Alterations in T and B Cell Receptor Repertoires Patterns in Patients With IL10 Signaling Defects and History of Infantile-Onset IBD
Patients with loss-of-function mutations in IL10 or IL10 receptor (IL10R) genes develop severe, medical-refractory, infantile-onset inflammatory bowel disease (IBD). We have previously reported significant alterations in innate and adaptive immune responses in these patients. Next generation sequenc...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-02-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2020.00109/full |
| _version_ | 1818266332932603904 |
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| author | Lael Werner Lael Werner Yu Nee Lee Yu Nee Lee Yu Nee Lee Yu Nee Lee Erez Rechavi Erez Rechavi Erez Rechavi Erez Rechavi Atar Lev Atar Lev Atar Lev Atar Lev Baruch Yerushalmi Galina Ling Neil Shah Holm H. Uhlig Holm H. Uhlig Holm H. Uhlig Batia Weiss Batia Weiss Raz Somech Raz Somech Raz Somech Raz Somech Scott B. Snapper Scott B. Snapper Dror S. Shouval Dror S. Shouval |
| author_facet | Lael Werner Lael Werner Yu Nee Lee Yu Nee Lee Yu Nee Lee Yu Nee Lee Erez Rechavi Erez Rechavi Erez Rechavi Erez Rechavi Atar Lev Atar Lev Atar Lev Atar Lev Baruch Yerushalmi Galina Ling Neil Shah Holm H. Uhlig Holm H. Uhlig Holm H. Uhlig Batia Weiss Batia Weiss Raz Somech Raz Somech Raz Somech Raz Somech Scott B. Snapper Scott B. Snapper Dror S. Shouval Dror S. Shouval |
| author_sort | Lael Werner |
| collection | DOAJ |
| description | Patients with loss-of-function mutations in IL10 or IL10 receptor (IL10R) genes develop severe, medical-refractory, infantile-onset inflammatory bowel disease (IBD). We have previously reported significant alterations in innate and adaptive immune responses in these patients. Next generation sequencing platforms enable a comprehensive assessment of T cell receptor (TCR) and B cell receptor (BCR) repertoire patterns. We aimed to characterize TCR and BCR features in peripheral blood of patients with deleterious IL10 signaling defects. DNA was isolated from blood of seven patients with IL10R mutations and one with an IL10 mutation, along with eight controls, and subjected to next generation sequencing of TRB and IgH loci. A significant increase in clonality was observed in both TCR and BCR repertoires in circulating lymphocytes of IL10/IL10R-deficient patients, but to a much greater extent in T cells. Furthermore, short CDR3β length and altered hydrophobicity were demonstrated in T cells of patients, but not in B cells, secondary to lower rates of insertions of nucleotides, but not deletions, at the V-, D-, or J-junctions. We were unable to observe specific T or B clones that were limited only to the patients or among controls. Moreover, the expanded T cells clones were unique to each patient. In conclusion, next generation sequencing of the TCR and BCR is a powerful tool for characterizing the adaptive immune cell phenotype and function in immune-mediated disorders. The oligoclonality observed among IL10/IL10R-deficient patients may suggest specialization of unique clones that likely have a role in mediating tissue damage. Nevertheless, the lack of shared clones between patients provides another piece of evidence that the adaptive immune response in IBD is not triggered against common antigens. Additional studies are required to define the specific antigens that interact with the expanded IL10/IL10R-deficient clones. |
| first_indexed | 2024-12-12T20:05:02Z |
| format | Article |
| id | doaj.art-73bb68229dc247a8a67ae3b9349d8ec7 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-12T20:05:02Z |
| publishDate | 2020-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-73bb68229dc247a8a67ae3b9349d8ec72022-12-22T00:13:40ZengFrontiers Media S.A.Frontiers in Immunology1664-32242020-02-011110.3389/fimmu.2020.00109502634Alterations in T and B Cell Receptor Repertoires Patterns in Patients With IL10 Signaling Defects and History of Infantile-Onset IBDLael Werner0Lael Werner1Yu Nee Lee2Yu Nee Lee3Yu Nee Lee4Yu Nee Lee5Erez Rechavi6Erez Rechavi7Erez Rechavi8Erez Rechavi9Atar Lev10Atar Lev11Atar Lev12Atar Lev13Baruch Yerushalmi14Galina Ling15Neil Shah16Holm H. Uhlig17Holm H. Uhlig18Holm H. Uhlig19Batia Weiss20Batia Weiss21Raz Somech22Raz Somech23Raz Somech24Raz Somech25Scott B. Snapper26Scott B. Snapper27Dror S. Shouval28Dror S. Shouval29Pediatric Gastroenterology Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Centre, Ramat Gan, IsraelSackler Faculty of Medicine, Tel Aviv University, Tel Aviv, IsraelSackler Faculty of Medicine, Tel Aviv University, Tel Aviv, IsraelPediatric Department A, Edmond and Lily Safra Children's Hospital, Sheba Medical Centre, Ramat Gan, IsraelImmunology Service, Edmond and Lily Safra Children's Hospital, Sheba Medical Centre, Ramat Gan, IsraelJeffrey Modell Foundation Center, Edmond and Lily Safra Children's Hospital, Sheba Medical Centre, Ramat Gan, IsraelSackler Faculty of Medicine, Tel Aviv University, Tel Aviv, IsraelPediatric Department A, Edmond and Lily Safra Children's Hospital, Sheba Medical Centre, Ramat Gan, IsraelImmunology Service, Edmond and Lily Safra Children's Hospital, Sheba Medical Centre, Ramat Gan, IsraelJeffrey Modell Foundation Center, Edmond and Lily Safra Children's Hospital, Sheba Medical Centre, Ramat Gan, IsraelSackler Faculty of Medicine, Tel Aviv University, Tel Aviv, IsraelPediatric Department A, Edmond and Lily Safra Children's Hospital, Sheba Medical Centre, Ramat Gan, IsraelImmunology Service, Edmond and Lily Safra Children's Hospital, Sheba Medical Centre, Ramat Gan, IsraelJeffrey Modell Foundation Center, Edmond and Lily Safra Children's Hospital, Sheba Medical Centre, Ramat Gan, IsraelPediatric Gastroenterology Unit, Soroka University Medical Center, Ben Gurion University of the Negev, Be'er Sheva, IsraelPediatric Gastroenterology Unit, Soroka University Medical Center, Ben Gurion University of the Negev, Be'er Sheva, IsraelDepartment of Gastroenterology, Great Ormond Street Hospital, London, United KingdomTranslational Gastroenterology Unit, Nuffield Department of Experimental Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United KingdomDepartment of Pediatrics, University of Oxford, Oxford, United Kingdom0NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, United KingdomPediatric Gastroenterology Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Centre, Ramat Gan, IsraelSackler Faculty of Medicine, Tel Aviv University, Tel Aviv, IsraelSackler Faculty of Medicine, Tel Aviv University, Tel Aviv, IsraelPediatric Department A, Edmond and Lily Safra Children's Hospital, Sheba Medical Centre, Ramat Gan, IsraelImmunology Service, Edmond and Lily Safra Children's Hospital, Sheba Medical Centre, Ramat Gan, IsraelJeffrey Modell Foundation Center, Edmond and Lily Safra Children's Hospital, Sheba Medical Centre, Ramat Gan, Israel1Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA, United States2Harvard Medical School, Boston, MA, United StatesPediatric Gastroenterology Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Centre, Ramat Gan, IsraelSackler Faculty of Medicine, Tel Aviv University, Tel Aviv, IsraelPatients with loss-of-function mutations in IL10 or IL10 receptor (IL10R) genes develop severe, medical-refractory, infantile-onset inflammatory bowel disease (IBD). We have previously reported significant alterations in innate and adaptive immune responses in these patients. Next generation sequencing platforms enable a comprehensive assessment of T cell receptor (TCR) and B cell receptor (BCR) repertoire patterns. We aimed to characterize TCR and BCR features in peripheral blood of patients with deleterious IL10 signaling defects. DNA was isolated from blood of seven patients with IL10R mutations and one with an IL10 mutation, along with eight controls, and subjected to next generation sequencing of TRB and IgH loci. A significant increase in clonality was observed in both TCR and BCR repertoires in circulating lymphocytes of IL10/IL10R-deficient patients, but to a much greater extent in T cells. Furthermore, short CDR3β length and altered hydrophobicity were demonstrated in T cells of patients, but not in B cells, secondary to lower rates of insertions of nucleotides, but not deletions, at the V-, D-, or J-junctions. We were unable to observe specific T or B clones that were limited only to the patients or among controls. Moreover, the expanded T cells clones were unique to each patient. In conclusion, next generation sequencing of the TCR and BCR is a powerful tool for characterizing the adaptive immune cell phenotype and function in immune-mediated disorders. The oligoclonality observed among IL10/IL10R-deficient patients may suggest specialization of unique clones that likely have a role in mediating tissue damage. Nevertheless, the lack of shared clones between patients provides another piece of evidence that the adaptive immune response in IBD is not triggered against common antigens. Additional studies are required to define the specific antigens that interact with the expanded IL10/IL10R-deficient clones.https://www.frontiersin.org/article/10.3389/fimmu.2020.00109/fullIBDVEOIBDNGST cell receptor repertoireB cell receptor repertoireIL10 |
| spellingShingle | Lael Werner Lael Werner Yu Nee Lee Yu Nee Lee Yu Nee Lee Yu Nee Lee Erez Rechavi Erez Rechavi Erez Rechavi Erez Rechavi Atar Lev Atar Lev Atar Lev Atar Lev Baruch Yerushalmi Galina Ling Neil Shah Holm H. Uhlig Holm H. Uhlig Holm H. Uhlig Batia Weiss Batia Weiss Raz Somech Raz Somech Raz Somech Raz Somech Scott B. Snapper Scott B. Snapper Dror S. Shouval Dror S. Shouval Alterations in T and B Cell Receptor Repertoires Patterns in Patients With IL10 Signaling Defects and History of Infantile-Onset IBD Frontiers in Immunology IBD VEOIBD NGS T cell receptor repertoire B cell receptor repertoire IL10 |
| title | Alterations in T and B Cell Receptor Repertoires Patterns in Patients With IL10 Signaling Defects and History of Infantile-Onset IBD |
| title_full | Alterations in T and B Cell Receptor Repertoires Patterns in Patients With IL10 Signaling Defects and History of Infantile-Onset IBD |
| title_fullStr | Alterations in T and B Cell Receptor Repertoires Patterns in Patients With IL10 Signaling Defects and History of Infantile-Onset IBD |
| title_full_unstemmed | Alterations in T and B Cell Receptor Repertoires Patterns in Patients With IL10 Signaling Defects and History of Infantile-Onset IBD |
| title_short | Alterations in T and B Cell Receptor Repertoires Patterns in Patients With IL10 Signaling Defects and History of Infantile-Onset IBD |
| title_sort | alterations in t and b cell receptor repertoires patterns in patients with il10 signaling defects and history of infantile onset ibd |
| topic | IBD VEOIBD NGS T cell receptor repertoire B cell receptor repertoire IL10 |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2020.00109/full |
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