Show simple item record

dc.contributor.advisorGeha, Raif
dc.contributor.authorWeeks, Sabrina Cathryn
dc.date.accessioned2021-07-20T03:59:17Z
dash.embargo.terms2022-07-19
dc.date.created2021
dc.date.issued2021-07-19
dc.date.submitted2021
dc.identifier.citationWeeks, Sabrina Cathryn. 2021. Contributions of BCL3 to Humoral Immunity. Master's thesis, Harvard Medical School.
dc.identifier.other28498707
dc.identifier.urihttps://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37368633*
dc.description.abstractThe inhibitors of NF-B (IB) are regulators of NF-B signaling that typically sequester NF-B subunits in the cytosol, thereby restraining the inflammatory response. Unlike other IB proteins, the atypical IB proteins, such as BCL3, are located in the nucleus; these proteins have the capacity to enhance as well as repress NF-B signaling. We identified in two siblings with recurrent infections, hypogammaglobulinemia and near absence of germinal centers in lymph nodes, who carried a novel homozygous variant in BCL3 affecting the canonical donor splice site after exon 2. Using CRISPR-Cas9 gene editing, previous members of the lab generated knock-in mice homozygous for the patients’ BCL3 variant (Bcl3ex2). Both the patients and mutant mice expressed ~5% of the normal level of full-length, WT BCL3 protein, generated through non-canonical splicing. In addition, alternative splicing generated a novel splice variant with a novel N-terminal sequence, followed by an intact WT sequence encoded by exons three through nine, that lacks the nuclear localization sequence. Bcl3ex2 mice exhibited intact development of transitional, follicular, and marginal zone B cells. However, they had hypogammaglobulinemia, an impaired antibody response to T-dependent antigens, impaired germinal center formation, and a paucity of follicular dendritic cells. This study identifies the first human primary immunodeficiency associated with defective BCL3 expression, thereby highlighting the role of BCL3 in the transcriptional regulation of T-dependent humoral immunity.
dc.format.mimetypeapplication/pdf
dc.language.isoen
dash.licenseLAA
dc.subjectBCL3
dc.subjectGerminal Center
dc.subjectHumoral Immunity
dc.subjectMouse
dc.subjectImmunology
dc.titleContributions of BCL3 to Humoral Immunity
dc.typeThesis or Dissertation
dash.depositing.authorWeeks, Sabrina Cathryn
dash.embargo.until2022-07-19
dc.date.available2021-07-20T03:59:17Z
thesis.degree.date2021
thesis.degree.grantorHarvard Medical School
thesis.degree.levelMasters
thesis.degree.nameMMSc IMM
dc.contributor.committeeMemberChou, Janet
dc.type.materialtext
thesis.degree.departmentMedical Science
dc.identifier.orcid0000-0003-2198-4777
dash.author.emailweekssabrina15@gmail.com


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record