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Academic Background

PhD, Johns Hopkins University, 1971

Janet Stavnezer, PhD

Mechanism and Regulation of Antibody Class Switch Recombination

B cells respond to immunization or infection by diversifying the antibodies they produce through two processes: antibody class switch recombination and somatic hypermutation of their antigen-binding regions. Switch recombination causes a change in antibody class expression from IgM to IgG, IgA or IgE, resulting in an increased ability of the antibody to remove the pathogen. Somatic hypermutation, in conjunction with B cell selection, results in increases in the antigen binding ability of the antibody.

Both class switch recombination and somatic hypermutation are initiated by the enzyme activation induced cytidine deaminase (AID), acting on the antibody genes. After AID acts, two different DNA repair pathways (base excision repair and mismatch repair) begin to attempt to repair the resulting dU bases. However, instead of accurately repairing the lesions, these repair processes result in the introduction of DNA breaks and mutations that lead to class switch recombination and mutation of the variable region genes. The figure below diagrams the process of class switch recombination.

The AID enzyme is highly induced in activated B cells, including germinal center B cells, and only occasionally found in other cell types, and sometimes in tumor cells. Although essential for a proper immune response, it is also dangerous as it occasionally targets non-Ig genes. We have performed a genomics search to attempt to identify genes targeted by AID, as evidenced by the presence of DNA double-strand breaks. We have identified reproducible AID-dependent DNA breaks that occur at several genomic sites. We are investigating whether these sites might be important for generation of B cell lymphomas, as it is known that translocations between S regions and oncogenes occur in activated B cells, and that this can lead to B cell lymphoma. We are currently investigating several aspects of these findings, for example, how AID is normally properly targeted to S regions, and how the DNA breaks introduced in S regions are normally properly shepherded toward class switch recombination.

Another project is to investigate why the C terminal 10 amino acids of AID are required for CSR but not for SHM. Our initial results have been published (Ranjit et al, 2011), and we are continuing to investigate the hypothesis that the C terminus recruits proteins involved in recombination of DNA breaks.

Diagram of Class Switch Recombination (CSR)

Diagram of Class Switch Recombination (CSR)

Top line shows Ig heavy chain genes in a B cell that expresses IgM and IgD (by alternative RNA processing). CSR occurs after AID deaminates dC residues within S regions that are transcriptionally active. RNA transcripts from the unrearranged heavy chain genes are called germline transcripts.

Middle line illustrates the intrachromosomal deletional recombination between two switch (S) regions during CSR from IgM to IgE. The DNA in between Sm and Se is excised from the chromosome as a circle.

Bottom line illustrates the chromosome after CSR showing that the identical VH region originally expressed with the Cmgene is now expressed with Ce gene in cells expressing IgE.

One or more keywords matched the following items that are connected to Stavnezer, Janet
Item TypeName
Academic Article Antibody class switching.
Academic Article The ability of CD40L, but not lipopolysaccharide, to initiate immunoglobulin switching to immunoglobulin G1 is explained by differential induction of NF-kappaB/Rel proteins.
Academic Article Activation of NF-kappaB/Rel by CD40 engagement induces the mouse germ line immunoglobulin Cgamma1 promoter.
Academic Article Reduced isotype switching in splenic B cells from mice deficient in mismatch repair enzymes.
Academic Article The mu switch region tandem repeats are important, but not required, for antibody class switch recombination.
Academic Article Immunoglobulin genes: generating diversity with AID and UNG.
Academic Article Ialpha exon-replacement mice synthesize a spliced HPRT-C(alpha) transcript which may explain their ability to switch to IgA. Inhibition of switching to IgG in these mice.
Academic Article Deletion of the nucleotide excision repair gene Ercc1 reduces immunoglobulin class switching and alters mutations near switch recombination junctions.
Academic Article Inducible DNA breaks in Ig S regions are dependent on AID and UNG.
Academic Article Copy choice mechanism of immunoglobulin heavy-chain switch recombination.
Academic Article The histone methyltransferase Suv39h1 increases class switch recombination specifically to IgA.
Academic Article Stimuli that enhance IgA class switching increase histone 3 acetylation at S alpha, but poorly stimulate sequential switching from IgG2b.
Academic Article Activation-induced cytidine deaminase-dependent DNA breaks in class switch recombination occur during G1 phase of the cell cycle and depend upon mismatch repair.
Academic Article APE1- and APE2-dependent DNA breaks in immunoglobulin class switch recombination.
Academic Article The roles of APE1, APE2, DNA polymerase beta and mismatch repair in creating S region DNA breaks during antibody class switch.
Academic Article Reassessment of the role of Mut S homolog 5 in Ig class switch recombination shows lack of involvement in cis- and trans-switching.
Academic Article Class switch recombination efficiency and junction microhomology patterns in Msh2-, Mlh1-, and Exo1-deficient mice depend on the presence of mu switch region tandem repeats.
Academic Article Immunoglobulin heavy-chain switching may be directed by prior induction of transcripts from constant-region genes.
Academic Article A B-cell-specific nuclear protein that binds to DNA sites 5' to immunoglobulin S alpha tandem repeats is regulated during differentiation.
Academic Article Role for mismatch repair proteins Msh2, Mlh1, and Pms2 in immunoglobulin class switching shown by sequence analysis of recombination junctions.
Academic Article Induction of immunoglobulin isotype switching in cultured I.29 B lymphoma cells. Characterization of the accompanying rearrangements of heavy chain genes.
Academic Article Complex regulation and function of activation-induced cytidine deaminase.
Academic Article AID recruits UNG and Msh2 to Ig switch regions dependent upon the AID C terminus [corrected].
Academic Article The DNA glycosylases Ogg1 and Nth1 do not contribute to Ig class switching in activated mouse splenic B cells.
Academic Article Activation-induced cytidine deaminase-initiated off-target DNA breaks are detected and resolved during S phase.
Academic Article Regulation of transcription of immunoglobulin germ-line gamma 1 RNA: analysis of the promoter/enhancer.
Academic Article Mlh1 can function in antibody class switch recombination independently of Msh2.
Academic Article The Smu tandem repeat region is critical for Ig isotype switching in the absence of Msh2.
Academic Article Mutations occur in the Ig Smu region but rarely in Sgamma regions prior to class switch recombination.
Academic Article Regulation of antibody production and class switching by TGF-beta.
Academic Article Characterization of an interleukin 4 (IL-4) responsive region in the immunoglobulin heavy chain germline epsilon promoter: regulation by NF-IL-4, a C/EBP family member and NF-kappa B/p50.
Academic Article Inhibitors of poly(ADP-ribose) polymerase increase antibody class switching.
Academic Article Antibody class switching: uncoupling S region accessibility from transcription.
Academic Article Evolution of isotype switching.
Academic Article Induction of germ-line immunoglobulin heavy chain transcripts by mitogens and interleukins prior to switch recombination.
Academic Article Shifts in targeting of class switch recombination sites in mice that lack mu switch region tandem repeats or Msh2.
Academic Article Mismatch repair converts AID-instigated nicks to double-strand breaks for antibody class-switch recombination.
Academic Article Enhanced IgA class switching in marginal zone and B1 B cells relative to follicular/B2 B cells.
Academic Article DNA polymerase beta is able to repair breaks in switch regions and plays an inhibitory role during immunoglobulin class switch recombination.
Academic Article Mechanism and regulation of class switch recombination.
Academic Article The surprising discovery that TGF beta specifically induces the IgA class switch.
Academic Article p53 represses class switch recombination to IgG2a through its antioxidant function.
Academic Article Mapping of switch recombination junctions, a tool for studying DNA repair pathways during immunoglobulin class switching.
Academic Article Activation-induced cytidine deaminase induces reproducible DNA breaks at many non-Ig Loci in activated B cells.
Academic Article Mutations, duplication, and deletion of recombined switch regions suggest a role for DNA replication in the immunoglobulin heavy-chain switch.
Concept Immunoglobulin Allotypes
Concept Immunoglobulin epsilon-Chains
Concept Immunoglobulin Variable Region
Concept Somatic Hypermutation, Immunoglobulin
Concept Immunoglobulin alpha-Chains
Concept Genes, Immunoglobulin
Concept Immunoglobulin gamma-Chains
Concept Immunoglobulin M
Concept Immunoglobulin G
Concept Immunoglobulin A
Concept Immunoglobulin Switch Region
Concept Immunoglobulin E
Concept Immunoglobulin Heavy Chains
Concept Immunoglobulin Isotypes
Concept Immunoglobulin Idiotypes
Concept Immunoglobulin Constant Regions
Concept Immunoglobulin Class Switching
Concept Immunoglobulin mu-Chains
Academic Article DNA polymerases ? and ? do not directly affect Ig variable region somatic hypermutation although their absence reduces the frequency of mutations.
Academic Article A DNA break- and phosphorylation-dependent positive feedback loop promotes immunoglobulin class-switch recombination.
Academic Article Differential expression of APE1 and APE2 in germinal centers promotes error-prone repair and A:T mutations during somatic hypermutation.
Academic Article IgH chain class switch recombination: mechanism and regulation.
Academic Article Response to comment on "IgH chain class switch recombination: mechanism and regulation".
Academic Article Individual substitution mutations in the AID C terminus that ablate IgH class switch recombination.
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  • Immunoglobulin D