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Altered Repertoire Diversity and Disease-Associated Clonal Expansions Revealed by T Cell Receptor Immunosequencing in Ankylosing Spondylitis Patients

Research output: Contribution to journalArticle

Aimee L. Hanson, Hendrik J. Nel, Linda Bradbury, Julie Phipps, Ranjeny Thomas, Kim Anh Lê Cao, Tony J. Kenna, Matthew A. Brown

Original languageEnglish
Pages (from-to)1289-1302
Number of pages14
JournalArthritis and Rheumatology
Volume72
Issue number8
DOIs
Published1 Aug 2020

King's Authors

Abstract

Objective: Ankylosing spondylitis (AS) is a common spondyloarthropathy primarily affecting the axial skeleton and strongly associated with HLA–B*27 carriage. Genetic evidence implicates both autoinflammatory processes and autoimmunity against an HLA–B*27–restricted autoantigen in immunopathology. In addition to articular symptoms, up to 70% of AS patients present with concurrent bowel inflammation, suggesting that adverse interactions between a genetically primed host immune system and the gut microbiome contribute to the disease. Accordingly, this study aimed to characterize adaptive immune responses to antigenic stimuli in AS. Methods: The peripheral CD4 and CD8 T cell receptor (TCR) repertoire was profiled in AS patients (n = 47) and HLA–B*27–matched healthy controls (n = 38). Repertoire diversity was estimated using the Normalized Shannon Diversity Entropy (NSDE) index, and univariate and multivariate statistical analyses were performed to characterize AS-associated clonal signatures. Furthermore, T cell proliferation and cytokine production in response to immunogenic antigen exposure were investigated in vitro in peripheral blood mononuclear cells from AS patients (n = 19) and HLA–B*27–matched healthy controls (n = 14). Results: Based on the NSDE measure of sample diversity across CD4 and CD8 T cell repertoires, AS patients showed increased TCR diversity compared to healthy controls (for CD4 T cells, P = 7.8 × 10−6; for CD8 T cells, P = 9.3 × 10−4), which was attributed to a significant reduction in the magnitude of peripheral T cell expansions globally. Upon in vitro stimulation, fewer T cells from AS patients than from healthy controls expressed interferon-γ (for CD8 T cells, P = 0.03) and tumor necrosis factor (for CD4 T cells, P = 0.01; for CD8 T cells, P = 0.002). In addition, the CD8 TCR signature was altered in HLA–B*27+ AS patients compared to healthy controls, with significantly expanded Epstein-Barr virus–specific clonotypes (P = 0.03) and cytomegalovirus-specific clonotypes (P = 0.02). HLA–B*27+ AS patients also showed an increased incidence of “public” CD8 TCRs, representing identical clonotypes emerging in response to common antigen encounters, including homologous clonotypes matching those previously isolated from individuals with bacterial-induced reactive arthritis. Conclusion: The dynamics of peripheral T cell responses in AS patients are altered, suggesting that differential antigen exposure and disrupted adaptive immunity are underlying features of the disease.

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