The AID Dilemma: Infection, or Cancer?

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Abstract

Activation-induced cytidine deaminase (AID), which is both essential and sufficient for forming antibody memory, is also linked to tumorigenesis. AID is found in many B lymphomas, in myeloid leukemia, and in pathogen-induced tumors such as adult T cell leukemia. Although there is no solid evidence that AID causes human tumors, AID-transgenic and AID-deficient mouse models indicate that AID is both sufficient and required for tumorigenesis. Recently, AID's ability to cleave DNA has been shown to depend on topoisomerase 1 (Top1) and a histone H3K4 epigenetic mark. When the level of Top1 protein is decreased by AID activation, it induces irreversible cleavage in highly transcribed targets. This finding and others led to the idea that there is an evolutionary link between meiotic recombination and class switch recombination, which share H3K4 trimethyl, topoisomerase, the MRN complex, mismatch repair family proteins, and exonuclease 3. As Top1 has recently been shown to be involved in many transcription-associated genome instabilities, it is likely that AID took advantage of basic genome instability or diversification to evolve its mechanism for immune diversity. AID targets are therefore not highly specific to immunoglobulin genes and are relatively abundant, although they have strict requirements for transcription-induced H3K4 trimethyl modification and repetitive sequences prone to forming non-B structures. Inevitably, AID-dependent cleavage takes place in nonimmunoglobulin targets and eventually causes tumors. However, battles against infection are waged in the context of acute emergencies, while tumorigenesis is rather a chronic, long-term process. In the interest of survival, vertebrates must have evolved AID to prevent infection despite its long-term risk of causing tumorigenesis.

Introduction

The successful smallpox vaccine introduced by Jenner in 1789 paved the way for future vaccines against a wide variety of bacterial and viral infections. While some of medical science's critical contributions to human healthcare have come through microbiology and immunology, the reasons behind the efficacy of vaccines have long remained a mystery. The question is twofold: how does the immune system recognize specific antigens out of the huge variety of antigens the body is exposed to? And, how does the immune system recognize pathogens as the same antigens previously encountered in a vaccine? These two questions are central to modern immunology. Two contrasting hypotheses to answer the first question were extensively debated from the 1950s through the 1970s, one proposing that we have a large number of genes encoding antigen receptors, and the other suggesting that a limited number of genes are mutated to amplify the antigen receptor repertoire. The subsequent development of recombinant technology contributed to proof that the latter hypothesis, proposed by Burnet, is basically correct. However, the precise mechanism is more complex than originally anticipated.

Vertebrates have two types of antibody diversification mechanisms, each taking place at a different lymphocyte differentiation phase. VDJ recombination creates an enormous repertoire of both T- and B-cell receptors by assembling various combinations of V, D, and J segments into one exon (Bassing et al., 2002, Fugmann et al., 2000, Gellert, 2002). The mechanism is highly regulated, and proceeds in step with the T and B lymphocyte developmental program. RAG1 and RAG2, which mediate VDJ recombination, are biochemically well characterized and appear to have been introduced rather recently in evolution, most likely by a transposon-like element (Kapitonov and Jurka, 2005, Schatz, 2004). However, VDJ recombination does not explain how antigenic antibody memory is generated, since its process is completely independent from antigen stimulation.

A second layer of diversity, somatic hypermutation (SHM), is introduced in the V exon of B lymphocytes by antigen stimulation. Evidence for SHM has accumulated through a series of experiments by Milstein, Weigert, and Cohn, among others. The most striking observation by Weigert et al. (1970) is that 7 out of 19 mouse Vλ amino acid sequences are highly homologous except for several amino acid substitutions, while the remaining 12 Vλ sequences are identical. Direct proof that SHM occurs through genetic modification was obtained through the work of Tonegawa, Weigert, and other researchers, who compared DNA sequences between the germline and rearranged immunoglobulin Vλ genes (Rajewsky, 1996).

Antigenic stimulation of mature B lymphocytes induces yet another genetic alteration, called class switch recombination (CSR), into the immunoglobulin heavy-chain locus. Class-switching phenomena were originally reported by Uhr, Nossal, and Cooper, whose combined observations clearly indicated that B cells that express IgM change their isotype to other classes after antigenic stimulation (Honjo et al., 2002). In 1978, Kataoka and Honjo proposed class switching to be caused by DNA recombination with a looping-out deletion (Honjo and Kataoka, 1978). This genetic alteration was (Honjo and Kataoka, 1978) directly demonstrated by cloning class-switched immunoglobulin loci (Cory et al., 1980, Dunnick et al., 1980, Maki et al., 1980, Rabbitts et al., 1980, Yaoita and Honjo, 1980).

By the end of the 1990s, we had learned that antigen-specific antibody memory is represented by two genetic alterations in the immunoglobulin locus: SHM, which is a point mutation in the V region exon, and CSR, a recombination event that replaces the CH gene in the heavy-chain locus. Many researchers looked for the enzymes or proteins regulating these genetic alterations. The gene inducing SHM was considered to be a mutator gene, and the gene for CSR was expected to encode a recombinase. The two proteins were assumed to be different.

The year 2000 brought the surprising discovery that a single protein, activation-induced cytidine deaminase (AID), regulates both SHM and CSR (Muramatsu et al., 2000, Revy et al., 2000). AID was cloned by subtractive hybridization between stimulated and nonstimulated CH12F3-2A B lymphoma cells, which switch efficiently from IgM to IgA when stimulated (Muramatsu et al., 1999, Nakamura et al., 1996). AID was demonstrated to regulate both SHM and CSR, both in studies of AID-deficient mice and through the identification of AID mutations in hyper-IgM syndrome type II (HIGM II) patients (Revy et al., 2000). Subsequently, using artificial constructs to measure SHM and CSR, it was demonstrated that AID induces SHM and CSR in nonlymphoid cells (Okazaki et al., 2002, Yoshikawa et al., 2002). It therefore became clear that AID is essential and sufficient to induce SHM and CSR.

AID overexpression was subsequently shown to cause tumors in mice, indicating that AID is indeed a mutator. Transgenic mice carrying AID cDNA under the chicken β actin promoter frequently develop T lymphoma and lung microadenoma, and less frequently, B lymphoma, muscle-derived tumors, and hepatoma (Okazaki et al., 2003). Inversely, AID deficiency reduces the frequency of c-myc/Ig chromosomal translocations that lead to the plasmacytoma formation associated with IL-6 overexpression (Ramiro et al., 2004). More recently, several lines of evidence have indicated that viruses that can cause tumors also frequently induce AID. These include the Epstein–Barr virus (EBV) (Epeldegui et al., 2007), HTLV-1 (Ishikawa et al., 2011), and hepatitis virus type C (Endo et al., 2007). In addition, Helicobacter pylori was shown to induce AID in gastric epithelial cells (Matsumoto et al., 2007). Another interesting association between AID and the Philadelphia chromosome-encoded Bcr-Abl kinase is considered to link AID with tumorigenesis or tumor progression (Feldhahn et al., 2007). Although AID's preferred target is the Ig locus, AID obviously attacks other genes as well, and there are many lines of evidence indicating that AID may be involved in tumorigenesis. Thus, although AID is essential for antibody memory generation as a core function of adaptive immunity, AID expression may simultaneously cause tumors. This dilemma regarding AID will be discussed from an evolutionary point of view.

Section snippets

Two Distinct AID Functions

AID function has been extensively studied using AID mutants. Strikingly, in HIGM II patients, AID mutation sites are found scattered across almost all of its 198 amino acid residues (Durandy et al., 2006, Revy et al., 2000). This finding clearly indicates that mutations of various AID regions affect CSR function. This could be due to the AID protein interacting with multiple proteins at its various regions, or to its structure being so unstable that point mutations in its various regions alter

DNA Cleavage Mechanism by AID

While it seems that AID's involvement in tumorigenesis must be closely linked with DNA cleavage, AID's molecular mechanism for DNA cleavage is still controversial. There are two contrasting hypotheses to explain how AID introduces DNA cleavage in the genome (Neuberger et al., 2003, Petersen-Mahrt et al., 2002).

CSR and Meiotic Recombination Homology

As mentioned above, H3K4me3 histone modification is an essential marker for all known specific recombinations—VDJ, meiotic, and CSR. This finding led us to compare the overall molecular mechanism of meiotic recombination with CSR (Table IV). It became clear that the two recombination mechanisms share many aspects and players in addition to the H3K4me3 mark. First, both recombination mechanisms depend on topoisomerase for DNA cleaving—Spo11, a member of the Top2 family, in meiotic recombination,

Coda

An evolutionary consideration of the AID mechanism reveals that AID shares its DNA cleavage mechanism with several types of genome instability mechanisms such as TAM and triplet contraction/expansion, which depend on Top1 nicking activity. These mechanisms also share a dependency on transcription, and probably on non-B structural formation induced by excessive negative supercoil. This indicates that AID does not necessarily uniquely target Ig genes. Many genes that form transcription-induced

Acknowledgments

We thank Drs. S. Fagarasan, K. Kinoshita, M. Muramatsu, R. Shinkura, and I. Okazaki for critical reading of this chapter, and Ms. Y. Shiraki for preparing the manuscript. This work was supported by Grant-in-Aid 17002015 for Specially Promoted Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.

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