{"id":{"repo_id":"uiuc","oai_identifier":"oai:www.ideals.illinois.edu:2142/122130"},"canonical_url":"https://search.dev.ndltd.org/etd/uiuc/oai:www.ideals.illinois.edu:2142/122130","repository":{"repo_id":"uiuc","name":"University of Illinois - Urbana-Champaign","base_url":"https://www.ideals.illinois.edu/oai-pmh"},"display":{"title":"The structure, biophysics and bioengineering of secretory immunoglobin A","abstract":"Submission published under a 24 month embargo labeled 'U of I Access', the embargo will last until 2025-12-01","abstract_html":"Submission published under a 24 month embargo labeled 'U of I Access', the embargo will last until 2025-12-01","abstract_has_math":false,"creators":["Kumar Bharathkar, Sonya"],"institution":"University of Illinois at Urbana-Champaign","degree_name":"Ph.D.","degree_level":"Dissertation","degree_discipline":"Biochemistry","degree_department":null,"school":null,"contributors":["Stadtmueller, Beth M","Nair, Satish K","Slauch, James M","Wu, Nicholas C"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2023,"date_issued":"2023-12","date_published":"2023-12","updated_at":"2026-07-22T22:25:00Z","subjects":["Effector Functions","Antibody Engineering","Antibody Developability","Antibody Functions","Secretory Immunoglobin A","Siga","Polymeric Iga","Piga","Diga","Miga","Iga","Mucosa","Secretory Component","Sc","Clostridiodes Difficile","Tcda","Tcdb","Cryo-em","Cryo Electron Microscopy","Surface Plasmon Resonance","Spr","Antibodies","Neutralization"],"languages":["en","eng"],"rights":["Copyright 2023 Sonya Kumar Bharathkar"],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://hdl.handle.net/2142/122130","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Stadtmueller, Beth M","Nair, Satish K","Slauch, James M","Wu, Nicholas C"]},{"key":"dc:creator","label":"Author","values":["Kumar Bharathkar, Sonya"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2023-12","2023-11-28"]},{"key":"dc:type","label":"Dc Type","values":["text"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Biochemistry"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Dissertation"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Ph.D."]},{"key":"thesis:institution_name","label":"Thesis Institution Name","values":["University of Illinois at Urbana-Champaign"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Effector Functions","Antibody Engineering","Antibody Developability","Antibody Functions","Secretory Immunoglobin A","Siga","Polymeric Iga","Piga","Diga","Miga","Iga","Mucosa","Secretory Component","Sc","Clostridiodes Difficile","Tcda","Tcdb","Cryo-em","Cryo Electron Microscopy","Surface Plasmon Resonance","Spr","Antibodies","Neutralization"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["en","eng"]},{"key":"dc:rights","label":"Dc Rights","values":["Copyright 2023 Sonya Kumar Bharathkar"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://hdl.handle.net/2142/122130"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Submission published under a 24 month embargo labeled 'U of I Access', the embargo will last until 2025-12-01","The student, Sonya Kumar Bharathkar, accepted the attached license on 2023-11-21 at 09:07.","The student, Sonya Kumar Bharathkar, submitted this Dissertation for approval on 2023-11-21 at 10:04.","This Dissertation was approved for publication on 2023-11-28 at 13:55.","DSpace SAF Submission Ingestion Package generated from Vireo submission #19980 on 2024-03-01 at 13:30:42","Secretory (S) Immunoglobulins (Igs) are the predominant class of antibodies that are produced and secreted into the vertebrate mucosa. In the mucosa, SIgs play multiple roles, which includes neutralization of toxins, coating and crosslinking of pathogenic and commensal microbes leading to the clearance of harmful antigens and the establishment of mucosal homeostasis. Until 2020, the molecular structures of SIgs remained unreported, masking their functional mechanisms, and limiting their development as therapeutics. In humans, SIgs are mainly composed of IgA, accordingly, called Secretory (S) IgA. In SIgA, IgA adopts a polymeric structure that is different from its serum counterpart, which is predominantly monomeric (m) IgA. The formation of SIgA begins in the lamina propria, where plasma cells assemble between two to five copies of mIgA, along with a protein called Joining chain (JC), to form polymeric (p) IgA. The pIgA, predominantly exists in dimeric (d) forms. The dIgA produced by plasma cells then binds the polymeric Immunoglobin Receptor (pIgR), a membrane bound receptor expressed on the basolateral surface of the mucosal epithelial cells, and subsequently gets transcytosed to the mucosa. There, the pIgR ectodomain (a.k.a Secretory Component; SC), which includes five Ig-domain, D1-D5, is cleaved and remains bound to the dIgA. This SC-dIgA complex is called SIgA. My PhD dissertation research aimed to determine the structures and assembly mechanisms of SIgA and use that information to engineer chimeric SIgA-based molecules to investigate SIgA based effector functions and SIgA therapeutic potential. In Chapter-1, I introduce SIgA's role in mucosal immunity as well as antibody engineering approaches and challenges. In Chapter-2, I report Cryo-EM structures of SIgA and dIgA revealing a first glimpse at the most abundant mammalian antibody and the functional significance of its structure. In Chapter-3, I report the biophysical characterization of SIgA assembly mechanisms, offering insights into SC-dIgA binding mechanisms. In Chapter-4, I report structure-based engineering of chimeric SIgAs (cSIgAs), their ability to neutralize Clostridiodes difficile antigens, their ability to serve as toolkit to investigate SIgA functions, and their potential to serve as biologics to treat disease. In the final chapter, Chapter 5, I explore the broader implications of my research on the assembly, structure, and bioengineering of SIgA."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["The structure, biophysics and bioengineering of secretory immunoglobin A"]}]}],"canonical_facts":{"dc:contributor":["Stadtmueller, Beth M","Nair, Satish K","Slauch, James M","Wu, Nicholas C"],"dc:creator":["Kumar Bharathkar, Sonya"],"dc:date":["2023-12","2023-11-28"],"dc:description":["Submission published under a 24 month embargo labeled 'U of I Access', the embargo will last until 2025-12-01","The student, Sonya Kumar Bharathkar, accepted the attached license on 2023-11-21 at 09:07.","The student, Sonya Kumar Bharathkar, submitted this Dissertation for approval on 2023-11-21 at 10:04.","This Dissertation was approved for publication on 2023-11-28 at 13:55.","DSpace SAF Submission Ingestion Package generated from Vireo submission #19980 on 2024-03-01 at 13:30:42","Secretory (S) Immunoglobulins (Igs) are the predominant class of antibodies that are produced and secreted into the vertebrate mucosa. In the mucosa, SIgs play multiple roles, which includes neutralization of toxins, coating and crosslinking of pathogenic and commensal microbes leading to the clearance of harmful antigens and the establishment of mucosal homeostasis. Until 2020, the molecular structures of SIgs remained unreported, masking their functional mechanisms, and limiting their development as therapeutics. In humans, SIgs are mainly composed of IgA, accordingly, called Secretory (S) IgA. In SIgA, IgA adopts a polymeric structure that is different from its serum counterpart, which is predominantly monomeric (m) IgA. The formation of SIgA begins in the lamina propria, where plasma cells assemble between two to five copies of mIgA, along with a protein called Joining chain (JC), to form polymeric (p) IgA. The pIgA, predominantly exists in dimeric (d) forms. The dIgA produced by plasma cells then binds the polymeric Immunoglobin Receptor (pIgR), a membrane bound receptor expressed on the basolateral surface of the mucosal epithelial cells, and subsequently gets transcytosed to the mucosa. There, the pIgR ectodomain (a.k.a Secretory Component; SC), which includes five Ig-domain, D1-D5, is cleaved and remains bound to the dIgA. This SC-dIgA complex is called SIgA. My PhD dissertation research aimed to determine the structures and assembly mechanisms of SIgA and use that information to engineer chimeric SIgA-based molecules to investigate SIgA based effector functions and SIgA therapeutic potential. In Chapter-1, I introduce SIgA's role in mucosal immunity as well as antibody engineering approaches and challenges. In Chapter-2, I report Cryo-EM structures of SIgA and dIgA revealing a first glimpse at the most abundant mammalian antibody and the functional significance of its structure. In Chapter-3, I report the biophysical characterization of SIgA assembly mechanisms, offering insights into SC-dIgA binding mechanisms. In Chapter-4, I report structure-based engineering of chimeric SIgAs (cSIgAs), their ability to neutralize Clostridiodes difficile antigens, their ability to serve as toolkit to investigate SIgA functions, and their potential to serve as biologics to treat disease. In the final chapter, Chapter 5, I explore the broader implications of my research on the assembly, structure, and bioengineering of SIgA."],"dc:format":["application/pdf"],"dc:identifier":["https://hdl.handle.net/2142/122130"],"dc:language":["en","eng"],"dc:rights":["Copyright 2023 Sonya Kumar Bharathkar"],"dc:subject":["Effector Functions","Antibody Engineering","Antibody Developability","Antibody Functions","Secretory Immunoglobin A","Siga","Polymeric Iga","Piga","Diga","Miga","Iga","Mucosa","Secretory Component","Sc","Clostridiodes Difficile","Tcda","Tcdb","Cryo-em","Cryo Electron Microscopy","Surface Plasmon Resonance","Spr","Antibodies","Neutralization"],"dc:title":["The structure, biophysics and bioengineering of secretory immunoglobin A"],"dc:type":["text"],"thesis:degree_discipline":["Biochemistry"],"thesis:degree_level":["Dissertation"],"thesis:degree_name":["Ph.D."],"thesis:institution_name":["University of Illinois at Urbana-Champaign"]},"updated_at":"2026-07-22T22:25:00Z"}