Binding of CLL Subset 4 B Cell Receptor Immunoglobulins to Viable Human Memory B Lymphocytes Requires a Distinctive IGKV Somatic Mutation
Abstract Amino acid replacement mutations in certain chronic lymphocytic leukemia (CLL) stereotyped B cell receptor (BCR) immunoglobulins (IGs) at defined positions within antigen-binding sites strongly imply antigen selection. Prime examples of this are CLL subset 4 BCR IGs using IGHV4-34/IGHD5-18/...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2017-01-01
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| Series: | Molecular Medicine |
| Online Access: | http://link.springer.com/article/10.2119/molmed.2017.00003 |
| _version_ | 1819053878594764800 |
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| author | Rosa Catera Yun Liu Chao Gao Xiao-Jie Yan Amanda Magli Steven L. Allen Jonathan E. Kolitz Kanti R. Rai Charles C. Chu Ten Feizi Kostas Stamatopoulos Nicholas Chiorazzi |
| author_facet | Rosa Catera Yun Liu Chao Gao Xiao-Jie Yan Amanda Magli Steven L. Allen Jonathan E. Kolitz Kanti R. Rai Charles C. Chu Ten Feizi Kostas Stamatopoulos Nicholas Chiorazzi |
| author_sort | Rosa Catera |
| collection | DOAJ |
| description | Abstract Amino acid replacement mutations in certain chronic lymphocytic leukemia (CLL) stereotyped B cell receptor (BCR) immunoglobulins (IGs) at defined positions within antigen-binding sites strongly imply antigen selection. Prime examples of this are CLL subset 4 BCR IGs using IGHV4-34/IGHD5-18/IGHJ6 and IGKV2-30/IGKJ2 rearrangements. Conspicuously, and unlike most CLL IGs, subset 4 IGs do not bind apoptotic cells. By testing the (auto)antigenic reactivities of subset 4 IGs toward viable lymphoid-lineage cells and specific autoantigens typically bound by IGHV4-34+ IGs, we found that IGs from both subset 4 and non-subset 4 IGHV4-34-expressing CLL cases bound naïve B cells. However, only subset 4 IGs reacted with memory B cells. Furthermore, subset 4 IGs did not bind DNA nor i or I carbohydrate antigens that are common targets of IGHV4-34-utilizing antibodies in systemic lupus erythematosus and cold agglutinin disease, respectively. Notably, we found that subset 4 IG binding to memory B lymphocytes depends on an aspartic acid at position 66 of FR3 in the rearranged IGKV2-30 gene; this amino acid residue is acquired by somatic mutation. Our findings illustrate the importance of positive and negative selection criteria for structural elements in CLL IGs and suggest that autoantigens driving normal B cells to become subset 4 CLL cells differ from those driving IGHV4-34+ B cells in other diseases. |
| first_indexed | 2024-12-21T12:42:44Z |
| format | Article |
| id | doaj.art-9e9c41d121d1407f8fb9aa6e622fb796 |
| institution | Directory Open Access Journal |
| issn | 1076-1551 1528-3658 |
| language | English |
| last_indexed | 2024-12-21T12:42:44Z |
| publishDate | 2017-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Medicine |
| spelling | doaj.art-9e9c41d121d1407f8fb9aa6e622fb7962022-12-21T19:03:44ZengBMCMolecular Medicine1076-15511528-36582017-01-0123111210.2119/molmed.2017.00003Binding of CLL Subset 4 B Cell Receptor Immunoglobulins to Viable Human Memory B Lymphocytes Requires a Distinctive IGKV Somatic MutationRosa Catera0Yun Liu1Chao Gao2Xiao-Jie Yan3Amanda Magli4Steven L. Allen5Jonathan E. Kolitz6Kanti R. Rai7Charles C. Chu8Ten Feizi9Kostas Stamatopoulos10Nicholas Chiorazzi11Karches Center for Oncology Research, The Feinstein Institute for Medical Research, Experimental ImmunologyKarches Center for Oncology Research, The Feinstein Institute for Medical Research, Experimental ImmunologyGlycosciences Laboratory, Department of Medicine, Imperial College LondonKarches Center for Oncology Research, The Feinstein Institute for Medical Research, Experimental ImmunologyKarches Center for Oncology Research, The Feinstein Institute for Medical Research, Experimental ImmunologyKarches Center for Oncology Research, The Feinstein Institute for Medical Research, Experimental ImmunologyKarches Center for Oncology Research, The Feinstein Institute for Medical Research, Experimental ImmunologyKarches Center for Oncology Research, The Feinstein Institute for Medical Research, Experimental ImmunologyKarches Center for Oncology Research, The Feinstein Institute for Medical Research, Experimental ImmunologyGlycosciences Laboratory, Department of Medicine, Imperial College LondonInstitute of Applied Biosciences, Centre for Research and Technology-HellasKarches Center for Oncology Research, The Feinstein Institute for Medical Research, Experimental ImmunologyAbstract Amino acid replacement mutations in certain chronic lymphocytic leukemia (CLL) stereotyped B cell receptor (BCR) immunoglobulins (IGs) at defined positions within antigen-binding sites strongly imply antigen selection. Prime examples of this are CLL subset 4 BCR IGs using IGHV4-34/IGHD5-18/IGHJ6 and IGKV2-30/IGKJ2 rearrangements. Conspicuously, and unlike most CLL IGs, subset 4 IGs do not bind apoptotic cells. By testing the (auto)antigenic reactivities of subset 4 IGs toward viable lymphoid-lineage cells and specific autoantigens typically bound by IGHV4-34+ IGs, we found that IGs from both subset 4 and non-subset 4 IGHV4-34-expressing CLL cases bound naïve B cells. However, only subset 4 IGs reacted with memory B cells. Furthermore, subset 4 IGs did not bind DNA nor i or I carbohydrate antigens that are common targets of IGHV4-34-utilizing antibodies in systemic lupus erythematosus and cold agglutinin disease, respectively. Notably, we found that subset 4 IG binding to memory B lymphocytes depends on an aspartic acid at position 66 of FR3 in the rearranged IGKV2-30 gene; this amino acid residue is acquired by somatic mutation. Our findings illustrate the importance of positive and negative selection criteria for structural elements in CLL IGs and suggest that autoantigens driving normal B cells to become subset 4 CLL cells differ from those driving IGHV4-34+ B cells in other diseases.http://link.springer.com/article/10.2119/molmed.2017.00003 |
| spellingShingle | Rosa Catera Yun Liu Chao Gao Xiao-Jie Yan Amanda Magli Steven L. Allen Jonathan E. Kolitz Kanti R. Rai Charles C. Chu Ten Feizi Kostas Stamatopoulos Nicholas Chiorazzi Binding of CLL Subset 4 B Cell Receptor Immunoglobulins to Viable Human Memory B Lymphocytes Requires a Distinctive IGKV Somatic Mutation Molecular Medicine |
| title | Binding of CLL Subset 4 B Cell Receptor Immunoglobulins to Viable Human Memory B Lymphocytes Requires a Distinctive IGKV Somatic Mutation |
| title_full | Binding of CLL Subset 4 B Cell Receptor Immunoglobulins to Viable Human Memory B Lymphocytes Requires a Distinctive IGKV Somatic Mutation |
| title_fullStr | Binding of CLL Subset 4 B Cell Receptor Immunoglobulins to Viable Human Memory B Lymphocytes Requires a Distinctive IGKV Somatic Mutation |
| title_full_unstemmed | Binding of CLL Subset 4 B Cell Receptor Immunoglobulins to Viable Human Memory B Lymphocytes Requires a Distinctive IGKV Somatic Mutation |
| title_short | Binding of CLL Subset 4 B Cell Receptor Immunoglobulins to Viable Human Memory B Lymphocytes Requires a Distinctive IGKV Somatic Mutation |
| title_sort | binding of cll subset 4 b cell receptor immunoglobulins to viable human memory b lymphocytes requires a distinctive igkv somatic mutation |
| url | http://link.springer.com/article/10.2119/molmed.2017.00003 |
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