Activation of the MEK-ERK Pathway Is Necessary but Not Sufficient for Breaking Central B Cell Tolerance
Newly generated bone marrow B cells are positively selected into the peripheral lymphoid tissue only when they express a B cell receptor (BCR) that is nonautoreactive or one that binds self-antigen with only minimal avidity. This positive selection process, moreover, is critically contingent on the...
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Frontiers Media S.A.
2018-04-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2018.00707/full |
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| author | Sarah A. Greaves Jacob N. Peterson Raul M. Torres Raul M. Torres Roberta Pelanda Roberta Pelanda |
| author_facet | Sarah A. Greaves Jacob N. Peterson Raul M. Torres Raul M. Torres Roberta Pelanda Roberta Pelanda |
| author_sort | Sarah A. Greaves |
| collection | DOAJ |
| description | Newly generated bone marrow B cells are positively selected into the peripheral lymphoid tissue only when they express a B cell receptor (BCR) that is nonautoreactive or one that binds self-antigen with only minimal avidity. This positive selection process, moreover, is critically contingent on the ligand-independent tonic signals transduced by the BCR. We have previously shown that when autoreactive B cells express an active form of the rat sarcoma (RAS) oncogene, they upregulate the receptor for the B cell activating factor (BAFFR) and undergo differentiation in vitro and positive selection into the spleen in vivo, overcoming central tolerance. Based on the in vitro use of pharmacologic inhibitors, we further showed that this cell differentiation process is critically dependent on the activation of the mitogen-activated protein kinase kinase pathway MEK (MAPKK)-extracellular signal-regulated kinase (ERK), which is downstream of RAS. Here, we next investigated if activation of ERK is not only necessary but also sufficient to break central B cell tolerance and induce differentiation of autoreactive B cells in vitro and in vivo. Our results demonstrate that activation of ERK is critical for upregulating BAFFR and overcoming suboptimal levels of tonic BCR signals or low amounts of antigen-induced BCR signals during in vitro B cell differentiation. However, direct activation of ERK does not lead high avidity autoreactive B cells to increase BAFFR levels and undergo positive selection and differentiation in vivo. B cell-specific MEK-ERK activation in mice is also unable to lead to autoantibody secretion, and this in spite of a general increase of serum immunoglobulin levels. These findings indicate that additional pathways downstream of RAS are required for high avidity autoreactive B cells to break central and/or peripheral tolerance. |
| first_indexed | 2024-12-21T14:04:59Z |
| format | Article |
| id | doaj.art-45717056a3c94f86b6811778358ae5bb |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-21T14:04:59Z |
| publishDate | 2018-04-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Immunology |
| spelling | doaj.art-45717056a3c94f86b6811778358ae5bb2022-12-21T19:01:15ZengFrontiers Media S.A.Frontiers in Immunology1664-32242018-04-01910.3389/fimmu.2018.00707354781Activation of the MEK-ERK Pathway Is Necessary but Not Sufficient for Breaking Central B Cell ToleranceSarah A. Greaves0Jacob N. Peterson1Raul M. Torres2Raul M. Torres3Roberta Pelanda4Roberta Pelanda5Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, United StatesDepartment of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, United StatesDepartment of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, United StatesDepartment of Biomedical Research, National Jewish Health, Denver, CO, United StatesDepartment of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, United StatesDepartment of Biomedical Research, National Jewish Health, Denver, CO, United StatesNewly generated bone marrow B cells are positively selected into the peripheral lymphoid tissue only when they express a B cell receptor (BCR) that is nonautoreactive or one that binds self-antigen with only minimal avidity. This positive selection process, moreover, is critically contingent on the ligand-independent tonic signals transduced by the BCR. We have previously shown that when autoreactive B cells express an active form of the rat sarcoma (RAS) oncogene, they upregulate the receptor for the B cell activating factor (BAFFR) and undergo differentiation in vitro and positive selection into the spleen in vivo, overcoming central tolerance. Based on the in vitro use of pharmacologic inhibitors, we further showed that this cell differentiation process is critically dependent on the activation of the mitogen-activated protein kinase kinase pathway MEK (MAPKK)-extracellular signal-regulated kinase (ERK), which is downstream of RAS. Here, we next investigated if activation of ERK is not only necessary but also sufficient to break central B cell tolerance and induce differentiation of autoreactive B cells in vitro and in vivo. Our results demonstrate that activation of ERK is critical for upregulating BAFFR and overcoming suboptimal levels of tonic BCR signals or low amounts of antigen-induced BCR signals during in vitro B cell differentiation. However, direct activation of ERK does not lead high avidity autoreactive B cells to increase BAFFR levels and undergo positive selection and differentiation in vivo. B cell-specific MEK-ERK activation in mice is also unable to lead to autoantibody secretion, and this in spite of a general increase of serum immunoglobulin levels. These findings indicate that additional pathways downstream of RAS are required for high avidity autoreactive B cells to break central and/or peripheral tolerance.https://www.frontiersin.org/article/10.3389/fimmu.2018.00707/fullB cellsB cell toleranceBCR signalingMAP kinaseERKB cell development |
| spellingShingle | Sarah A. Greaves Jacob N. Peterson Raul M. Torres Raul M. Torres Roberta Pelanda Roberta Pelanda Activation of the MEK-ERK Pathway Is Necessary but Not Sufficient for Breaking Central B Cell Tolerance Frontiers in Immunology B cells B cell tolerance BCR signaling MAP kinase ERK B cell development |
| title | Activation of the MEK-ERK Pathway Is Necessary but Not Sufficient for Breaking Central B Cell Tolerance |
| title_full | Activation of the MEK-ERK Pathway Is Necessary but Not Sufficient for Breaking Central B Cell Tolerance |
| title_fullStr | Activation of the MEK-ERK Pathway Is Necessary but Not Sufficient for Breaking Central B Cell Tolerance |
| title_full_unstemmed | Activation of the MEK-ERK Pathway Is Necessary but Not Sufficient for Breaking Central B Cell Tolerance |
| title_short | Activation of the MEK-ERK Pathway Is Necessary but Not Sufficient for Breaking Central B Cell Tolerance |
| title_sort | activation of the mek erk pathway is necessary but not sufficient for breaking central b cell tolerance |
| topic | B cells B cell tolerance BCR signaling MAP kinase ERK B cell development |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2018.00707/full |
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