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Pathogenesis of ankylosing spondylitis — recent advances and future directions

Key Points

  • More than 100 genetic loci have been associated with ankylosing spondylitis (AS), but together they explain less than 30% of AS heritability

  • Multiple genes involved in antigen processing and presentation are associated with AS

  • Investigation into the cellular sources and regulation of IL-17 production is crucial to understanding the pathogenesis of AS

  • Cells involved in type 3 immunity produce IL-17 and include innate lymphoid cells and γδ T cells

  • Given the efficacy of the anti-IL-17 monoclonal antibody secukinumab in the treatment of AS, other therapies targeting type 3 immunity could also be effective

Abstract

Over the past 5 years, advances in high-throughput techniques and studies involving large cohorts of patients have led to considerable advances in the identification of novel genetic associations and immune pathways involved in ankylosing spondylitis (AS). These discoveries include genes encoding cytokine receptors, transcription factors, signalling molecules and transport proteins. Although progress has been made in understanding the functions and potential pathogenic roles of some of these molecules, much work remains to be done to comprehend their complex interactions and therapeutic potential in AS. In this Review, we outline the current knowledge of AS pathogenesis, including genetic risk associations, HLA-B27-mediated pathology, perturbations in antigen-presentation pathways and the contribution of the type 3 immune response.

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Figure 1: Antigen processing and presentation: potential link to AS.
Figure 2: Type 3 immunity and AS.

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All the authors researched the data for the article, made substantial contributions to discussion of content, wrote the article, and edited/reviewed the manuscript before submission. V.R. and E.G. contributed equally to this work.

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Correspondence to Nigil Haroon.

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Genome-wide significance

In most genome-wide association studies, the threshold that an association must reach to be considered statistically significant is a high P value (≥5 × 10−8) owing to the multiple tests conducted in such studies.

Seronegative diseases

Diseases not associated with serum autoantibodies.

M1 family of zinc metallopeptidases

Aminopeptidases that cleave polypeptides from the N-terminus and are dependent on a single zinc ion for activity.

Immunochip platform

A microarray chip containing probes that recognize approximately195,000 single nucleotide polymorphisms and 700 small insertion and/or deletions; the main aim of this platform is to fine-map |genetic associations identified in 11 autoimmune and inflammatory diseases.

Data-independent acquisition mass spectrometry

Mass spectrometry technique in which all ions generated are fragmented and analysed without pre-selection.

Autophagy

A process that involves the orderly degradation of dysfunctional intracellular components through their delivery to lysosomes in structures called autophagosomes.

Endoplasmic reticulum-associated degradation

(ERAD). A process that facilitates the degradation of misfolded proteins in the endoplasmic reticulum by transporting them to the cytoplasm, where ubiquitylation followed by proteasome-mediated degradation occurs.

Coat protein complex II

Vesicle coat protein that aids anterograde transport of proteins from the endoplasmic reticulum to the Golgi apparatus.

SKG mice

Mice carrying a hypomorphic single nucleotide polymorphism in ZAP70 (a T cell receptor signalling molecule), which predisposes T cells to a T helper 17 cell phenotype. Under specific pathogen-free conditions, SKG mice are disease-free; however, a single dose of curdlan, an IL-23-inducing molecule, induces progressive spondyloathropathy characterized by axial and peripheral arthritis, dermatitis and colitis.

Innate-like lymphocytes

Cells of the lymphocyte lineage that express T cell receptors of limited diversity and are restricted by non-classical MHC molecules such as CD1 or MR1. These cells typically recognize non-peptide antigens and are activated faster than regular peptide-restricted adaptive immune cells.

Mucosal-associated invariant T (MAIT) cells

A population of innate-like lymphocytes that recognize bacterially derived vitamin B metabolites presented on the non-classical MHC molecule MR1.

Synovio-enthesal complex

Anatomical unit comprising the fibrous insertion of tendon or ligament enthesis and the adjacent synovial membrane of the bursa.

Fate-mapping studies

Studies that investigate the origin of cell populations through labelling and tracking of cells of interest. Immunological studies typically use membrane-incorporated dyes, or genetic switches that result in constitutive fluorochrome expression if a cell marker is expressed.

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Ranganathan, V., Gracey, E., Brown, M. et al. Pathogenesis of ankylosing spondylitis — recent advances and future directions. Nat Rev Rheumatol 13, 359–367 (2017). https://doi.org/10.1038/nrrheum.2017.56

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