviewed and/or edited the manuscript before submission.

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Correspondence to Francesco Ciccia.

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Nature Reviews Rheumatology thanks R. Inman and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Entheses

The sites at which ligaments and tendons attach to the bones.

Epistatic interaction

Interaction among gene alleles at multiple locations that influence the phenotype.

Ectopic lymphoid neogenesis

The formation of lymphoid structures in the target tissues of chronic inflammation.

SKG mice

Mice with attenuated T cell receptor signalling that develop spontaneous inflammatory arthritis with extra-articular manifestations, including inflammatory bowel disease, under conventional conditions.

Mechanostat

A cellular and molecular system that senses the mechanical strain exerted on bones.

Paneth cells

Specialized epithelial cells located at the bottom of intestinal crypts that contribute to the maintenance of sterility in the crypts.

Zonulin

A molecule that modulates the permeability of tight junctions between intestinal epithelial cells.

Minicircle technology

The use of small circular DNA elements to induce the expression of genes in vivo or in vitro.

TNFΔARE mice

Mice with a deletion of the AU-rich element (ARE) from the TNF gene; ARE controls the stability of the TNF mRNA; therefore these mice have increased production of TNF.

Pyroptosis

An inflammatory form of lytic programmed cell death that occurs following inflammasome activation.

Necroptosis

A form of inflammatory cell death similar to necrosis that is regulated in a caspase-dependent manner and that can be induced by extracellular stimuli such as TNF.

TNF receptor complex I

A receptor complex of TNF that contains a death domain that mediates the induction of apoptosis and necroptosis.

Linear ubiquitin assembly complex

A three-protein complex with ubiquitin ligase activity that forms ubiquitin chains linked to the first lysine and is involved in intracellular signalling.

Procrustean

Forced classification into an arbitrary standard, deriving from the Procrustean bed ancient Greek myth.

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Mauro, D., Thomas, R., Guggino, G. et al. Ankylosing spondylitis: an autoimmune or autoinflammatory disease?. Nat Rev Rheumatol 17, 387–404 (2021). https://doi.org/10.1038/s41584-021-00625-y

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