Enthesitis-related arthritis: An immunology-focused review
DOI:
https://doi.org/10.14748/r1dxsz40Keywords:
autoinflammation, gut-joint axis, enthesitis-related arthritis, juvenile idiopathic arthritis, HLA-B27, TRBV9, cross-reactive peptides, IL-23/IL-17 axisAbstract
Introduction: Enthesitis-related arthritis (ERA) is the juvenile idiopathic arthritis (JIA) subtype most likely to progress to chronic spondyloarthropathy in adulthood. Mechanistic understanding has advanced substantially over the past decade, with identification of public T cell receptor motifs in HLA-B27-positive ankylosing spondylitis, structural characterization of the cross-reactive peptides these receptors recognize, and successful proof-of-concept of T cell-targeted therapy in adults. In parallel, the autoinflammatory contributions long associated with HLA-B27—protein misfolding and the unfolded protein response, β2-microglobulin-free heavy chain homodimers, KIR3DL2 engagement, entheseal mechanoinflammation, and gut-derived IL-23—have been characterized in increasing molecular detail.
Aim: The aim of this article is to present an immunology-focused mechanism-anchored synthesis of ERA that integrates these advances, reframing the disease as juvenile-onset spondyloarthropathy rather than as a phenotypically defined JIA subtype.
Approach: This is a thesis-driven narrative review organizing classification, genetics, and immunology around an explicit two-arm mechanistic framework. Literature was identified through structured PubMed/MEDLINE searches from inception to May 2026, supplemented by hand-searching and forward citation tracking.
Key Proposition: Enthesitis-related arthritis reflects the coincidence of two mechanistically independent contributions: HLA-restricted CD8⁺ T cell recognition of cross-reactive microbial and self-peptides (autoimmune arm) and a set of autoinflammatory amplifiers (HLA-B27 misfolding, homodimer formation, entheseal mechanoinflammation, gut-derived IL-23 signaling, IL-23/IL-17 pathway genetics). The authors propose that these contributions interact in a more-than-additive manner, although the precise interaction model remains to be formally characterized. HLA-B27 carries disproportionate weight because it contributes to both arms through a single molecule, but it is neither necessary nor sufficient.
Implications: The framework reorganizes the immunology of ERA around mechanism rather than phenotype, clarifies why specific molecular layers are differentially engaged across the disease spectrum, and identifies pediatric validation of the public TRBV9 clonotype, including its therapeutic implications, as a near-term research priority.
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