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Case report for recurrent and new-onset SLE patients treated by high-dose glucocorticoid therapy: Characteristics of peripheral TCR beta chain CDR3 repertoires.

ABSTRACT: High-dose glucocorticoid therapy has been widely applied in clinical practice in systemic lupus erythematosus (SLE)patients, but less is known about the changes of T cells, especially the T cell receptor (TCR) repertoires, during the treatment. The aim of this paper is to describe the changes of TCR that recurrent and new-onset SLE patients treated by high-dose glucocorticoid therapy.Drugs of clinical treatment of SLE mainly include glucocorticoid, immunosuppressive agents, nonsteroidal anti-inflammatory drugs and B cell targeted drugs, etc, but the clinical symptoms were in remission and recurrent of onset patients with SLE.Refer to the diagnostic criteria for SLE in 2011 by the American society of rheumatology.All patients were treated with High-dose glucocorticoid therapy and surveyed the TCR repertoires at 3 monitoring moments (before treatment, one month after treatment, and 3 months after treatment) to analyze the relationship between the characteristics of TCR repertoire and the highdose glucocorticoid therapy.We found that high-dose glucocorticoid therapy resulted in clinical symptom remission, as well as change of diversity, highly expanded clones (HEC), usage of TCR beta chain variable gene (TRBV)/TCR beta chain joining gene (TRBJ), and overlapped sequences of TCR beta chain complementarity determining region 3 (CDR3) repertoires. This suggests that the effect of high-dose glucocorticoids on TCR repertoires is closely related to individual autoimmune T cells.In this study, we have shown that we could evaluate the effect of therapy, the pathogenesis, and the prognosis for the patients with SLE by monitoring the TCR CDR3 repertoires. It could afford a new method to find the therapeutic target of SLE.

SUBMITTER: Yu J

PROVIDER: S-EPMC5728901 | biostudies-other | 2017 Dec

REPOSITORIES: biostudies-other

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Case report for recurrent and new-onset SLE patients treated by high-dose glucocorticoid therapy: Characteristics of peripheral TCR beta chain CDR3 repertoires.

Yu Jiang J Shi Bin B Ma Long L Liu Chunmei C Sun Suhong S Ma Rui R Qiu Yuehong Y Yao Xinsheng X

Medicine 20171201 49

<h4>Rationale</h4>High-dose glucocorticoid therapy has been widely applied in clinical practice in systemic lupus erythematosus (SLE)patients, but less is known about the changes of T cells, especially the T cell receptor (TCR) repertoires, during the treatment. The aim of this paper is to describe the changes of TCR that recurrent and new-onset SLE patients treated by high-dose glucocorticoid therapy.<h4>Patient concerns</h4>Drugs of clinical treatment of SLE mainly include glucocorticoid, immu ...[more]

PMID: 29245286

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Project description:BackgroundCD4 T lymphocyte activation requires T cell receptor (TCR) engagement by peptide/MHC (major histocompatibility complex) (pMHC). The TCR complementarity-determining region 3 (CDR3) contains variable ? and ? loops critical for pMHC recognition. During any immune response, tuning of TCR usage through progressive clonal selection occurs. Th1 and Th2 cells operate at different avidities for activation and display distinct transcriptional programs, although polarization may be plastic, influenced by pathogens and cytokines. We therefore hypothesized that CDR3?? sequence features may intrinsically influence CD4 phenotype during progression of a response.ResultsWe show that CD4 polarization involves distinct CDR3? usage: Th1 and Th17 cells favored short TCR CDR3? sequences of 12 and 11 amino acids, respectively, while Th2 cells favored elongated CDR3? loops of 14 amino acids, with lower predicted affinity. The dominant Th2- and Th1-derived TCR? sequences with 14 amino acid CDR3 loops and 12 amino acid CDR3 loops, respectively, were expressed in TCR transgenics. The functional impact of these TCR? transgenes was assessed after in vivo priming with a peptide/adjuvant. The short, Th1-derived receptor transgenic T cell lines made IFN?, but not IL-4, 5 or 13, while the elongated, Th2-derived receptor transgenic T cell lines made little or no IFN?, but increased IL-4, 5 and 13 with progressive re-stimulations, mirrored by GATA-3 up-regulation. T cells from primed Th2 TCR? transgenics selected dominant TCR V? expansions, allowing us to generate TCR?? transgenics carrying the favored, Th2-derived receptor heterodimer. Primed T cells from TCR?? transgenics made little or no IL-17 or IFN?, but favored IL-9 after priming with Complete Freund's adjuvant and IL-4, 5, 9, 10 and 13 after priming with incomplete Freund's. In tetramer-binding studies, this transgenic receptor showed low binding avidity for pMHC and polarized T cell lines show TCR avidity for Th17 > Th1 > Th2. While transgenic expression of a Th2-derived, 'elongated' TCR-CDR3? and the TCR?? pair, clearly generated a program shifted away from Th1 immunity and with low binding avidity, cytokine-skewing could be over-ridden by altering peptide challenge dose.ConclusionWe propose that selection from responding clones with distinctive TCRs on the basis of functional avidity can direct a preference away from Th1 effector responses, favoring Th2 cytokines.

Dataset Information

Case report for recurrent and new-onset SLE patients treated by high-dose glucocorticoid therapy: Characteristics of peripheral TCR beta chain CDR3 repertoires.

Publications

Case report for recurrent and new-onset SLE patients treated by high-dose glucocorticoid therapy: Characteristics of peripheral TCR beta chain CDR3 repertoires.

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