Show simple item record

dc.contributor.authorZhu, Alex Lee
dc.date.accessioned2019-04-05T13:24:45Z
dc.date.created2018-05
dc.date.issued2018-05-04
dc.date.submitted2018
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:39010112*
dc.description.abstractForming complementarity to previously unseen foreign material is a key function of the antibody response. The antibody-ligand binding surface is created by a diversity of V gene encoded and non-encoded complementarity determining regions (CDRs) displayed by the germline B cell receptor (BCR). New antigen is thought to be chiefly engaged by the stochastically derived CDR3, calling into question the role of diversity in remaining germline encoded CDR1 and CDR2 regions. To functionally address this role, we generated humanized animals in which antibody response proceeds with normal CDR3 diversification and antibody light chain (LC) usage, yet is constrained to one or four human VH genes. We find that while these animals accommodated IgG antibody responses to diverse protein antigens, single VH gene mice failed to generate antibodies against bacterial exopolysaccharides—components of carbohydrate nanospheres present in bacterial biofilms which constitute thymus independent type-2 antigens (TI-2). IgM responses to TI-2 antigens are mounted exclusively through BCR cross-linking; thus, production of IgM to TI-2 antigens could be a direct measure of antigen accommodation by the BCR. Single VH gene mice could generate antibodies to TNP-ficoll, indicating that the TI-2 IgM response was not compromised; rather, it was exopolysaccharide geometry that could not be accommodated. By contrast, animals with four-VH genes generated robust IgM responses to the exopolysaccharides, indicating that diversity in the VH gene repertoire could overcome this geometric constraint. Our data thus demonstrates that VH gene diversity functions to engage CDR3-independent antigen geometries and may have been evolutionarily retained for this purpose.
dc.format.mimetypeapplication/pdf
dc.language.isoen
dash.licenseLAA
dc.titleV Gene Diversity Allows the B Cell Receptor to Accommodate Specific Antigen Shapes
dc.typeThesis or Dissertation
dash.depositing.authorZhu, Alex Lee
dc.date.available2019-04-05T13:24:45Z
thesis.degree.date2018
thesis.degree.grantorHarvard Medical School
thesis.degree.levelMasters
thesis.degree.nameMaster of Medical Sciences
dc.contributor.committeeMemberLingwood, Daniel
dc.contributor.committeeMemberPillai, Shiv
dc.contributor.committeeMemberCarroll, Michael C.
dc.type.materialtext
dash.identifier.vireohttp://etds.lib.harvard.edu/hms/admin/view/753
dc.description.keywordsAdaptive immunity; evolution; antibodies; variable region genes
dc.identifier.orcid0000-0003-1712-8310
dash.author.emailalex.lee.zhu@gmail.com


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record