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Arthritis Rheumatol. 2017 Apr;69(4):774-784. doi: 10.1002/art.40028.

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

Author information

1
Adaptive Biotechnologies Corporation, South San Francisco, California, and Adaptive Biotechnologies Corporation, Seattle, Washington.
2
Adaptive Biotechnologies Corporation, South San Francisco, California, and Adaptive Biotechnologies Corporation and Fred Hutchinson Cancer Research Center, Seattle, Washington.
3
Alternate Allele Consulting, Orinda, California.
4
University of Minnesota, Minneapolis.
5
Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada.

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.

PMID:
28002888
DOI:
10.1002/art.40028
[Indexed for MEDLINE]
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