Elsevier

Molecular Immunology

Volume 57, Issue 1, January 2014, Pages 28-37
Molecular Immunology

Inflammatory pathways in spondyloarthritis

https://doi.org/10.1016/j.molimm.2013.07.016Get rights and content

Highlights

  • Genes in TNF, IL-1, IL-6 and IL-23/IL-17 pathways are genetically associated with SpA.

  • Functional and clinical studies identify TNF and IL-23/IL-17 as key pathways in SpA.

  • Recent data point out transmembrane TNF and IL-17 as important players in SpA.

Abstract

Spondyloarthritis is the second most common form of chronic inflammatory arthritis and a unique hallmark of the disease is pathologic new bone formation. Several cytokine pathways have been genetically associated with ankylosing spondylitis (AS), the prototypic subtype of SpA, and additional evidence from human and animal studies support a role of these pathways in the disease. TNF has a key role in SpA as blockade significantly reduces inflammation and destruction, however the treatment does not halt new bone formation. New insights into the TNF pathway were recently obtained from an animal model specifically overexpressing the transmembrane form of TNF. This model leads to axial and peripheral new bone formation which is not seen in soluble TNF overexpression models, indicating different pathogenic roles of soluble and transmembrane TNF in arthritis development. Besides TNF, the IL-23/IL-17 axis is emerging as an important inflammatory pathway in SpA, as a SNP in the IL-23R locus has been associated with developing AS, mice overexpressing IL-23 develop SpA-like features and IL-17 blockade has been shown to be efficacious for AS patients in a phase II trial. In this review, we focus on the cytokine pathways that have recently been genetically associated with SpA, i.e. TNF, IL-1, IL-6 and IL-23/IL-17. We review the current genetic, experimental and human in vivo data available and discuss how these different pathways are involved in the pathophysiology of SpA. Additionally, we discuss how these pathways relate to the pathogenic new bone formation in SpA.

Introduction

Ankylosing spondylitis (AS) is the prototypical form of spondyloarthritis (SpA), a prevalent and invalidating form of chronic inflammatory arthritis of presumably autoinflammatory rather than autoimmune aetiology (Ambarus et al., 2012, Dougados and Baeten, 2011, Park et al., 2012). Extensive genome wide association scan studies have recently provided major insights in the genetic architecture of AS. The discovery of a number of novel genetic associations beyond HLA-B27 pointed towards already known as well as unexpected inflammatory cytokine pathways that may be involved in the pathogenesis of AS. Single nucleotide polymorphisms in cytokines, their receptors, and their intracellular signalling molecules identified TNF, IL-1, IL-6 and IL-23/IL-17 as cytokine pathways of major interest. Here we will review our current knowledge of the involvement of these cytokine pathways in the pathophysiology of the disease. As the current understanding is that the pathophysiology of SpA is driven by similar and broadly overlapping cellular and molecular mechanisms in the different phenotypic forms of the disease, including AS, we will discuss SpA as one disease but indicate differences between SpA subtypes where appropriate (Baeten et al., 2013). We will review the available evidence from (a) genetic associations, (b) studies in animal models, (c) expression of these cytokines in human SpA and (d) therapeutic effects of cytokine blockade in human SpA. Finally, we will discuss how these inflammatory pathways may interact with pathologic new bone formation in SpA.

Section snippets

Genetics

GWAS identified three genetic associations of AS with TNF signalling pathways: TNFRSF1A, TRADD, and TNFSF15. First, the transmembrane receptor TNFRSF1A (TNFR1) is one of the main receptors involved in TNF signalling (Corona-Sanchez et al., 2012, Davidson et al., 2011, Evans et al., 2011, Karaderi et al., 2012). Signalling through TNFR1 can be associated with NF-κB-mediated cell survival and growth or, alternatively, with apoptosis via TRADD. TNFR1 is widely expressed on hematopoietic and

Genetics

GWAS in AS indicated an association with IL1R2 (Reveille et al., 2010). However, this association was not reproduced in the Han Chinese population (Z. Lin et al., 2012). In a meta-analysis of genetic data in AS for possible SNPs in the IL-1 signalling pathway, three SNPs in the gene for the pro-inflammatory cytokine IL-1α were reported significant, though with very small odds ratios. In addition SNPs were found in the IL-1 receptor antagonist (IL1RN) gene as well in the gene encoding for IL-1R2

Genetics

AS shows a strong genetic association with IL23R polymorphisms, which has now been replicated in several Caucasian populations (Burton et al., 2007, Danoy et al., 2010, Reveille et al., 2010). The protective variant rs11209026 results in a R381Q substitution and functional studies in healthy individuals showed the variant to be a loss of function leading to impaired Th17 effector responses (Di Meglio et al., 2011, Pidasheva et al., 2011, Sarin et al., 2011). In concordance with these data,

Genetics

As mentioned previously, AS is genetically associated with a SNP in STAT3, an intracellular molecule which mediates signalling of not only IL-23 but also IL-6. Additionally, recent data also suggest an association with a SNP in IL-6 (Brown et al., unpublished data).

Animal models

The gp130 subunit of the IL-6 receptor signals through both the STAT and SHP-2/ras/Erk pathways and two different experimental models exist where IL-6 signalling is modulated by genetic modification of gp130. Mice with a specific

Disconnect between inflammation and pathological new bone formation

A key question in the molecular pathophysiology of SpA is how inflammation interacts with structural damage. Structural damage in SpA is characterised by two distinct features: erosive bone damage and pathological new bone formation. Surprisingly, both features can be observed simultaneously in the same joints such as the sacroiliac joints in AS and small joints of the hands in PsA. The mechanisms driving cartilage and bone destruction appear to be molecularly similar to RA (Vandooren et al.,

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