Germinal centers are permissive to subdominant antibody responses
IntroductionA protective humoral response to pathogens requires the development of high affinity antibodies in germinal centers (GC). The combination of antigens available during immunization has a strong impact on the strength and breadth of the antibody response. Antigens can display various level...
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Frontiers Media S.A.
2024-01-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1238046/full |
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| author | Philippe A. Robert Philippe A. Robert Theinmozhi Arulraj Theinmozhi Arulraj Michael Meyer-Hermann Michael Meyer-Hermann |
| author_facet | Philippe A. Robert Philippe A. Robert Theinmozhi Arulraj Theinmozhi Arulraj Michael Meyer-Hermann Michael Meyer-Hermann |
| author_sort | Philippe A. Robert |
| collection | DOAJ |
| description | IntroductionA protective humoral response to pathogens requires the development of high affinity antibodies in germinal centers (GC). The combination of antigens available during immunization has a strong impact on the strength and breadth of the antibody response. Antigens can display various levels of immunogenicity, and a hierarchy of immunodominance arises when the GC response to an antigen dampens the response to other antigens. Immunodominance is a challenge for the development of vaccines to mutating viruses, and for the development of broadly neutralizing antibodies. The extent by which antigens with different levels of immunogenicity compete for the induction of high affinity antibodies and therefore contribute to immunodominance is not known.MethodsHere, we perform in silico simulations of the GC response, using a structural representation of antigens with complex surface amino acid composition and topology. We generate antigens with complex domains of different levels of immunogenicity and perform simulations with combinations of these domains.ResultsWe found that GC dynamics were driven by the most immunogenic domain and immunodominance arose as affinity maturation to less immunogenic domain was inhibited. However, this inhibition was moderate since the less immunogenic domain exhibited a weak GC response in the absence of the most immunogenic domain. Less immunogenic domains reduced the dominance of GC responses to more immunogenic domains, albeit at a later time point.DiscussionThe simulations suggest that increased vaccine valency may decrease immunodominance of the GC response to strongly immunogenic domains and therefore, act as a potential strategy for the natural induction of broadly neutralizing antibodies in GC reactions. |
| first_indexed | 2024-03-08T14:50:19Z |
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| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-03-08T14:50:19Z |
| publishDate | 2024-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-a6212b5a50a5482a911a812a65a249502024-01-11T04:25:50ZengFrontiers Media S.A.Frontiers in Immunology1664-32242024-01-011410.3389/fimmu.2023.12380461238046Germinal centers are permissive to subdominant antibody responsesPhilippe A. Robert0Philippe A. Robert1Theinmozhi Arulraj2Theinmozhi Arulraj3Michael Meyer-Hermann4Michael Meyer-Hermann5Department of Systems Immunology and Braunschweig Integrated Centre of Systems Biology, Helmholtz Centre for Infection Research, Braunschweig, GermanyDepartment of Biomedicine, University of Basel, Basel, SwitzerlandDepartment of Systems Immunology and Braunschweig Integrated Centre of Systems Biology, Helmholtz Centre for Infection Research, Braunschweig, GermanyDepartment of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, United StatesDepartment of Systems Immunology and Braunschweig Integrated Centre of Systems Biology, Helmholtz Centre for Infection Research, Braunschweig, GermanyInstitute for Biochemistry, Biotechnology and Bioinformatics, Technische Universität Braunschweig, Braunschweig, GermanyIntroductionA protective humoral response to pathogens requires the development of high affinity antibodies in germinal centers (GC). The combination of antigens available during immunization has a strong impact on the strength and breadth of the antibody response. Antigens can display various levels of immunogenicity, and a hierarchy of immunodominance arises when the GC response to an antigen dampens the response to other antigens. Immunodominance is a challenge for the development of vaccines to mutating viruses, and for the development of broadly neutralizing antibodies. The extent by which antigens with different levels of immunogenicity compete for the induction of high affinity antibodies and therefore contribute to immunodominance is not known.MethodsHere, we perform in silico simulations of the GC response, using a structural representation of antigens with complex surface amino acid composition and topology. We generate antigens with complex domains of different levels of immunogenicity and perform simulations with combinations of these domains.ResultsWe found that GC dynamics were driven by the most immunogenic domain and immunodominance arose as affinity maturation to less immunogenic domain was inhibited. However, this inhibition was moderate since the less immunogenic domain exhibited a weak GC response in the absence of the most immunogenic domain. Less immunogenic domains reduced the dominance of GC responses to more immunogenic domains, albeit at a later time point.DiscussionThe simulations suggest that increased vaccine valency may decrease immunodominance of the GC response to strongly immunogenic domains and therefore, act as a potential strategy for the natural induction of broadly neutralizing antibodies in GC reactions.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1238046/fullgerminal center (GC)agent-based model (ABM)vaccine modelimmunodominance (ID)antibodies |
| spellingShingle | Philippe A. Robert Philippe A. Robert Theinmozhi Arulraj Theinmozhi Arulraj Michael Meyer-Hermann Michael Meyer-Hermann Germinal centers are permissive to subdominant antibody responses Frontiers in Immunology germinal center (GC) agent-based model (ABM) vaccine model immunodominance (ID) antibodies |
| title | Germinal centers are permissive to subdominant antibody responses |
| title_full | Germinal centers are permissive to subdominant antibody responses |
| title_fullStr | Germinal centers are permissive to subdominant antibody responses |
| title_full_unstemmed | Germinal centers are permissive to subdominant antibody responses |
| title_short | Germinal centers are permissive to subdominant antibody responses |
| title_sort | germinal centers are permissive to subdominant antibody responses |
| topic | germinal center (GC) agent-based model (ABM) vaccine model immunodominance (ID) antibodies |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1238046/full |
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