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Distinct and overlapping roles of canonical and non- canonical NF[kappa]B signals in B cell biology /


The task of the adaptive immune system is to respond and clear pathogens. Tailoring responses based on pathogen type and retain memory of the pathogenic encounter for subsequent challenges are also requisite. For this, millions of individual B lymphocytes in the developing immune system express unique antigen receptors, creating a vast repertoire of potential antigen-recognition specificities. Regulation of lymphocyte selection and development is tightly controlled, as aberrant selection can result in autoreactive or diminished responses, thus pathogenesis. The NF[kappa]B transcription factor family is essential for lymphocyte proliferative responses during immune activation, but there is also evidence that it may play a role in lymphocyte development. The NF[kappa]B family comprises dimers of 5 related subunits; p50, p52, p65 (RelA), cRel, and RelB, which control gene expression by binding [kappa]B elements in the regulatory regions of target genes. Signals from antigen and innate immune receptors cause rapid, transient activation of NF[kappa]B through the NEMO/IKK-dependent, so called "canonical" signaling pathway, resulting in immediate degradation of I[kappa]Bs and nuclear translocation of pre-existing RelA and cRel containing dimers. A second "alternative" NF[kappa]B pathway has been described downstream of TNFR family members such as BAFF-R which results in persistent activation of NF[kappa]B via kinase NIKNF[kappa]B was initially discovered in B-cells. Since then the many components of the NF[kappa]B system have been identified and a mathematical model recapitulates the functioning of this dynamical system in fibroblasts, yet in B lymphocytes studies have generally focused on an individual NF[kappa]B component and systems level understanding remains lacking. This thesis describes our attempts to provide a predictive understanding of the functional role of canonical and non- canonical NF[kappa]B regulation in the context of B cell development and activation. Chapter one gives an overview of mechanism by which B cells are produced and maintained along with current understanding of NF[kappa]B roles within this progression. Chapter two reports on NF[kappa]B effectors required for B lymphocyte maturation and development. Chapter three describes how BAFF-R stimulation contributes to BCR-triggered proliferation via two distinct NF[kappa]B[ signaling mechanisms provided by the non-canonical pathway. Finally, chapter four summarizes our findings in the context of current and future studies in the field.

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