CLL stereotyped B-cell receptor immunoglobulin sequences are recurrent in the B-cell repertoire of healthy individuals: Apparent lack of central and early peripheral tolerance censoring
IntroductionThe leukemic cells of patients with chronic lymphocytic leukemia (CLL) are often unique, expressing remarkably similar IGHV-IGHD-IGHJ gene rearrangements, “stereotyped BCRs”. The B-cell receptors (BCRs) on CLL cells are also distinctive in often deriving from autoreactive B lymphocytes,...
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Frontiers Media S.A.
2023-03-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2023.1112879/full |
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| author | Stefano Vergani Davide Bagnara Andreas Agathangelidis Andreas Agathangelidis Anita Kar Yun Ng Gerardo Ferrer Andrea N. Mazzarello Florencia Palacios Sophia Yancopoulos Xiao-Jie Yan Jaqueline C. Barrientos Kanti R. Rai Kostas Stamatopoulos Nicholas Chiorazzi |
| author_facet | Stefano Vergani Davide Bagnara Andreas Agathangelidis Andreas Agathangelidis Anita Kar Yun Ng Gerardo Ferrer Andrea N. Mazzarello Florencia Palacios Sophia Yancopoulos Xiao-Jie Yan Jaqueline C. Barrientos Kanti R. Rai Kostas Stamatopoulos Nicholas Chiorazzi |
| author_sort | Stefano Vergani |
| collection | DOAJ |
| description | IntroductionThe leukemic cells of patients with chronic lymphocytic leukemia (CLL) are often unique, expressing remarkably similar IGHV-IGHD-IGHJ gene rearrangements, “stereotyped BCRs”. The B-cell receptors (BCRs) on CLL cells are also distinctive in often deriving from autoreactive B lymphocytes, leading to the assumption of a defect in immune tolerance.ResultsUsing bulk and single-cell immunoglobulin heavy and light chain variable domain sequencing, we enumerated CLL stereotype-like IGHV-IGHD-IGHJ sequences (CLL-SLS) in B cells from cord blood (CB) and adult peripheral blood (PBMC) and bone marrow (BM of healthy donors. CLL-SLS were found at similar frequencies among CB, BM, and PBMC, suggesting that age does not influence CLL-SLS levels. Moreover, the frequencies of CLL-SLS did not differ among B lymphocytes in the BM at early stages of development, and only re-circulating marginal zone B cells contained significantly higher CLL-SLS frequencies than other mature B-cell subpopulations. Although we identified CLL-SLS corresponding to most of the CLL major stereotyped subsets, CLL-SLS frequencies did not correlate with those found in patients. Interestingly, in CB samples, half of the CLL-SLS identified were attributed to two IGHV-mutated subsets. We also found satellite CLL-SLS among the same normal samples, and they were also enriched in naïve B cells but unexpectedly, these were ~10-fold higher than standard CLL-SLS. In general, IGHV-mutated CLL-SLS subsets were enriched among antigen-experienced B-cell subpopulations, and IGHV-unmutated CLL-SLS were found mostly in antigen-inexperienced B cells. Nevertheless, CLL-SLS with an IGHV-mutation status matching that of CLL clones varied among the normal B-cell subpopulations, suggesting that specific CLL-SLS could originate from distinct subpopulations of normal B cells. Lastly, using single-cell DNA sequencing, we identified paired IGH and IGL rearrangements in normal B lymphocytes resembling those of stereotyped BCRs in CLL, although some differed from those in patients based on IG isotype or somatic mutation.DiscussionCLL-SLS are present in normal B-lymphocyte populations at all stages of development. Thus, despite their autoreactive profile they are not deleted by central tolerance mechanisms, possibly because the level of autoreactivity is not registered as dangerous by deletion mechanisms or because editing of L-chain variable genes occurred which our experimental approach could not identify. |
| first_indexed | 2024-04-09T23:52:05Z |
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| id | doaj.art-13e9226ca5f64baa9b66e56ee46ce5d9 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-09T23:52:05Z |
| publishDate | 2023-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-13e9226ca5f64baa9b66e56ee46ce5d92023-03-17T05:12:14ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2023-03-011310.3389/fonc.2023.11128791112879CLL stereotyped B-cell receptor immunoglobulin sequences are recurrent in the B-cell repertoire of healthy individuals: Apparent lack of central and early peripheral tolerance censoringStefano Vergani0Davide Bagnara1Andreas Agathangelidis2Andreas Agathangelidis3Anita Kar Yun Ng4Gerardo Ferrer5Andrea N. Mazzarello6Florencia Palacios7Sophia Yancopoulos8Xiao-Jie Yan9Jaqueline C. Barrientos10Kanti R. Rai11Kostas Stamatopoulos12Nicholas Chiorazzi13Karches Center for Oncology Research, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United StatesKarches Center for Oncology Research, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United StatesCentre for Research and Technology Hellas, Institute of Applied Biosciences, Thessaloniki, GreeceDepartment of Biology, School of Science, National and Kapodistrian University of Athens, Athens, GreeceKarches Center for Oncology Research, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United StatesKarches Center for Oncology Research, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United StatesKarches Center for Oncology Research, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United StatesKarches Center for Oncology Research, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United StatesNew York Genome Center, New York, NY, United StatesKarches Center for Oncology Research, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United StatesKarches Center for Oncology Research, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United StatesKarches Center for Oncology Research, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United StatesCentre for Research and Technology Hellas, Institute of Applied Biosciences, Thessaloniki, GreeceKarches Center for Oncology Research, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United StatesIntroductionThe leukemic cells of patients with chronic lymphocytic leukemia (CLL) are often unique, expressing remarkably similar IGHV-IGHD-IGHJ gene rearrangements, “stereotyped BCRs”. The B-cell receptors (BCRs) on CLL cells are also distinctive in often deriving from autoreactive B lymphocytes, leading to the assumption of a defect in immune tolerance.ResultsUsing bulk and single-cell immunoglobulin heavy and light chain variable domain sequencing, we enumerated CLL stereotype-like IGHV-IGHD-IGHJ sequences (CLL-SLS) in B cells from cord blood (CB) and adult peripheral blood (PBMC) and bone marrow (BM of healthy donors. CLL-SLS were found at similar frequencies among CB, BM, and PBMC, suggesting that age does not influence CLL-SLS levels. Moreover, the frequencies of CLL-SLS did not differ among B lymphocytes in the BM at early stages of development, and only re-circulating marginal zone B cells contained significantly higher CLL-SLS frequencies than other mature B-cell subpopulations. Although we identified CLL-SLS corresponding to most of the CLL major stereotyped subsets, CLL-SLS frequencies did not correlate with those found in patients. Interestingly, in CB samples, half of the CLL-SLS identified were attributed to two IGHV-mutated subsets. We also found satellite CLL-SLS among the same normal samples, and they were also enriched in naïve B cells but unexpectedly, these were ~10-fold higher than standard CLL-SLS. In general, IGHV-mutated CLL-SLS subsets were enriched among antigen-experienced B-cell subpopulations, and IGHV-unmutated CLL-SLS were found mostly in antigen-inexperienced B cells. Nevertheless, CLL-SLS with an IGHV-mutation status matching that of CLL clones varied among the normal B-cell subpopulations, suggesting that specific CLL-SLS could originate from distinct subpopulations of normal B cells. Lastly, using single-cell DNA sequencing, we identified paired IGH and IGL rearrangements in normal B lymphocytes resembling those of stereotyped BCRs in CLL, although some differed from those in patients based on IG isotype or somatic mutation.DiscussionCLL-SLS are present in normal B-lymphocyte populations at all stages of development. Thus, despite their autoreactive profile they are not deleted by central tolerance mechanisms, possibly because the level of autoreactivity is not registered as dangerous by deletion mechanisms or because editing of L-chain variable genes occurred which our experimental approach could not identify.https://www.frontiersin.org/articles/10.3389/fonc.2023.1112879/fullCLL (chronic lymphocytic leukemia)B cell development and differentiationB cell repertoirestereotyped antigen receptorsVDJ sequencing |
| spellingShingle | Stefano Vergani Davide Bagnara Andreas Agathangelidis Andreas Agathangelidis Anita Kar Yun Ng Gerardo Ferrer Andrea N. Mazzarello Florencia Palacios Sophia Yancopoulos Xiao-Jie Yan Jaqueline C. Barrientos Kanti R. Rai Kostas Stamatopoulos Nicholas Chiorazzi CLL stereotyped B-cell receptor immunoglobulin sequences are recurrent in the B-cell repertoire of healthy individuals: Apparent lack of central and early peripheral tolerance censoring Frontiers in Oncology CLL (chronic lymphocytic leukemia) B cell development and differentiation B cell repertoire stereotyped antigen receptors VDJ sequencing |
| title | CLL stereotyped B-cell receptor immunoglobulin sequences are recurrent in the B-cell repertoire of healthy individuals: Apparent lack of central and early peripheral tolerance censoring |
| title_full | CLL stereotyped B-cell receptor immunoglobulin sequences are recurrent in the B-cell repertoire of healthy individuals: Apparent lack of central and early peripheral tolerance censoring |
| title_fullStr | CLL stereotyped B-cell receptor immunoglobulin sequences are recurrent in the B-cell repertoire of healthy individuals: Apparent lack of central and early peripheral tolerance censoring |
| title_full_unstemmed | CLL stereotyped B-cell receptor immunoglobulin sequences are recurrent in the B-cell repertoire of healthy individuals: Apparent lack of central and early peripheral tolerance censoring |
| title_short | CLL stereotyped B-cell receptor immunoglobulin sequences are recurrent in the B-cell repertoire of healthy individuals: Apparent lack of central and early peripheral tolerance censoring |
| title_sort | cll stereotyped b cell receptor immunoglobulin sequences are recurrent in the b cell repertoire of healthy individuals apparent lack of central and early peripheral tolerance censoring |
| topic | CLL (chronic lymphocytic leukemia) B cell development and differentiation B cell repertoire stereotyped antigen receptors VDJ sequencing |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2023.1112879/full |
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