In:
Hepatology Research, Wiley, Vol. 49, No. 6 ( 2019-06), p. 653-662
Abstract:
Primary biliary cholangitis (PBC) is an autoimmune liver disease with unknown pathogenesis. In PBC, activation of T‐cell receptor (TCR) signaling is associated with inflammatory cytokine production through N‐Ras upregulation. Although the CD4 + T cell TCR repertoire could be associated with PBC pathogenesis, it has not been evaluated. Thus, we analyzed the PBC‐CD4 + T cell TCR repertoire using next generation sequencing (NGS). Methods Four PBC patients (one treatment‐naïve and three receiving ursodeoxycholic acid) and three healthy individuals were enrolled. NRAS expression in CD4 + T cells was assessed by quantitative reverse transcription–polymerase chain reaction (qRT‐PCR). N‐Ras dynamics in CD4 + T cells were assessed by qRT‐PCR and GTP‐N‐Ras activation assay. The TCR α‐ (TRA) and β‐chain (TRB) repertoires on CD4 + T cells were analyzed by NGS and profiled using hierarchical analysis. Motif analysis was undertaken to elucidate the structure of PBC‐specific TCRs. Results NRAS was upregulated in PBC relative to control CD4 + T cells ( P 〈 0.05), and N‐Ras enhanced T cell activation in CD4 + T cells. Among 2668 TRAs and 841 TRBs, 20 and 11, respectively, were differentially expressed in PBC compared to that in controls ( P 〈 0.05, fold‐change 〉 2). Among them, TRAV29/J22, TRBV6–5/J2–6, and TRBV10–1/J2–1 were expressed in PBC but the expression was negligible in the controls, with more mature and longer forms observed in PBC‐CD4 + T cells. Conclusions N‐Ras was upregulated in PBC‐CD4 + T cells, and it enhanced TCR activation, indicating that PBC‐CD4 + T cells were activated by N‐Ras upregulation with differentially expressed TCR repertoires on their surfaces.
Type of Medium:
Online Resource
ISSN:
1386-6346
,
1872-034X
Language:
English
Publisher:
Wiley
Publication Date:
2019
detail.hit.zdb_id:
2006439-1
detail.hit.zdb_id:
1387041-5
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