Axial spondyloarthritis (axSpA) is a chronic inflammatory disease of the spine and sacroiliac joints whose strongest genetic risk factor, the MHC class I molecule HLA-B27, has resisted mechanistic explanation since its discovery in 1973. The genetic basis of axSpA susceptibility comprises three unresolved questions raised in Ermann's 2020 review of axSpA pathogenesis: (1) by what precise mechanism HLA-B27 confers disease risk; (2) which actual causal variants and effector genes underlie the more than one hundred loci associated with the disease, most of which point only to intergenic regions; and (3) whether non-radiographic axSpA and ankylosing spondylitis differ in genetic risk architecture or only in cohort composition. Major recent advances — identification of public TRAV21/TRBV9 T-cell receptors that recognize HLA-B27-bound self- and bacterial peptides, clinical proof-of-concept of TRBV9-targeted antibody therapy, and fine-mapping in the largest multi-ancestry genome-wide meta-analysis — have sharpened the hypotheses (arthritogenic peptide, misfolding/unfolded protein response, cell-surface homodimers engaging innate receptors) without deciding among them; the causal-variant map remains prioritization rather than identification; and no controlled head-to-head comparison has settled whether the two clinical forms share one genetic architecture.

Background

Axial spondyloarthritis (axSpA) is a chronic inflammatory rheumatic disease mainly affecting the sacroiliac joints and the spine; it causes inflammatory back pain and, over years, structural damage in the form of bone erosions and pathological new-bone formation (syndesmophytes) that can fuse the spine. It belongs to the spondyloarthritis family, together with psoriatic arthritis, arthritis associated with inflammatory bowel disease, reactive arthritis after infections, and acute anterior uveitis (inflammation of the front chamber of the eye). The radiographic form, ankylosing spondylitis (AS), is defined by definite sacroiliitis visible on plain radiographs, while non-radiographic axSpA (nr-axSpA) describes patients with the same clinical and inflammatory picture — often sacroiliac inflammation detectable only by magnetic resonance imaging — whose radiographs are not yet abnormal. Whether these are one disease at different stages or two entities with different biology is itself part of the question. The strongest genetic risk factor is HLA-B27, a human leukocyte antigen class I molecule: a highly polymorphic cell-surface protein that binds peptide fragments of proteins inside the cell and presents them to CD8+ T cells, the cytotoxic arm of adaptive immunity that kills cells displaying foreign or abnormal peptides. HLA-B27 is carried by roughly 80–95% of AS patients but only a small, population-dependent fraction of the general population, making it one of the strongest known genetic associations with any common human disease; yet the mechanism of this association has remained unexplained for five decades. Three main hypotheses compete. The arthritogenic peptide (molecular mimicry) hypothesis holds that HLA-B27 presents self-peptides that resemble microbial peptides, so that CD8+ T cells expanded during infection cross-react with the patient's own tissues. The misfolding hypothesis holds that HLA-B27 folds inefficiently in the endoplasmic reticulum (the cellular compartment where MHC class I molecules assemble with peptides), activating the unfolded protein response, a stress-signaling program that can raise IL-23 (a pro-inflammatory immune-signaling protein) and promote inflammatory type-17 immune responses. The homodimer hypothesis holds that HLA-B27 heavy chains form unusual disulfide-linked dimers at the cell surface that engage innate receptors such as KIR3DL2 (a killer immunoglobulin-like receptor on natural killer and T cells), stimulating pathogenic cytokine production. Supporting the peptide-handling route, variants of ERAP1 (endoplasmic reticulum aminopeptidase 1, the enzyme that trims peptides before MHC class I loading) affect AS risk only in HLA-B27-positive individuals — a gene–gene interaction (epistasis) that any correct mechanism must explain. Beyond HLA-B27, genome-wide association studies (GWAS), which scan hundreds of thousands of common genetic markers for statistical association with disease, have mapped more than one hundred risk loci for AS, involving antigen presentation (ERAP1, ERAP2), the IL-23/type-17 T-cell axis (IL23R, TYK2, STAT3), and macrophage and T-cell genes. Fine-mapping is the attempt to narrow each associated genomic region — usually a stretch of linked inherited variants — down to the actual causal DNA change and its effector gene; this has proven difficult because most AS associations lie in intergenic regulatory regions of small individual effect, and the HLA region of chromosome 6 is extraordinarily polymorphic. Polygenic risk scores (PRS), which aggregate the effects of thousands of associated markers into one number per individual, already distinguish AS patients from controls diagnostically but do not identify causal variants. Recent momentum has come from T-cell repertoire sequencing: 'public' T-cell receptors (shared across unrelated patients) using the TRAV21 and TRBV9 variable gene segments are clonally expanded in the joints and eyes of HLA-B27-positive patients, recognize both self- and bacterial-derived HLA-B27-bound peptides (including a bacterial peptide from the YeiH protein), and a monoclonal antibody (seniprutug/BCD-180) selectively depleting TRBV9+ T cells showed clinical activity in a randomized phase-2 trial. This therapeutic proof of concept indicates that answering the mechanism question is both feasible and clinically consequential.

Problem Statement

Determine the genetic basis of susceptibility to axial spondyloarthritis, as posed by Ermann's 2020 review of axSpA pathogenesis. The problem comprises three jointly defining questions: (i) Mechanism of HLA-B27 — by what molecular and cellular mechanism does HLA-B27 confer disease risk: presentation of disease-driving (arthritogenic) peptides to CD8+ T cells, misfolding in the endoplasmic reticulum with unfolded-protein-response signaling, formation of cell-surface HLA-B27 homodimers that engage innate receptors, or some other or combined mechanism; and which specific HLA-B27-bound peptide(s) or aberrant interaction(s) are disease-relevant? A valid answer must be consistent with the established genetic observations, including the ERAP1–HLA-B27 epistasis. (ii) Causal variants — which actual causal DNA variants and effector genes underlie the risk associations at the many loci identified by genome-wide association studies, most of which currently point only to intergenic regions rather than to identified causal alleles or genes? (iii) Genetic architecture of the two disease forms — do non-radiographic axial spondyloarthritis and ankylosing spondylitis differ in genetic risk architecture (HLA-B27 and MHC involvement, polygenic risk burden, locus effect sizes), or do the apparent differences between the two forms reflect cohort heterogeneity, classification imprecision, and ascertainment — and can the available data discriminate between these alternatives or do they leave the question undetermined? These three questions jointly define the problem and share one scientific objective, the genetic basis of axSpA susceptibility.

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