Contributions of BCL3 to Humoral Immunity
Final Thesis.pdf (1.469Mb)
Access StatusFull text of the requested work is not available in DASH at this time ("dark deposit"). For more information on dark deposits, see our FAQ.
Weeks, Sabrina Cathryn
MetadataShow full item record
CitationWeeks, Sabrina Cathryn. 2021. Contributions of BCL3 to Humoral Immunity. Master's thesis, Harvard Medical School.
AbstractThe inhibitors of NF-B (IB) are regulators of NF-B signaling that typically sequester NF-B subunits in the cytosol, thereby restraining the inflammatory response. Unlike other IB proteins, the atypical IB 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 (Bcl3ex2). 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. Bcl3ex2 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.
Citable link to this pagehttps://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37368633