Discovery of T Cell Receptor β Motifs Specific to HLA–B27–Positive Ankylosing Spondylitis by Deep Repertoire Sequence Analysis

Abstract

Objective: Ankylosing spondylitis (AS), a chronic inflammatory disorder, has a notable association with HLA–B27. One hypothesis suggests that a common antigen that binds to HLA–B27 is important for AS disease pathogenesis. This study was undertaken to determine sequences and motifs that are shared among HLA–B27–positive AS patients, using T cell repertoire next-generation sequencing. Methods: To identify motifs enriched among B27-positive AS patients, we performed T cell receptor β (TCRβ) repertoire sequencing on samples from 191 B27-positive AS patients, 43 B27-negative AS patients, and 227 controls, and we obtained >77 million TCRβ clonotype sequences. First, we assessed whether any of 50 previously published sequences were enriched in B27-positive AS patients. We then used training and test cohorts to identify discovered motifs that were enriched in B27-positive AS patients versus controls. Results: Six previously published and 11 discovered motifs were enriched in the B27-positive AS samples as compared to controls. After combining motifs related by sequence, we identified a total of 15 independent motifs. Both the full set of 15 motifs and a set of 6 published motifs were enriched in the B27-positive AS patients as compared to B27-positive healthy individuals (P = 0.049 and P = 0.001, respectively). Using an independent cohort, we validated that at least some of these motifs were associated with AS, and not simply with B27-positive status. Conclusion: We identified TCRβ motifs that are enriched in B27-positive AS patients as compared to B27-positive healthy controls. This suggests that a common antigen, presented by HLA–B27 and detected by CD8+ T cells, may be associated with AS disease pathogenesis.