Highly skewed T-cell receptor V-beta chain repertoire in the bone marrow is associated with response to immunosuppressive drug therapy in children with very severe aplastic anemia

Schuster, Friedhelm R.; Hubner, Bernd; Führer, Monika; Eckermann, Olaf; Gombert, Michael; Dornmair, Klaus; Binder,; Reuther, Susanne; Krell, Pina Fanny Ida; Keller, Thomas

doi:10.1038/bcj.2011.6

Cited by 16 publications

(17 citation statements)

References 15 publications

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“…Healthy adult controls demonstrated high complexity scores with low standard deviation (127±8). As described earlier, 20 bone marrow from healthy children had a high CS SPECTRATYPING similar to adult controls.…”

Section: Skewing Of Complementarity Determining Region 3 Length Polymsupporting

confidence: 68%

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Next-generation-sequencing-spectratyping reveals public T-cell receptor repertoires in pediatric very severe aplastic anemia and identifies a chain CDR3 sequence associated with hepatitis-induced pathogenesis

et al. 2013

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Current diagnostic approaches that characterize T-cell deficiency by analyzing diversity of T-cell receptor sequences effectuate limited informational gain about the actual restrictiveness. For deeper insight into T-cell receptor repertoires we developed next-generation-sequencing-spectratyping, which employs high coverage Roche/454 sequencing of T-cell receptor (b)-chain amplicons. For automated analysis of high-throughput-sequencing data, we developed a freely available software, the TCR profiler. Gene usage, length, encoded amino acid sequence and sequence diversity of the complementarity determining region 3 were determined and comprehensively integrated into a novel complexity score. Repertoires of CD8 + T cells from children with idiopathic or hepatitis-induced very severe aplastic anemia (n=7), children two months after bone marrow transplantation (n=7) and healthy controls (children n=5, adults n=5) were analyzed. Complexity scores clearly distinguished between healthy and diseased, and even between different immune deficiency states. The repertoire of aplastic anemia patients was dominated by public (i.e. present in more than one person) T-cell receptor clonotypes, whereas only 0.2% or 1.9% were public in normal children and adults, respectively. The CDR3 sequence ASSGVGFSGANVLT was highly prevalent in 3 cases of hepatitis-induced anemia (15-32% of all sequences), but was only low expressed in idiopathic aplastic anemia (2-5%, n=4) or healthy controls (<1%). Fifteen high frequent sequences were present exclusively in aplastic anemia patients. Next-generation-sequencing-spectratyping allows in-depth analysis of Tcell receptor repertoires and their restriction in clinical samples. A dominating clonotype was identified in hepatitis-induced anemia that may be associated with disease pathogenesis and several aplastic-anemia-associated, putatively autoreactive clonotypes were sequenced.Next-generation-sequencing-spectratyping reveals public T-cell receptor repertoires in pediatric very severe aplastic anemia and identifies a b chain CDR3 sequence associated with hepatitis-induced pathogenesis

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Section: Skewing Of Complementarity Determining Region 3 Length Polymsupporting

confidence: 68%

“…This finding corresponds well to our earlier observations. 20 Based on CSSPEC-TRATYPING, a distinction between diseased cohorts was not possible because of the associated high standard deviations. Healthy adult controls demonstrated high complexity scores with low standard deviation (127±8).…”

Section: Skewing Of Complementarity Determining Region 3 Length Polymmentioning

confidence: 99%

Next-generation-sequencing-spectratyping reveals public T-cell receptor repertoires in pediatric very severe aplastic anemia and identifies a chain CDR3 sequence associated with hepatitis-induced pathogenesis

et al. 2013

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“…A correlation between the frequency of the clonotypes and haematological response to IST supports the disease specificity of these clonotypes, indicating that they may be used as markers to assess disease activity, treatment response and relapse [22,23]. It has been reported that in addition to the decline in the frequency of the immunodominant clones, restoration of TCR variability can be observed in aAA patients who respond to IST [12,24]. At the time of disease relapse, the original, putatively pathogenetic dominant clones reappear and are sometimes accompanied by Table 1.…”

Section: Cd8 1 T Cellsmentioning

confidence: 76%

The complex pathophysiology of acquired aplastic anaemia

Zeng

Katsanis

2015

Clinical and Experimental Immunology

109

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Summary Immune‐mediated destruction of haematopoietic stem/progenitor cells (HSPCs) plays a central role in the pathophysiology of acquired aplastic anaemia (aAA). Dysregulated CD8+ cytotoxic T cells, CD4+ T cells including T helper type 1 (Th1), Th2, regulatory T cells and Th17 cells, natural killer (NK) cells and NK T cells, along with the abnormal production of cytokines including interferon (IFN)‐γ, tumour necrosis factor (TNF)‐α and transforming growth factor (TGF)‐β, induce apoptosis of HSPCs, constituting a consistent and defining feature of severe aAA. Alterations in the polymorphisms of TGF‐β, IFN‐γ and TNF‐α genes, as well as certain human leucocyte antigen (HLA) alleles, may account for the propensity to immune‐mediated killing of HSPCs and/or ineffective haematopoiesis. Although the inciting autoantigens remain elusive, autoantibodies are often detected in the serum. In addition, recent studies provide genetic and molecular evidence that intrinsic and/or secondary deficits in HSPCs and bone marrow mesenchymal stem cells may underlie the development of bone marrow failure.

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“…12 A Gaussian CDR3 length distribution pattern was observed for both TRA and TRB reads, suggesting the diverse and well-distributed TCR repertoire populations in healthy donor ID 001 (Fig. 1d).…”

Section: Establishment Of Tcr Sequencing Platform By Ion Torrent Pgmmentioning

confidence: 89%

Quantitative T cell repertoire analysis by deep cDNA sequencing of T cell receptor α and β chains using next-generation sequencing (NGS)

et al. 2014

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Quantitative T cell repertoire analysis by deep cDNA sequencing of T cell receptor α and β chains using next-generation sequencing (NGS), OncoImmunology, 3:12, e968467 Immune responses play a critical role in various disease conditions including cancer and autoimmune diseases. However, to date, there has not been a rapid, sensitive, comprehensive, and quantitative analysis method to examine T-cell or B-cell immune responses. Here, we report a new approach to characterize T cell receptor (TCR) repertoire by sequencing millions of cDNA of TCR a and b chains in combination with a newly-developed algorithm. Using samples from lung cancer patients treated with cancer peptide vaccines as a model, we demonstrate that detailed information of the V-(D)-J combination along with complementary determining region 3 (CDR3) sequences can be determined. We identified extensive abnormal splicing of TCR transcripts in lung cancer samples, indicating the dysfunctional splicing machinery in T lymphocytes by prior chemotherapy. In addition, we found three potentially novel TCR exons that have not been described previously in the reference genome. This newly developed TCR NGS platform can be applied to better understand immune responses in many disease areas including immune disorders, allergies, and organ transplantations.

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Highly skewed T-cell receptor V-beta chain repertoire in the bone marrow is associated with response to immunosuppressive drug therapy in children with very severe aplastic anemia

Cited by 16 publications

References 15 publications

Next-generation-sequencing-spectratyping reveals public T-cell receptor repertoires in pediatric very severe aplastic anemia and identifies a chain CDR3 sequence associated with hepatitis-induced pathogenesis

Next-generation-sequencing-spectratyping reveals public T-cell receptor repertoires in pediatric very severe aplastic anemia and identifies a chain CDR3 sequence associated with hepatitis-induced pathogenesis

The complex pathophysiology of acquired aplastic anaemia

Quantitative T cell repertoire analysis by deep cDNA sequencing of T cell receptor α and β chains using next-generation sequencing (NGS)

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