Premium
Altered Repertoire Diversity and Disease‐Associated Clonal Expansions Revealed by T Cell Receptor Immunosequencing in Ankylosing Spondylitis Patients
Author(s) -
Hanson Aimee L.,
Nel Hendrik J.,
Bradbury Linda,
Phipps Julie,
Thomas Ranjeny,
Lê Cao KimAnh,
Kenna Tony J.,
Brown Matthew A.
Publication year - 2020
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.41252
Subject(s) - immunology , biology , immune system , t cell receptor , antigen , ankylosing spondylitis , t cell , human leukocyte antigen , allotype , autoimmunity
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 CD 4 and CD 8 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 CD 4 and CD 8 T cell repertoires, AS patients showed increased TCR diversity compared to healthy controls (for CD 4 T cells, P = 7.8 × 10 −6 ; for CD 8 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 CD 8 T cells, P = 0.03) and tumor necrosis factor (for CD 4 T cells, P = 0.01; for CD 8 T cells, P = 0.002). In addition, the CD 8 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.