Valerie Odegard

Bio: Valerie Odegard is an academic researcher from Yale University. The author has contributed to research in topics: Somatic hypermutation & T cell. The author has an hindex of 6, co-authored 12 publications receiving 593 citations.

Targeting of somatic hypermutation.

Abstract: Somatic hypermutation (SHM) introduces mutations in the variable region of immunoglobulin genes at a rate of approximately 10(-3) mutations per base pair per cell division, which is 10(6)-fold higher than the spontaneous mutation rate in somatic cells. To ensure genomic integrity, SHM needs to be targeted specifically to immunoglobulin genes. The rare mistargeting of SHM can result in mutations and translocations in oncogenes, and is thought to contribute to the development of B-cell malignancies. Despite years of intensive investigation, the mechanism of SHM targeting is still unclear. We review and attempt to reconcile the numerous and sometimes conflicting studies on the targeting of SHM to immunoglobulin loci, and highlight areas that hold promise for further investigation.

Expression of activation-induced cytidine deaminase is regulated by cell division, providing a mechanistic basis for division-linked class switch recombination.

Abstract: Class switch recombination (CSR) is the process by which B cells alter the effector function properties of their Ig molecules. The decision to switch to a particular Ig isotype is determined primarily by the mode of B cell activation and cytokine exposure. More recent work indicates that the likelihood or probability of switching increases with successive cell divisions and is largely independent of time. We have analyzed different molecular features of CSR using cell division as a reference point in an attempt to gain insight into the mechanism of division-linked switching. Our results indicated that the accessibility of Ig heavy chain constant regions targeted for CSR was established after the cells had undergone a single cell division and did not vary significantly with subsequent cell divisions. In contrast, expression of activation-induced cytidine deaminase (AID) mRNA was found to increase with successive divisions, exhibiting a striking correlation with the frequency of CSR. Levels of AID in a given division remained constant at different time points, strongly suggesting that the regulation of AID expression was division-linked and independent of time. In addition, constitutive AID expression from a transgene accelerated division-linked CSR. Thus, we propose that the division-linked increase in AID expression provides an underlying molecular explanation for division-linked CSR.

Roles of the Ig κ Light Chain Intronic and 3′ Enhancers in Igk Somatic Hypermutation

Abstract: Somatic hypermutation (SHM) of the rearranged Ig genes is required for the affinity maturation of Abs. SHM is almost exclusively targeted to the rearranged Ig loci, but the mechanism of this gene-specific targeting remains unclear. The Ig kappa L chain locus contains multiple enhancers, including the MAR/intronic (iE(kappa)) and 3' enhancers (3'E(kappa)). Previous transgenic studies indicate that both kappa enhancers are individually necessary for SHM of Igk. In contrast, later studies of Ag-selected V(kappa) genes in 3'E(kappa)(-/-) mice found no absolute requirement for 3'E(kappa) in kappa SHM. To address the roles of the two kappa enhancers in SHM in a physiological context, we analyzed SHM of the endogenous Igk in mice with a targeted deletion of either iE(kappa) or 3'E(kappa) in Peyer's patch germinal center B cells. Our findings indicate that, although 3'E(kappa) is quantitatively important for SHM of Igk, iE(kappa) is not required for kappa SHM. In addition, a reduction of kappa mRNA levels is also detected in activated 3'E(kappa)(-/-) B cells. These findings suggest that iE(kappa) and 3'E(kappa) play distinct roles in regulating Igk transcription and SHM.

TCR Complex Immunotherapeutics

Abstract: Single chain fusion proteins that specifically bind to a TCR complex or a component thereof, such as TCRα, TCRβ, or CD3e, along with compositions and methods of use thereof are provided.

Mechanism and regulation of class switch recombination.

Abstract: Antibody class switching occurs in mature B cells in response to antigen stimulation and costimulatory signals. It occurs by a unique type of intrachromosomal deletional recombination within special G-rich tandem repeated DNA sequences [called switch, or S, regions located upstream of each of the heavy chain constant (C(H)) region genes, except Cdelta]. The recombination is initiated by the B cell-specific activation-induced cytidine deaminase (AID), which deaminates cytosines in both the donor and acceptor S regions. AID activity converts several dC bases to dU bases in each S region, and the dU bases are then excised by the uracil DNA glycosylase UNG; the resulting abasic sites are nicked by apurinic/apyrimidinic endonuclease (APE). AID attacks both strands of transcriptionally active S regions, but how transcription promotes AID targeting is not entirely clear. Mismatch repair proteins are then involved in converting the resulting single-strand DNA breaks to double-strand breaks with DNA ends appropriate for end-joining recombination. Proteins required for the subsequent S-S recombination include DNA-PK, ATM, Mre11-Rad50-Nbs1, gammaH2AX, 53BP1, Mdc1, and XRCC4-ligase IV. These proteins are important for faithful joining of S regions, and in their absence aberrant recombination and chromosomal translocations involving S regions occur.

Molecular Mechanisms of Antibody Somatic Hypermutation

Abstract: Functional antibody genes are assembled by V-D-J joining and then diversified by somatic hypermutation. This hypermutation results from stepwise incorporation of single nucleotide substitutions into the V gene, underpinning much of antibody diversity and affinity maturation. Hypermutation is triggered by activation-induced deaminase (AID), an enzyme which catalyzes targeted deamination of deoxycytidine residues in DNA. The pathways used for processing the AID-generated U:G lesions determine the variety of base substitutions observed during somatic hypermutation. Thus, DNA replication across the uracil yields transition mutations at C:G pairs, whereas uracil excision by UNG uracil-DNA glycosylase creates abasic sites that can also yield transversions. Recognition of the U:G mismatch by MSH2/MSH6 triggers a mutagenic patch repair in which polymerase eta plays a major role and leads to mutations at A:T pairs. AID-triggered DNA deamination also underpins immunoglobulin variable (IgV) gene conversion, ...

The regulation of IgA class switching

Abstract: IgA class switching is the process whereby B cells acquire the expression of IgA, the most abundant antibody isotype in mucosal secretions. IgA class switching occurs via both T-cell-dependent and T-cell-independent pathways, and the antibody targets both pathogenic and commensal microorganisms. This Review describes recent advances indicating that innate immune recognition of microbial signatures at the epithelial-cell barrier is central to the selective induction of mucosal IgA class switching. In addition, the mechanisms of IgA class switching at follicular and extrafollicular sites within the mucosal environment are summarized. A better understanding of these mechanisms may help in the development of more effective mucosal vaccines.

Two levels of protection for the B cell genome during somatic hypermutation

Abstract: Somatic hypermutation, the mechanism by which activated B cells in the blood produce a diversity of immunoglobulin genes giving rise to high-affinity antibodies, plays a vital role in protecting the body from infection. Yet it also represents a major risk to genomic stability, with the potential to generate B-cell tumours if unchecked or wrongly directed. The somatic hypermutation reaction is initiated by activation induced deaminase (AID), and it is widely assumed that the risk of inappropriate hypermutation is averted by careful targeting of this enzyme. New work in mice suggests that this is not the case. Rather, AID deaminates a large fraction of the expressed genome, including numerous oncogenes linked to B-cell malignancies. Widespread mutation of the genome is averted in a surprising manner: by gene-specific, error-free DNA repair mediated by base excision and mismatch repair. Somatic hypermutation introduces point mutations into immunoglobulin genes in germinal centre B cells during an immune response. The reaction is initiated by cytosine deamination by the activation-induced deaminase (AID) and completed by error-prone processing of the resulting uracils by mismatch and base excision repair factors1. Somatic hypermutation represents a threat to genome integrity2 and it is not known how the B cell genome is protected from the mutagenic effects of somatic hypermutation nor how often these protective mechanisms fail. Here we show, by extensive sequencing of murine B cell genes, that the genome is protected by two distinct mechanisms: selective targeting of AID and gene-specific, high-fidelity repair of AID-generated uracils. Numerous genes linked to B cell tumorigenesis, including Myc, Pim1, Pax5, Ocab (also called Pou2af1), H2afx, Rhoh and Ebf1, are deaminated by AID but escape acquisition of most mutations through the combined action of mismatch and base excision repair. However, approximately 25% of expressed genes analysed were not fully protected by either mechanism and accumulated mutations in germinal centre B cells. Our results demonstrate that AID acts broadly on the genome, with the ultimate distribution of mutations determined by a balance between high-fidelity and error-prone DNA repair.