TY - JOUR
T1 - In rheumatoid arthritis, synovitis at different inflammatory sites is dominated by shared but patient-specific T cell clones
AU - Musters, Anne
AU - Klarenbeek, Paul L.
AU - Doorenspleet, Marieke E.
AU - Balzaretti, Giulia
AU - Esveldt, Rebecca E. E.
AU - van Schaik, Barbera D. C.
AU - Jongejan, Aldo
AU - Tas, Sander W.
AU - van Kampen, Antoine H. C.
AU - Baas, Frank
AU - de Vries, Niek
PY - 2018
Y1 - 2018
N2 - Genetic and immunological evidence clearly points to a role for T cells in the pathogenesis of rheumatoid arthritis (RA). Selective targeting of such disease-associated T cell clones might be highly effective while having few side effects. However, such selective targeting may only be feasible if the same T cell clones dominate the immune response at different sites of inflammation. We leveraged high-throughput technology to quantitatively assess whether different T cell clones dominate the inflammatory infiltrate at various sites of inflammation in this prototypic autoimmune disease. In 13 RA patients, we performed quantitative next-generation sequencing–based human TCRb repertoire analysis in simultaneously obtained samples from inflamed synovial tissue (ST) from distinct locations within one joint, from multiple joints, and from synovial fluid (SF) and peripheral blood (PB). Identical TCRb clones dominate inflammatory responses in ST samples taken from different locations within a single joint and when sampled in different joints. Although overall ST–SF overlap was comparable to higher ST–ST values, the overlap in dominant TCRb clones in ST–SF comparisons was much lower than ST–ST and comparable to the low ST–PB overlap. In individual RA patients, a limited number of TCRb clones dominate the immune response in the inflamed ST regardless of the location within a joint and which joint undergoes biopsy; in contrast, there is limited overlap of ST with SF or PB TCR repertoires. This limited breadth of the T cell response in ST of the individual RA patient indicates that development of immunotherapies that selectively modulate dominant T cell responses might be feasible.
AB - Genetic and immunological evidence clearly points to a role for T cells in the pathogenesis of rheumatoid arthritis (RA). Selective targeting of such disease-associated T cell clones might be highly effective while having few side effects. However, such selective targeting may only be feasible if the same T cell clones dominate the immune response at different sites of inflammation. We leveraged high-throughput technology to quantitatively assess whether different T cell clones dominate the inflammatory infiltrate at various sites of inflammation in this prototypic autoimmune disease. In 13 RA patients, we performed quantitative next-generation sequencing–based human TCRb repertoire analysis in simultaneously obtained samples from inflamed synovial tissue (ST) from distinct locations within one joint, from multiple joints, and from synovial fluid (SF) and peripheral blood (PB). Identical TCRb clones dominate inflammatory responses in ST samples taken from different locations within a single joint and when sampled in different joints. Although overall ST–SF overlap was comparable to higher ST–ST values, the overlap in dominant TCRb clones in ST–SF comparisons was much lower than ST–ST and comparable to the low ST–PB overlap. In individual RA patients, a limited number of TCRb clones dominate the immune response in the inflamed ST regardless of the location within a joint and which joint undergoes biopsy; in contrast, there is limited overlap of ST with SF or PB TCR repertoires. This limited breadth of the T cell response in ST of the individual RA patient indicates that development of immunotherapies that selectively modulate dominant T cell responses might be feasible.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85049834202&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/29891556
U2 - https://doi.org/10.4049/jimmunol.1800421
DO - https://doi.org/10.4049/jimmunol.1800421
M3 - Article
C2 - 29891556
SN - 0022-1767
VL - 201
SP - 417
EP - 422
JO - Journal of immunology (Baltimore, Md.
JF - Journal of immunology (Baltimore, Md.
IS - 2
ER -