{"id":{"repo_id":"cambridge","oai_identifier":"oai:www.repository.cam.ac.uk:1810/390449"},"canonical_url":"https://search.dev.ndltd.org/etd/cambridge/oai:www.repository.cam.ac.uk:1810/390449","repository":{"repo_id":"cambridge","name":"Cambridge University","base_url":"https://api.repository.cam.ac.uk/server/oai/request"},"display":{"title":"The role of cell autonomous complement in B cell function and regulation","abstract":"B cells are a cornerstone of the adaptive immune response as they not only differentiate into antibody-producing plasma cells, mediating protection from pathogens, but also have several antibody-independent, immune-regulatory functions. Even with these essential roles, some aspects of their function and regulation are not fully understood, including the role of complement system - an ancient arm of the innate immune system that also plays a key role in B cell biology. It is well-known that extracellular complement receptor signaling, and complement-tagging of antigen is necessary for the activation and amplification of the B cell response. However, it is unclear if intracellular, cell-autonomous complement signaling occurs, and/or plays an important role, in the function of B cells in a similar manner to that described in T cells. In this thesis, I explore if an intracellular complement system exists in B cells and investigate its role in immune responses, with a focus on C5. We show that both mouse and human B cells express C5, C5aR1, and C5aR2, and that modulation of these complement proteins leads to altered B cell responses in vitro. We further demonstrate that cell-autonomous complement plays an important role in B cells responses in vivo, as mice lacking the ability to produce cell-autonomous complement from B cells have altered germinal center and antigen-specific antibody responses following immunization. Single-cell RNA sequencing of immunized mice implicated B cell C5 in the regulation of proliferative and metabolic pathways. Additionally, we found that cell-autonomous C5 has differing effects in male and female B cells. Taken together, our data suggest that cell-autonomous complement may play a previously unappreciated and crucial role in modulating B cells responses in different contexts, and that this function may be subject to sexual dimorphism.","abstract_html":"B cells are a cornerstone of the adaptive immune response as they not only differentiate into antibody-producing plasma cells, mediating protection from pathogens, but also have several antibody-independent, immune-regulatory functions. Even with these essential roles, some aspects of their function and regulation are not fully understood, including the role of complement system - an ancient arm of the innate immune system that also plays a key role in B cell biology. It is well-known that extracellular complement receptor signaling, and complement-tagging of antigen is necessary for the activation and amplification of the B cell response. However, it is unclear if intracellular, cell-autonomous complement signaling occurs, and/or plays an important role, in the function of B cells in a similar manner to that described in T cells. In this thesis, I explore if an intracellular complement system exists in B cells and investigate its role in immune responses, with a focus on C5. We show that both mouse and human B cells express C5, C5aR1, and C5aR2, and that modulation of these complement proteins leads to altered B cell responses in vitro. We further demonstrate that cell-autonomous complement plays an important role in B cells responses in vivo, as mice lacking the ability to produce cell-autonomous complement from B cells have altered germinal center and antigen-specific antibody responses following immunization. Single-cell RNA sequencing of immunized mice implicated B cell C5 in the regulation of proliferative and metabolic pathways. Additionally, we found that cell-autonomous C5 has differing effects in male and female B cells. Taken together, our data suggest that cell-autonomous complement may play a previously unappreciated and crucial role in modulating B cells responses in different contexts, and that this function may be subject to sexual dimorphism.","abstract_has_math":false,"creators":["Beltran, Emily"],"institution":"University of Cambridge","degree_name":"Doctor of Philosophy (PhD)","degree_level":"Doctoral","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Clatworthy, Menna","Kemper, Claudia"],"committee_chairs":[],"committee_members":[],"year":2025,"date_issued":"2025-05-26","date_published":"2025-05-26","updated_at":"2026-07-22T22:23:53Z","subjects":["immunology","complement","B cell"],"languages":["eng"],"rights":[],"rights_urls":["https://www.repository.cam.ac.uk/bitstreams/2272cbf0-9ec1-4cba-bca1-f60a021c4ae2/download","http://purl.org/NET/rdflicense/allrightsreserved"],"identifier_entries":[]},"links":{"outbound_url":"https://doi.org/10.17863/CAM.121999","outbound_label":"DOI","outbound_source":"dc:identifier.doi"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Clatworthy, Menna","Kemper, Claudia"]},{"key":"dc:contributor.sponsor","label":"Sponsor","values":["Cambridge Trust, NIH Oxford-Cambridge Scholars Program/NHLBI"]},{"key":"dc:creator","label":"Author","values":["Beltran, Emily"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.issued","label":"Date","values":["2025-05-26"]},{"key":"dc:publisher.institution","label":"Dc Publisher Institution","values":["University of Cambridge"]},{"key":"dc:relation.isreferencedby.uri","label":"Dc Relation Isreferencedby URI","values":["https://www.repository.cam.ac.uk/handle/1810/390449"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]},{"key":"dc:type.qualificationlevel","label":"Dc Type Qualificationlevel","values":["Doctoral"]},{"key":"dc:type.qualificationname","label":"Dc Type Qualificationname","values":["Doctor of Philosophy (PhD)"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["immunology","complement","B cell"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["eng"]},{"key":"dc:rights","label":"Dc Rights","values":["https://www.repository.cam.ac.uk/bitstreams/2272cbf0-9ec1-4cba-bca1-f60a021c4ae2/download","http://purl.org/NET/rdflicense/allrightsreserved"]},{"key":"dc:rights.embargotype","label":"Dc Rights Embargotype","values":["controlled.access"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.doi","label":"DOI","values":["https://doi.org/10.17863/CAM.121999"]},{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://www.repository.cam.ac.uk/bitstreams/c65daa3f-899d-4bf6-a1b3-f56b5634adb4/download"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["B cells are a cornerstone of the adaptive immune response as they not only differentiate into antibody-producing plasma cells, mediating protection from pathogens, but also have several antibody-independent, immune-regulatory functions. 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We further demonstrate that cell-autonomous complement plays an important role in B cells responses in vivo, as mice lacking the ability to produce cell-autonomous complement from B cells have altered germinal center and antigen-specific antibody responses following immunization. Single-cell RNA sequencing of immunized mice implicated B cell C5 in the regulation of proliferative and metabolic pathways. Additionally, we found that cell-autonomous C5 has differing effects in male and female B cells. 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Even with these essential roles, some aspects of their function and regulation are not fully understood, including the role of complement system - an ancient arm of the innate immune system that also plays a key role in B cell biology. It is well-known that extracellular complement receptor signaling, and complement-tagging of antigen is necessary for the activation and amplification of the B cell response. However, it is unclear if intracellular, cell-autonomous complement signaling occurs, and/or plays an important role, in the function of B cells in a similar manner to that described in T cells. In this thesis, I explore if an intracellular complement system exists in B cells and investigate its role in immune responses, with a focus on C5. We show that both mouse and human B cells express C5, C5aR1, and C5aR2, and that modulation of these complement proteins leads to altered B cell responses in vitro. We further demonstrate that cell-autonomous complement plays an important role in B cells responses in vivo, as mice lacking the ability to produce cell-autonomous complement from B cells have altered germinal center and antigen-specific antibody responses following immunization. Single-cell RNA sequencing of immunized mice implicated B cell C5 in the regulation of proliferative and metabolic pathways. Additionally, we found that cell-autonomous C5 has differing effects in male and female B cells. 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