B cells in the balance: Offsetting self-reactivity avoidance with protection against foreign
Antibodies are theoretically limitless in their diversity and specificity to foreign antigens; however they are constrained by the need to avoid binding to self. Germinal centers (GC) allow diversification and maturation of the antibody response towards the foreign antigen. While self-tolerance mech...
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2022-07-01
|
| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.951385/full |
| _version_ | 1811312507603648512 |
|---|---|
| author | Clara Young Clara Young Angelica W. Y. Lau Angelica W. Y. Lau Deborah L. Burnett Deborah L. Burnett |
| author_facet | Clara Young Clara Young Angelica W. Y. Lau Angelica W. Y. Lau Deborah L. Burnett Deborah L. Burnett |
| author_sort | Clara Young |
| collection | DOAJ |
| description | Antibodies are theoretically limitless in their diversity and specificity to foreign antigens; however they are constrained by the need to avoid binding to self. Germinal centers (GC) allow diversification and maturation of the antibody response towards the foreign antigen. While self-tolerance mechanisms controlling self-reactivity during B cell maturation are well recognized, the mechanisms by which GCs balance self-tolerance and foreign binding especially in the face of cross-reactivity between self and foreign, remain much less well defined. In this review we explore the extent to which GC self-tolerance restricts affinity maturation. We present studies suggesting that the outcome is situationally dependent, affected by affinity and avidity to self-antigen, and the extent to which self-binding and foreign-binding are interdependent. While auto-reactive GC B cells can mutate away from self while maturing towards the foreign antigen, if no mutational trajectories allow for self-reactive redemption, self-tolerance prevails and GC responses to the foreign pathogen are restricted, except when self-tolerance checkpoints are relaxed. Finally, we consider whether polyreactivity is subject to the same level of restriction in GC responses, especially if polyreactivity is linked to an increase in foreign protection, as occurs in certain broadly neutralizing antibodies. Overall, the outcomes for GC B cells that bind self-antigen can range from redemption, transient relaxation in self-tolerance or restriction of the antibody response to the foreign pathogen. |
| first_indexed | 2024-04-13T10:38:29Z |
| format | Article |
| id | doaj.art-bbdbad66e54e4111ae9cebb859f70819 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-13T10:38:29Z |
| publishDate | 2022-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-bbdbad66e54e4111ae9cebb859f708192022-12-22T02:50:00ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-07-011310.3389/fimmu.2022.951385951385B cells in the balance: Offsetting self-reactivity avoidance with protection against foreignClara Young0Clara Young1Angelica W. Y. Lau2Angelica W. Y. Lau3Deborah L. Burnett4Deborah L. Burnett5Immunology Division, Garvan Institute of Medical Research, Darlinghurst, NSW, AustraliaSt Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Darlinghurst, NSW, AustraliaImmunology Division, Garvan Institute of Medical Research, Darlinghurst, NSW, AustraliaSt Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Darlinghurst, NSW, AustraliaImmunology Division, Garvan Institute of Medical Research, Darlinghurst, NSW, AustraliaSt Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Darlinghurst, NSW, AustraliaAntibodies are theoretically limitless in their diversity and specificity to foreign antigens; however they are constrained by the need to avoid binding to self. Germinal centers (GC) allow diversification and maturation of the antibody response towards the foreign antigen. While self-tolerance mechanisms controlling self-reactivity during B cell maturation are well recognized, the mechanisms by which GCs balance self-tolerance and foreign binding especially in the face of cross-reactivity between self and foreign, remain much less well defined. In this review we explore the extent to which GC self-tolerance restricts affinity maturation. We present studies suggesting that the outcome is situationally dependent, affected by affinity and avidity to self-antigen, and the extent to which self-binding and foreign-binding are interdependent. While auto-reactive GC B cells can mutate away from self while maturing towards the foreign antigen, if no mutational trajectories allow for self-reactive redemption, self-tolerance prevails and GC responses to the foreign pathogen are restricted, except when self-tolerance checkpoints are relaxed. Finally, we consider whether polyreactivity is subject to the same level of restriction in GC responses, especially if polyreactivity is linked to an increase in foreign protection, as occurs in certain broadly neutralizing antibodies. Overall, the outcomes for GC B cells that bind self-antigen can range from redemption, transient relaxation in self-tolerance or restriction of the antibody response to the foreign pathogen.https://www.frontiersin.org/articles/10.3389/fimmu.2022.951385/fullsomatic hypermutationautoantibody redemptionB cell tolerancegerminal centeraffinity maturationautoreactivity |
| spellingShingle | Clara Young Clara Young Angelica W. Y. Lau Angelica W. Y. Lau Deborah L. Burnett Deborah L. Burnett B cells in the balance: Offsetting self-reactivity avoidance with protection against foreign Frontiers in Immunology somatic hypermutation autoantibody redemption B cell tolerance germinal center affinity maturation autoreactivity |
| title | B cells in the balance: Offsetting self-reactivity avoidance with protection against foreign |
| title_full | B cells in the balance: Offsetting self-reactivity avoidance with protection against foreign |
| title_fullStr | B cells in the balance: Offsetting self-reactivity avoidance with protection against foreign |
| title_full_unstemmed | B cells in the balance: Offsetting self-reactivity avoidance with protection against foreign |
| title_short | B cells in the balance: Offsetting self-reactivity avoidance with protection against foreign |
| title_sort | b cells in the balance offsetting self reactivity avoidance with protection against foreign |
| topic | somatic hypermutation autoantibody redemption B cell tolerance germinal center affinity maturation autoreactivity |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.951385/full |
| work_keys_str_mv | AT clarayoung bcellsinthebalanceoffsettingselfreactivityavoidancewithprotectionagainstforeign AT clarayoung bcellsinthebalanceoffsettingselfreactivityavoidancewithprotectionagainstforeign AT angelicawylau bcellsinthebalanceoffsettingselfreactivityavoidancewithprotectionagainstforeign AT angelicawylau bcellsinthebalanceoffsettingselfreactivityavoidancewithprotectionagainstforeign AT deborahlburnett bcellsinthebalanceoffsettingselfreactivityavoidancewithprotectionagainstforeign AT deborahlburnett bcellsinthebalanceoffsettingselfreactivityavoidancewithprotectionagainstforeign |