Longitudinal analysis of peripheral blood T cell receptor diversity in patients with systemic lupus erythematosus by next-generation sequencing

Abstract

IntroductionT cells play an important role in the pathogenesis of systemic lupus erythematosus (SLE). Clonal expansion of T cells correlating with disease activity has been observed in peripheral blood (PB) of SLE subjects. Recently, next-generation sequencing (NGS) of the T cell receptor (TCR) β loci has emerged as a sensitive way to measure the T cell repertoire. In this study, we utilized NGS to assess whether changes in T cell repertoire diversity in PB of SLE patients correlate with or predict changes in disease activity.MethodsTotal RNA was isolated from the PB of 11 SLE patients. Each subject had three samples, collected at periods of clinical quiescence and at a flare. Twelve age-matched healthy controls (HC) were used for reference. NGS was used to profile the complementarity-determining region 3 (CDR3) of the rearranged TCR β loci.ResultsRelative to the HC, SLE patients (at quiescence) demonstrated a 2.2-fold reduction in repertoire diversity in a given PB volume (P <0.0002), a more uneven distribution of the repertoire (Gini coefficient, HC vs SLE, P = 0.015), and a trend toward increased percentage of expanded clones in the repertoire (clone size >1.0 %, HC vs SLE, P = 0.078). No significant correlation between the overall repertoire diversity and clinical disease activity was observed for most SLE patients with only two of eleven SLE patients showing a decreasing trend in repertoire diversity approaching the flare time point. We did not observe any overlap of CDR3 amino acid sequences or a preferential Vβ or Jβ gene usage among the top 100 expanded clones from all SLE patients. In both HC and SLE, the majority of the expanded clones were remarkably stable over time (HC = 5.5 ±0.5 months, SLE = 7.2 ±2.4 months).ConclusionsA significant decrease in T cell repertoire diversity was observed in PB of SLE patients compared to HC. However, in most SLE patients, repertoire diversity did not change significantly with increases in disease activity to a flare. Thus, without a priori knowledge of disease-specific clones, monitoring TCR repertoire in PB from SLE patients is not likely to be useful to predict changes in disease activity.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-015-0655-9) contains supplementary material, which is available to authorized users.

T‐cell receptor and B‐cell receptor repertoire profiling in adaptive immunity

“…For example, in patients with systemic lupus erythematosus, Thapa et al . found no significant alterations between TCRβ repertoires at timepoints of disease quiescence and at a flare.…”

Single‐cell technologies are revolutionizing the approach to rare cells

“…Thus the T‐cell repertoire contains enormous diversity, as well as flexibility, for alterations of this repertoire in face of changing conditions. Decreased TCR diversity can result from various disease states, such as systemic lupus erythematosus 29 . Typically, the T‐cell repertoire also becomes somewhat narrower during old age accompanied by changes in clonal frequencies, reduced immune function and diminished response to vaccinations 30 .…”

“…Decreased TCR diversity can result from various disease states, such as systemic lupus erythematosus. 29 Typically, the T-cell repertoire also becomes somewhat narrower during old age accompanied by changes in clonal frequencies, reduced immune function and diminished response to vaccinations. 30 While this decline in immune function is not completely understood, it is likely to result from a combination of thymic involution and infections by latent pathogens such as cytomegalovirus.…”

CD4+ T cells from patients with primary biliary cholangitis show T cell activation and differentially expressed T‐cell receptor repertoires

“…Recently, advances in next-generation sequencing (NGS) have allowed comprehensive analyses of diverse TCR repertoires, 22,23 and the method has since been applied to evaluate TCR repertoires in autoimmune diseases. [24][25][26][27] Therefore, we aimed to verify the N-Ras upregulation in PBC-CD4 + T cells and the respective TCR repertoire from patients with PBC, to elucidate the immunological disorders responsible for the upregulation of TCR signaling and N-Ras expression. In this study, the expression and structure of TRAs and TRBs on PBC-CD4 + T cells were profiled by NGS, and the results revealed immunological characteristics of PBC-CD4 + T cells.…”