Discovery of T-Cell Receptor Beta Motifs Specific to HLA-B27(+) Ankylosing Spondylitis by Deep Repertoire Sequence Analysis.

Publication Type:

Journal Article

Source:

Arthritis & rheumatology (Hoboken, N.J.) (2016)

Abstract:

OBJECTIVE: Ankylosing spondylitis (AS), a chronic inflammatory disorder, has a striking association with HLA-B27. One hypothesis suggests that a common antigen that binds to HLA-B27 is important for AS disease pathogenesis. We utilized T-cell repertoire next-generation sequencing to determine sequences and motifs that are shared among HLA-B27 positive (B27(+) ) AS patients.

METHODS: To identify motifs enriched among B27(+) AS patients, we performed T-cell receptor beta (TCRβ) repertoire sequencing from 191 B27(+) AS patients, 43 B27(neg) AS patients and 227 controls, and we obtained >77 million TCRβ clonotype sequences. First, we assessed whether any of 50 previously published sequences are enriched in B27(+) AS patients. We then used training and test cohorts to identify discovered motifs that are enriched in B27(+) AS patients versus controls.

RESULTS: Six previously published and 11 discovered motifs were enriched in the B27(+) AS samples as compared to controls. After collapsing motifs related by sequencing, we identified a total of 15 independent motifs. Both the full 15 and 6 published motif sets are enriched in the B27(+) AS patients as compared to B27(+) healthy individuals (p value = 0.049 and 0.001, respectively). Using an independent cohort, we validated that at least some of these motifs are associated with AS, and not simply B27+ status.

CONCLUSION: We identified TCRβ motifs that are enriched in B27(+) AS patients as compared to healthy controls who are also B27(+) . This suggests that a common antigen, presented by HLA-B27 and detected by CD8(+) T cells, may be associated with AS disease pathogenesis. This article is protected by copyright. All rights reserved.