





































Abstract
Activation induced cytidine deaminase (AID) is an important enzyme that creates 
mutations in DNA via deamination of a cytosine base into a uracil. AID, also referred to 
as activation induced deaminase (AICDA), plays a crucial part in the human immune 
response as it is essential for isotype switching and cellular differentiation. However, 
aberrant expressions in some pathways has been implicated in a plethora of diseases. There 
is a pressing need for research and comparison of current literature that informs related 
therapies. Previous studies have explored potential mechanisms by which AID works and 
subsequently ways to target gene therapies based on this information. Due to AID’s 
complexity, there have been many challenges along the path that led to our current 
understanding of the beneficial and harmful nature of AID. Furthermore, a better 
understanding of the way AID works can aid with the development of more efficacious 
therapies. Although further research on the topic and additional testing in humans and 
animal models are needed, it is clear that AID may play an important role in the 
development of therapeutic treatments in diseases like cancer, lupus, and type 1 diabetes.

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Activation Induced Cytidine Deaminase
Image by Emw - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=8764396



Introduction

Previous studies and research have established that AID regulates secondary 
antibody diversi�cation. There are many di�erent immunoglobulin (Ig) 
diversi�cation processes, such as somatic hypermutation (SHM), class 
switch recombination (CSR), and gene conversion (GC)4. SHM allows for 
B cells to diversify in order to respond to threats to the immune system,5

while CSR allows for the generation of di�erent classes of antibodies5. GC 
is a process in which mutations can occur in the antibody genes5. AID is 
central to CSR/SHM and plasma cell di�erentiation and is encoded by 
AICDA and B lymphocyte maturation protein 1
(Blimp-1) which is a transcription factor encoded by Prdm16. AID and its 
transcription factors underpin Ab and autoantibody responses7 . The 
deamination results in a change from a cytosine base to a uracil base in Ig 
genes, and this can result in either CSR or SHM, depending on the 
deoxyribonucleic acid (DNA) repair pathway. AID expression is 
upregulated by in�ammatory cytokines like interferon-γ and tumor necrosis 
factor (TNF)-α which induces p53 mutations in in�ammatory or cancer 
cells. Although AID is typically associated with and expressed in B-cells, it 
can also be expressed, for example, in embryonic germ cells or pluripotent 
cells like oocytes. AID proteins have been shown to be expressed during 
early B-cell development in both human fetal liver and adult bone marrow 9.

It is important to note that AID is a potent enzyme which instigates 
genomic diversity for both bene�cial10 and harmful outcomes in humans. 
This can best be depicted in Figure 1, which summarizes much of the 
following section. AID di�ers from other Apolipoprotein B mrRNA 
Editing Catalytic Polypeptides (APOBECs) speci�cally due to the size and 
orientation of its substrate speci�city loop12. It has a larger loop that extends 
away from the active site and thus can accommodate two purines next to a 
target C12. Despite some sequence similarity to APOBEC cytidine 
deaminases, AID’s critical function in Ab diversi�cation in CSR cannot be 
substituted by other APOBEC proteins10. While aberrant deaminase 
activity can certainly threaten the genome, recent biotechnological e�orts 
have focused on harnessing and targeting deaminase activity in base editors 
that are related to AID11.

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Figure 1: A diagram summarizing some of the beneficial and harmful outcomes of AID

AID, a potent DNA mutator, must be tightly regulated to prevent any
o �-target e�ects which can result in a plethora of problems including 

mutations in non-Ig genes, genomic instability, interchromosomal 
translocations, and cellular neoplastic transformation13. AID has previously 
been implicated in the tumorigenic process in B cell tumors potentially 
through the induction of chromosomal translocations and mutations in 
tumor suppressor genes and oncogenes14. AID expression has also been 
implicated in the pathogenesis of human B cell malignancies15. Indeed, 
accumulating evidence suggests AID is pro-oncogenic and induces cancer-
promoting mutations or chromosomalrearrangements16. Another 
detrimental impact of AID is the generation of autoimmunity, which can 
occur after on-target point mutations in variable genes produce antibodies 
with high a�nity for self-proteins11. These detrimental e�ects are important 
to consider when choosing to target AID in potential research projects. 
Other studies have proposed more novel functions for AID. For instance, 
one has suggested that AID functions as an adaptor protein that represses 
viral transcription, which would have implications for the development of 
anti-HIV therapeutics and other therapies 17. Moreover, AID can exert non 
canonical functions when aberrantly expressed in epithelial cells and was

Berkeley Pharma Tech Journal of Medicine | 109



long known to lack speci�c inhibitors which prevented therapeutic 
applications to modulate AID functions18.

Mechanism

Historically, the discovery of AID and its essential role in antibody 
diversi�cation kindled a debate over AID’s nucleic acid substrate, which 
inspired the DNA deamination model and identi�cation of downstream 
players in the CSR pathway such as the DNA glycosylase UNG19. 
Subsequently, this discovery led to a race to uncover ssDNA as the target of 
AID’s enzymatic activity and its dependence on transcription for 
deamination19. It is important to note that AID deaminates C→U only on 
ssDNA and does not function on dsDNA or RNA12. Figure 2 depicts this 
type of deamination reaction. Nearly two decades prior to this research, 
there was an observation that noncoding RNA transcripts originated from 
within the IgH locus and could be playing a role in CSR19.

Figure 2: Cytosine to Uracil deamination reaction wherein an amine group is removed

SHM generates point mutations in the Ig variable regions while CSR 
exchanges the Ig heavy chain constant region, and ultimately this gives rise 
to antibodies with enhanced a�nity and new e�ector functions20. AID 
initiates both these processes through deamination of cytosine to uracil in Ig 
variable and switch gene regions, and the resultingU:G mismatches are

Berkeley Pharma Tech Journal of Medicine | 110



subsequently processed by uracil-DNA glycosylase (UNG2) and a pathway 
that requires

The mechanism by which AID works has not been entirely discerned. 
Namely, the mechanism of AID targeting has especially been a
long-standing mystery10. Currently, there are many di�erent �ndings that 
are piecing together the puzzle of how exactly AID works. In terms of 
frequency, the number of molecules containing deamination in both DNA 
strands at the acceptor switch region corresponds to its class switch
e�ciency. It has been proposed that the minimal requirement for a DNA 
double-strand break (DSB) formation is as low as only one AID deamination 
event on both DNA strands4. There are also several proposed mechanisms 
for AID function. AID may target template and non-template strands at 
similar frequencies and predominantly after R-loops are processed by 
cellular enzymes that expose DNA on both DNA strands4. Additionally,  
AID footprints may be distributed evenly across the entire length of the S 
region, unlike SHM, which is not evenly distributed over a distance; thus 
AID deaminates S and V regions with distinct mechanisms. It has also been 
suggested that AID-mediated DNA demethylation occurs due to the 
deamination of methylated cytidine residues in single-stranded DNA, 
followed by DNA repair7.

A long-standing hypothesis on AID targeting, known as the hotspot 
hypothesis, has recently been under re-evaluation. This hypothesis 
considered a short sequence motif (AGCT) conserved in all S regions as 
functionally important for CSR, proposing that it exerts its function via its 
overlapping AID hotspot structure23. However, an initial weakness of this 
theory was that these sequences are very common in the genome23. Another 
study determined one of the �rst crystal structures of maltose-binding 
protein (MBP)-fused AID and its complex with cytidine
(C), deoxycytidine (dC), and deoxycytidine monophosphate (dCMP). These 
structures can help explain the discrimination between DNA and RNA in 
AID catalysis and reveal that AID has a bifurcated
substrate-binding surface10. This supports the theory that one AID 
recognizes two adjacent ssDNA overhangs from one structured substrate to 
achieve high a�nity10. G4 structured substrates induce AID cooperative

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oligomerization, which could promote clustered mutations in the Ig S 
regions10. Overall, the bifurcated substrate binding surface and 
oligomerization interface are both an essential component of CSR and help 
elucidate recognition of structured substrates as an important
AID-targeting mechanism, speci�cally in the Ig S regions10. It has therefore 
been suggested that G4 substrates mimicking Ig S regions are preferred AID 
targets in vitro. This recent �nding is a departure from our previous 
understanding of AID targeting. This data also posits that AID preference 
for these substrates is likely due to their bundled ssDNA overhangs 
structure rather than the primary sequence motif, which was long believed 
to bewhy AID preferred these substrates10. It is important to recognize that 
a de�nitive complex structure with fully characterized substrate 
conformation is still lacking and must be developed10.

Many proposed therapies suggest that selective inhibition of AID may 
ameliorate the conditions. Ultimately,further experimentation and analysis 
with more sensitive techniques that may eventually be developed is needed 
to more fully understand the mechanism of AID inhibition. Given that the 
crystal structure of AID has recently been resolved, future e�orts would 
certainly bene�t from structural modeling approaches10. A more de�nitive 
structure could serve as a template for potential therapeutic intervention 
against AID10. Progress on AID structure is very timely alongside the 
growing knowledge about Ig class switch region nucleic acid structures, 
which are supported by functional studies24. Already, we are seeing 
promising results from initiatives focusing on AID. Platforms like 
GENEVESTIGATOR consolidate publicly available studies from 
microarrays, mRNA sequencing, and more under healthy conditions versus 
diseased states25. Using these comparisons is one potential strategy for a 
comprehensive analysis of the role of AID in the pathobiology of immune-
or in�ammatory-based diseases and cancer25. It has also been suggested that 
we may eventually be able to analyze AID gene signatures to get decisive 
determinants of patient-speci�c or patient-group-speci�c antiviral response, 
which could allow us to understand how viruses can impact di�erent 
individuals25.

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Estrogen and AID

Estrogen has been found to reverse the repression of AID, resulting in a 
subsequent boost in AID expression. This is proposed to occur through the 
upregulation of HoxC4, which, together with NF-κB, critically mediates 
AID promoter activation6. There may, however, be additional epigenetic 
mechanisms at play that serve to regulate AID expression. Estrogen reverses 
HDI-mediated inhibition of AID and CSR in Ab and autoantibody 
responses through the downregulation of B cell miR-26a, which targets AID 
mRNA’s 3’UTR6. As epigenetic modi�ers, SCFA HDIs, like miR-26a and 
miR-125a, inhibit AID expression and CSR through the upregulation of 
select B cell miRNAs, which silence AID26. This is interesting as it may 
provide an explanation for the female bias in autoantibody-mediated 
autoimmune diseases like lupus2. Yet, an experimental and fully functioning 
in vivo model of the human immune system is needed in order to 
understand the epigenetic mechanisms relating to the human Ab and 
autoantibody response6.

Autoimmune Diseases

Cellular reprogramming, broadly, is a mechanism that must be further 
explored. Currently, there are three approaches to induce reprogramming: 
cell fusion, nuclear transfer, and iPSC14. Cell fusion is a great way to 
understand nuclear plasticity and is a main element of many cancer 
processes14. Nuclear transfer, more commonly referred to as cloning, has 
potential therapeutic applications, although ethical concerns exist14. iPSC 
technology is anexcellent option given that it has potential therapeutic 
applications for clinical use without ethical concerns and can be used to 
model human diseases and screen potential new treatments27. DNA 
methylation is a major barrier to induced pluripotent stem (iPS) cell 
reprogramming, and putative DNA demethylase protein AID can erase 
DNA methylation at pluripotency gene promoters, which will subsequently 
allow cellular reprogramming14.

Autoimmune diseases are detrimental to the health and wellbeing of 
individuals globally.

Berkeley Pharma Tech Journal of Medicine | 113



One example of such a disease is common variable immunode�ciency
(CVID), which is a primary immunode�ciency characterized by 
hypogammaglobulinemia and di�erent degrees of B cell compartment 
alteration28. We found reduced Bcl-2 protein levels in memory B cells from 
CVID.

Hypertension is another medical condition where the study of AID can be 
useful. In the USA, nearly 50% of the adult population has hypertension, and 
prevalence increases to ~80% at advanced age29. B cell Ig production is 
dependent on a subset of B cells called GC B cells, which are dependent on 
AID and may play a causal role in the pathophysiology of hypertension. The 
GC reaction is driven by IL-21 and T follicular helper (Tfh) cells, which are 
transcription factors associated with AID and have been demonstrated to 
play a role in hypertension and hypertensive end-organ damage30. It is 
possible that B cells and Ig contribute to hypertension in speci�c cases as in 
autoimmune diseases or preeclampsia31. However, future studies should 
investigate inducible genetic B cell deletion in adult animals to determine if 
B cells are viable therapeutic targets for hypertension31.

Multiple Sclerosis (MS) is another debilitating chronic disease. B cell 
depleting therapies are a potential way to ameliorate symptoms in MS given 
that B cells play a critical role in the MS disease process32. There is a presence 
of B cells in active lesions and the cerebrospinal �uid of MS patients32. In a 
recent study, the community was able toglean more information on the role 
of secondary diversity of the BCR in experimental autoimmune 
encephalomyelitis (EAE) and identify IgG class-switched B cells as potential 
therapeutic targets for the treatment of MS32. AID was also found to 
presumably still exert some subtle e�ect on rMOG-induced (myelin 
oligodendrocyte glycoprotein) disease trajectory32.

Arthritis is a debilitating disease that can result in a lot of pain A potential 
novel treatment for in�ammatory arthritis includes Fraxinellone33. The 
therapeutic e�ect of fraxinellone was associated with the inhibition of 
cellular di�erentiation and activation. It has been shown to attenuate the 
clinical and histologic features of in�ammatory arthritis in mice33. There

Berkeley Pharma Tech Journal of Medicine | 114



was a lower expression of AID and Blimp-1 following treatment with 
Fraxinellone33.

Remarkably, it also alleviated synovial in�ammation and osteoclastogenesis 
in mice33. Other drugs such as belimumab, a targeted therapy approved for 
systemic lupus erythematosus (SLE), serve as examples of how targeted 
therapies that disrupt the AID pathway can be bene�cial34. Further 
investigation is needed to see the side e�ects on normal cells.

Cancer

AID, as previously mentioned, has been largely suggested to induce cancer-
promoting mutation. AID is expressed in more than 40%   of primary human 
chronic lymphocytic leukemia (CLL) cases, but AID expression can be 
harnessed for antileukemic e�ect after inhibition of the RAD51 
homologous recombination (HR) factor
4,4’-diisothiocyanatostilbene-2-2’-disulfonic acid (DIDS)16. This is a novel 
antineoplastic role of AID that can be triggered by inhibition of HR, which 
is a new paradigm to treat AID-expressing tumors and has had proof of 
principle studies conducted16. This treatment has also been suggested for 
use in type 1 diabetes6. Another avenue that has been considered is the 
chronic administration of HSP90 inhibitors, which decreases AID protein 
levels and has been shown to reduce disease severity in a mouse model of 
acute B cell lymphoblastic leukemia in which AID accelerates disease 
progression18. This is promising, as a proof-of-concept study has been 
published that showed HSP90 inhibitors directly target AID in vivo, and 
endogenous humanAID is sensitive to them 18. Yet another study has 
suggested that targeting AID is bene�cial in the immunotherapy ofAID 
positive tumors because siRNA silencing of AID in plasmacytoma 
dramatically increases its susceptibility to immunotherapy by cytotoxic T 
lymphocytes15. Overall, AID has shown to be a promising target in the 
aforementioned instances and more research may yield additional insights.

Berkeley Pharma Tech Journal of Medicine | 115



Conclusion

Although further research will help the scientific community to glean more 
clear insights, it is clear that elucidating how AID works will help with the 
development of novel therapeutic strategies for a multitude of diseases. 
Disrupting the AID pathway can have potential therapeutic e�ects. 
However, it is important to remain cognizant of the fact that AID is a 
complex component of the human immune system, which is in and of itself 
a complex system. With that in mind, therapeutic approaches targeting AID 
must undergo a variety of testing and considerations.

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