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Somatic hypermutation

Somatic hypermutation (SHM) is a programmed mutagenesis process in activated B lymphocytes that introduces point mutations into the variable (V) regions of immunoglobulin genes, enabling the diversification and affinity maturation of antibodies during adaptive immune responses.^[1] This mechanism occurs at a remarkably high rate of approximately 10^{-3} mutations per base pair per generation, which is about a million-fold higher than the spontaneous genomic mutation rate, allowing B cells to rapidly evolve higher-affinity antibodies against pathogens.^[2] SHM takes place primarily in the germinal centers of secondary lymphoid organs, such as lymph nodes and spleen, during the germinal center reaction following antigen encounter and T cell help.^[1] The process is initiated by the enzyme activation-induced cytidine deaminase (AID), which deaminates cytosine to uracil in single-stranded DNA exposed during immunoglobulin gene transcription, creating U:G mismatches.^[1] These mismatches are then processed by error-prone DNA repair pathways: base excision repair involving uracil-DNA glycosylase (UNG) leads to C:G mutations, while mismatch repair with MutSα (MSH2-MSH6) generates A:T mutations, and translesion synthesis polymerases such as DNA polymerase η (Pol η) and Pol ζ extend the mutations across the lesion.^[1] The mutations are targeted to a ~2 kb region surrounding the rearranged V(D)J segments of immunoglobulin heavy and light chain loci, with hotspots at RGYW/WRCY motifs (R = purine, Y = pyrimidine, W = A/T) due to AID's sequence preference.^[1] Successful SHM contributes to affinity maturation, where B cells expressing antibodies with superior antigen binding undergo positive selection, proliferate, and differentiate into plasma cells or memory B cells, thereby enhancing humoral immunity.^[1] However, SHM is tightly regulated—through AID's nuclear export via CRM1 and cell-cycle restriction—to minimize off-target mutations that could promote genomic instability and B cell malignancies like lymphomas.^[1] Dysregulation of SHM pathways is implicated in immunodeficiencies and cancers, underscoring its dual role in immunity and disease.^[3]

Overview

Definition and Process

Somatic hypermutation (SHM) is a programmed mutagenic process that introduces point mutations into the variable regions of immunoglobulin genes in activated B cells, enabling the generation of antibodies with higher affinity for antigens.^[1] This process occurs at a rate of approximately $10^{-3} mutations per base pair per generation, which is about a million times higher than the spontaneous mutation rate in the genome.^[4] SHM primarily targets the complementarity-determining regions (CDRs) and framework regions (FWRs) of the immunoglobulin heavy and light chain variable genes, facilitating affinity maturation during the immune response.00706-7) SHM is initiated in germinal centers of secondary lymphoid organs, such as lymph nodes and spleen, following B cell activation by antigen exposure and T cell help. This microenvironment provides the necessary signals, including CD40 ligand interaction and cytokines, to induce the expression of key factors involved in the process. Only activated B cells undergoing proliferation in these germinal centers are competent for SHM, ensuring that mutations are confined to antigen-specific clones.^[5] The process begins with the transcription of immunoglobulin loci, which exposes single-stranded DNA regions accessible for modification.^[6] Activation-induced cytidine deaminase (AID) is then recruited to these transcribed regions, where it catalyzes the deamination of cytosine bases to uracils, creating U:G mismatches predominantly in the variable exons. These mismatches are subsequently processed by error-prone DNA repair mechanisms, which introduce point mutations including transitions at G:C pairs and transversions at both G:C and A:T pairs, thereby diversifying the antibody repertoire. Mutations are not randomly distributed but preferentially occur at specific hotspots defined by the RGYW/WRCY sequence motifs, where R denotes a purine (A or G), Y a pyrimidine (C or T), and W an A or T base.90612-n) For instance, the motif AGCT (an RGYW example) shows elevated mutation frequency due to AID's substrate preference for these sequences during deamination.^[7] This targeting enhances the efficiency of generating functional antibody variants while minimizing off-target effects.^[8]

Biological Significance

Somatic hypermutation (SHM) plays a pivotal role in generating antibody diversity by introducing point mutations into the variable regions of immunoglobulin genes in B cells, thereby expanding the repertoire beyond that achieved by V(D)J recombination alone and enabling more precise recognition of diverse pathogens.^[9] This diversification allows B cell receptors to evolve variants with enhanced binding specificity, facilitating the adaptive immune system's ability to mount effective responses against evolving antigens.^[9] In the process of affinity maturation, SHM contributes to the iterative selection of B cells bearing advantageous mutations within germinal centers, where mutated B cells compete for antigen and T cell help, leading to the proliferation of clones with superior antigen-binding properties.^[9] This selection pressure refines the antibody response over multiple rounds, culminating in the production of high-affinity antibodies that dominate the humoral immune output.^[10] SHM is evolutionarily conserved across jawed vertebrates (gnathostomes), where it is essential for humoral immunity through the action of activation-induced cytidine deaminase (AID), a gnathostome-specific enzyme absent in jawless vertebrates.^[11] Its absence, as seen in AID deficiencies causing hyper-IgM syndrome type 2, results in profound immunodeficiencies characterized by defective antibody diversification and recurrent infections due to reliance on low-affinity IgM responses.^[12] Quantitatively, SHM-driven affinity maturation can enhance antibody affinity by 100-fold in germinal center responses, with theoretical models indicating potential increases up to 1000-fold from unmutated precursors to optimized variants under optimal mutation and selection conditions.^[10]

Targeting

Sequence Specificity

Somatic hypermutation (SHM) exhibits a strong preference for specific sequence motifs known as hotspots, which guide the initial deamination events and subsequent mutations. The primary hotspots for cytosine deamination by activation-induced cytidine deaminase (AID) are the WRCY motifs on the non-template strand (where W is A or T, R is A or G, and Y is C or T), and their reverse complements, RGYW motifs, which target guanine bases.^[13]^[14] These motifs account for the majority of transition mutations at G/C pairs during the initial phase of SHM. For transversion mutations in the secondary phase, additional hotspots such as WA and TW motifs become prominent, reflecting the involvement of error-prone DNA polymerases like polymerase eta.^[14]^[15] Mutation patterns in SHM display notable biases influenced by the direction of transcription. The process preferentially mutates the non-transcribed (non-template) strand, leading to strand asymmetry where mutations are more frequent on the non-template strand, consistent with the direction of RNA polymerase progression and AID's access to single-stranded DNA.^[16]^[4] Furthermore, mutation rates are substantially higher in the variable (V) regions of immunoglobulin genes compared to the constant (C) regions, with SHM largely confined to VDJ segments and their immediate flanks, sparing the C regions to preserve effector functions.^[17]^[18] Although SHM is tightly targeted to immunoglobulin loci, low-level off-target mutations occur in non-immunoglobulin genes such as BCL6 and PAX5, contributing to potential oncogenic risks in B cells.^[19]^[20] These off-target effects are minimized by specific targeting factors that enhance AID recruitment to Ig loci while restricting activity elsewhere.^[21] Sequencing studies of mutated immunoglobulin genes in vivo have demonstrated that approximately 50-60% of all SHM events occur at these hotspot motifs, underscoring their central role in the mutation process.^[22] This enrichment highlights how sequence specificity ensures efficient diversification of antibody complementarity-determining regions while limiting deleterious mutations.^[13]

Genomic Loci Involvement

Somatic hypermutation (SHM) primarily targets the variable (V) regions of immunoglobulin (Ig) genes in mature B cells, specifically the rearranged V domains of heavy chain (VH) and light chain (Vκ and Vλ) genes. These loci undergo point mutations at rates approximately 10^6-fold higher than the genomic background, enabling the diversification of antibody binding sites during affinity maturation in germinal centers.^[23] The targeting is tightly focused on the V regions, extending roughly 1-2 kb downstream from the promoter, to introduce substitutions that can enhance antigen affinity without disrupting the overall gene structure.^[23] While SHM mainly affects V regions, it also occurs at lower levels in the switch (S) regions of the Ig heavy chain locus, which are involved in class-switch recombination (CSR). These S regions, located upstream of constant region genes, experience mutations that facilitate DNA breaks and recombination, though the process is distinct from V region hypermutation in frequency and outcome. However, the primary mutagenic activity remains confined to V loci to preserve antibody functionality.^[23] In pathological contexts, such as B cell lymphomas, SHM aberrantly targets non-Ig loci, including proto-oncogenes like MYC, BCL6, and PIM1, as well as tumor suppressors. These off-target mutations, often at rates similar to Ig loci, can deregulate gene expression and promote oncogenesis by altering promoter or enhancer regions, contributing to diseases like diffuse large B cell lymphoma.^[24] For instance, mutations in the 5' noncoding regions of MYC have been linked to transcriptional upregulation in germinal center-derived malignancies.^[25] Species-specific variations in SHM targeting arise from differences in Ig gene arrangements. In birds, such as chickens, the light chain locus features a single functional V gene diversified mainly by gene conversion from upstream pseudogenes, with SHM playing a secondary role limited to point mutations post-conversion in the bursa of Fabricius.^[26] Similarly, in rabbits (a lagomorph), the κ light chain locus is primarily diversified by gene conversion using upstream V gene segments in the appendix, where SHM occurs at reduced frequency compared to mammalian V regions, reflecting the pseudogene-rich organization.^[27]

Mechanisms

Activation-Induced Deaminase Role

Activation-induced cytidine deaminase (AID), encoded by the AICDA gene, is the enzyme that initiates somatic hypermutation (SHM) by deaminating deoxycytidine (dC) residues to deoxyuridine (dU) in DNA.00742-6) This process was first identified in 1999 by the Honjo laboratory through subtractive cDNA analysis of murine germinal center B cells, revealing AID as a novel member of the APOBEC family of RNA-editing deaminases specifically upregulated upon B cell activation.^[28] Mutations in AICDA cause autosomal recessive hyper-IgM syndrome type 2 (HIGM2), characterized by defective class-switch recombination and SHM due to impaired antibody diversification, as demonstrated in patient studies linking biallelic loss-of-function variants to the disease.00079-9) Structurally, AID is a compact protein of approximately 24 kDa, featuring a catalytic domain with a zinc-binding motif essential for its cytidine deaminase activity, and nuclear localization/export signals that regulate its subcellular distribution.^[29] Functionally, AID exhibits strict specificity for single-stranded DNA (ssDNA), binding and deaminating cytidines within transcription bubbles or other ssDNA regions, but not double-stranded DNA or RNA substrates. This ssDNA preference ensures targeted mutagenesis primarily at immunoglobulin loci during SHM, where deamination creates U:G mismatches that are subsequently processed to generate point mutations.^[29] AID expression is tightly restricted to activated B cells, particularly germinal center B lymphocytes undergoing antigen-driven selection, where it is induced by stimuli such as CD40 ligation and cytokines.^[28] This cell-type specificity prevents off-target mutagenesis in non-lymphoid tissues, with AID levels peaking transiently during the immune response to balance diversification and genomic stability. AID's deamination activity is transcription-dependent, occurring co-transcriptionally as the enzyme is recruited to immunoglobulin promoters where RNA polymerase II (Pol II) stalls or pauses, exposing ssDNA substrates on the non-template strand. Such Pol II stalling, often at promoter-proximal regions or transcription barriers, facilitates AID access and enhances mutation hotspots within variable region exons. In terms of kinetics, AID operates processively, deaminating multiple cytidines in a single binding event to produce clustered mutations that mimic the mutation patterns observed in SHM. This processivity, combined with downstream repair, drives the rapid generation of antibody diversity essential for affinity maturation.

DNA Repair Pathways

Somatic hypermutation relies on error-prone DNA repair pathways to convert cytosine deamination-induced uracils into point mutations, primarily in immunoglobulin variable regions. These pathways, including base excision repair (BER) and mismatch repair (MMR), process uracil lesions generated by activation-induced deaminase (AID), leading to nucleotide substitutions that diversify antibody sequences. Translesion synthesis (TLS) polymerases play a central role in introducing errors during gap filling, with the choice of pathway influencing mutation spectra. In the BER pathway, uracil-DNA glycosylase (UNG) recognizes and excises the AID-generated uracil, creating an abasic (AP) site.^[30] AP endonuclease 1 (APE1) then incises the phosphodiester backbone at the AP site, generating a single-strand break with a 3'-OH end.^[30] This lesion is processed by error-prone TLS polymerases, such as DNA polymerase η (Pol η), which preferentially inserts adenine opposite the AP site but can also insert guanine, resulting in C:G to T:A transitions or C:G to G:C transversions.^[4] Studies in UNG-deficient models demonstrate that BER contributes significantly to C/G-targeted mutations, with Pol η essential for a substantial portion of these events.^[31] The MMR pathway initiates when the MutSα heterodimer (MSH2/MSH6) binds the U:G mismatch formed by AID deamination.^[30] This recruits MutLα (MLH1/PMS2) and exonuclease 1 (EXO1), which resect the DNA strand containing the uracil, producing a single-stranded gap of several nucleotides.^[30] Error-prone TLS polymerases, including Pol η, Pol ι, and Pol ζ, then fill the gap; Pol η drives the majority of A:T mutations by inserting incorrect bases opposite undamaged template strands, while Pol ι and Pol ζ contribute to clustered or tandem mutations.^[4] In MSH2- or EXO1-deficient B cells, A:T mutagenesis is severely impaired, confirming MMR's dominance in generating these mutations.^[32] Alternative pathways involve direct TLS across unrepaired lesions, where polymerases like REV1 insert cytidine opposite AP sites or uracils, promoting C:G to G:C transversions, while replication forks stalling at lesions amplify mutational diversity through polymerase switching.^[30] Monoubiquitination of PCNA facilitates recruitment of these low-fidelity polymerases, enhancing error introduction during S-phase progression.^[4] The interplay of these pathways establishes a biphasic mutation pattern: phase 1, dominated by BER and replication errors, yields primarily C/G transitions (e.g., C to T), while phase 2, driven by MMR and TLS, introduces transversions at C/G pairs and mutations at A/T pairs, with polymerase selection (e.g., Pol η over high-fidelity Pol δ) determining the shift.^[30] This balance ensures broad sequence diversification without excessive genomic instability.^[4]

Somatic Gene Conversion

Somatic gene conversion represents an alternative mechanism to point mutations in somatic hypermutation, wherein activation-induced deaminase (AID) generates double-strand breaks in the immunoglobulin variable (V) region, which are subsequently repaired using upstream pseudogene sequences as templates through homologous recombination.^[33] This process replaces segments of the functional V gene with sequences from the pseudogenes, often targeting complementarity-determining regions (CDRs) to diversify the antibody repertoire while preserving the overall reading frame.^[26] The repair pathway, primarily synthesis-dependent strand annealing (SDSA), facilitates unidirectional transfer of DNA tracts ranging from 8 to 200 base pairs, with a 5' to 3' polarity.^[34] This mechanism is predominant in certain species, such as chickens and rabbits, where it drives most immunoglobulin diversification post-V(D)J recombination. In chickens, B cells in the bursa of Fabricius utilize a cluster of approximately 25 light chain pseudogenes and 80 heavy chain pseudogenes located upstream of the functional V gene to template conversions, enabling rapid diversification without reliance on junctional diversity from V(D)J recombination.^[34] Similarly, in rabbits, somatic gene conversion employs upstream VH pseudogenes to modify the predominantly used VH1 gene segment in heavy chain VDJ rearrangements, contributing to the majority of antibody variability.^[35] In contrast, mammals like humans and mice primarily rely on point mutations for diversification, with gene conversion playing a minor role.^[33] Unlike point somatic hypermutation, which introduces random single-nucleotide changes via error-prone DNA repair, gene conversion produces block replacements that incorporate pre-existing sequence variations from multiple pseudogene donors, thereby generating targeted diversity in CDRs while minimizing frameshifts.^[33] Evidence for this process in birds stems from sequencing studies in the bursa of Fabricius, where over one million gene conversion events were identified in chicken B cells, revealing repetitive CDR patterns derived from pseudogene templates and confirming the absence of junctional diversity as the primary source of variation.^[26] In rabbits, analysis of cloned VH1 rearrangements showed clusters of nucleotide replacements matching germline pseudogenes, underscoring gene conversion's role in mammalian B cell diversification.^[35]

Regulation

Cellular and Temporal Controls

Somatic hypermutation (SHM) is confined to germinal center (GC) B cells, specifically the rapidly dividing centroblasts located in the dark zone of the GC structure within secondary lymphoid organs. This restriction ensures that SHM does not occur in naive B cells prior to antigen encounter or in memory B cells that have exited the GC. The process requires T cell-dependent signals, particularly from follicular helper T (Tfh) cells, which express CD40 ligand (CD40L) to engage CD40 on GC B cells; this interaction is essential for B cell survival, proliferation, and the induction of activation-induced deaminase (AID), the enzyme driving SHM.^[36] Without CD40L-mediated help, GC formation and subsequent SHM are severely impaired, as demonstrated in CD40L-deficient models where B cells fail to enter the hypermutating phase.^[36] Temporally, SHM is tightly synchronized with the GC reaction, initiating as GCs emerge approximately 4–8 days after immunization in lymphoid tissues such as lymph nodes and spleen. The peak of SHM activity occurs around 4–7 days post-immunization, coinciding with the height of B cell proliferation in the dark zone, where cells undergo iterative divisions every 4–6 hours to amplify mutation opportunities.^[37] This coupling to the cell cycle ensures that mutations accumulate progressively with each division, but SHM is downregulated upon terminal differentiation into plasma cells, which exit the proliferative GC environment and cease AID expression. Regulatory checkpoints maintain the fidelity and efficiency of SHM; the rate of B cell proliferation directly modulates mutation load, with faster division cycles enabling higher cumulative mutations per clone over the GC lifespan. Apoptosis serves as a critical quality control mechanism, preferentially eliminating low-affinity B cell clones in the light zone through competition for Tfh signals and antigen, thereby pruning the repertoire to favor high-affinity variants.

Epigenetic Influences

Epigenetic modifications play a crucial role in facilitating access to immunoglobulin (Ig) loci for activation-induced deaminase (AID) during somatic hypermutation (SHM), thereby enabling targeted mutagenesis while restricting off-target activity. Histone modifications, in particular, create a permissive chromatin environment at SHM hotspots. The trimethylation of histone H3 at lysine 4 (H3K4me3) is enriched at variable (V) region genes and switch (S) regions of Ig loci, serving as a key mark that recruits AID through interaction with the transcription elongation factor Spt5. This modification is induced upon B cell activation and is essential for AID-mediated deamination, as disruption of H3K4me3 reduces SHM frequency without altering transcription levels. Additionally, histone acetylation, such as H3K9ac and H4K12ac, promotes chromatin opening at the V_H domain, enhancing accessibility for the transcription machinery and AID, with hyperacetylation observed specifically in mutating regions compared to non-mutating constant regions. DNA methylation dynamics further regulate SHM by modulating locus accessibility in a stage-specific manner. In germinal center B cells, where SHM predominantly occurs, DNA demethylation is observed at Ig promoters and enhancers following B cell activation, mediated in part by AID's deamination of 5-methylcytosine (5mC) to generate substrates for base excision repair and TET enzyme activity. This hypomethylation correlates with increased transcription and AID targeting at the V regions, contrasting with higher methylation levels in naive B cells. Conversely, hypermethylation at non-Ig loci and off-target sites maintains repressive chromatin states, preventing aberrant SHM and limiting mutagenesis to active Ig genes; for instance, methylated transgenes exhibit reduced mutability unless demethylated. Non-coding RNAs, including long non-coding RNAs (lncRNAs), contribute to precise AID recruitment by guiding the enzyme to specific genomic regions. Lariat-derived non-coding RNAs, generated from intron lariats during Ig transcription, interact with AID and the RNA exosome complex to direct deamination to single-stranded DNA exposed in R-loops at V and S regions. Similarly, divergently transcribed lncRNAs from promoter-associated antisense strands facilitate AID targeting by stabilizing RNA exosome activity and promoting local chromatin accessibility. Recent advances using CRISPR-based epigenome editing have elucidated the role of three-dimensional chromatin architecture in SHM regulation. Targeted disruption of CTCF binding sites at Ig enhancers and V regions alters loop extrusion mediated by cohesin, disrupting multiway chromatin hubs that bring distant enhancers into proximity with V segments. This results in reduced locus accessibility and diminished SHM rates, confirming that CTCF-anchored loops are critical for concentrating AID activity at Ig loci without impacting basal transcription.

Outcomes and Implications

Affinity Maturation

Affinity maturation is the process by which B cells in germinal centers iteratively refine antibody affinity through somatic hypermutation (SHM) followed by stringent selection, resulting in antibodies with enhanced binding strength to antigens.^[38] In the dark zone of germinal centers, centroblasts proliferate rapidly while undergoing SHM to introduce point mutations in immunoglobulin variable region genes, generating a diverse pool of B cell variants.^[39] These mutated B cells then migrate to the light zone, where they transition to centrocytes and compete for antigen displayed on follicular dendritic cells and for help from T follicular helper (Tfh) cells.^[39] In the light zone, competition dynamics favor B cells expressing higher-affinity antibodies, as they capture and internalize more antigen, leading to greater presentation of antigen-MHC complexes to Tfh cells and eliciting stronger CD40L and cytokine signaling, such as IL-21.^[39] High-affinity B cells receive these survival signals, which upregulate anti-apoptotic proteins like Bcl-xL, promoting their re-entry into the dark zone for further proliferation and mutation, while low-affinity counterparts undergo apoptosis due to insufficient signals.^[40] This iterative cycling—typically 5–6 divisions per round—amplifies advantageous mutations over multiple generations, with selected clones expanding clonally.^[38] Evidence from monoclonal antibody sequencing in germinal centers demonstrates progressive affinity increases, with early-stage clones showing low diversity and subsequent rounds yielding variants with 3–5 V_H mutations that boost affinity by 5- to 15-fold in dominant clones.^[38] Single-cell sequencing and imaging studies confirm that this selection reduces clonal diversity over time, as high-affinity lineages outcompete others, leading to homogenized populations of superior antibodies by late germinal center stages.^[38] Quantitative models of this Darwinian selection process highlight how SHM mutation rates must balance diversity generation with fidelity to avoid excessive deleterious mutations that could degrade affinity.^[10] Agent-based simulations show that a constant high mutation rate per cell division results in only about 25% of progeny maintaining or improving affinity after six divisions, whereas a decreasing rate—starting high for diversity and tapering to preserve gains—doubles success rates to 50% and enables larger clonal expansions of high-affinity cells.^[10] These models underscore the evolutionary optimization in germinal centers, where regulated SHM rates align with selection pressures to maximize long-term antibody efficacy.^[41]

Pathological Consequences

Dysregulation of somatic hypermutation (SHM) through deficiencies in key enzymes can result in severe immunodeficiencies, particularly hyper-IgM syndrome type 2 (HIGM2), an autosomal recessive disorder caused by mutations in the activation-induced cytidine deaminase (AID) gene.^[42] In AID-deficient patients, both SHM and class-switch recombination (CSR) are profoundly impaired, leading to elevated serum IgM levels, reduced or absent IgG, IgA, and IgE, and the inability to generate high-affinity antibodies or switch to other isotypes.^[43] This results in recurrent bacterial and opportunistic infections, including sinopulmonary infections, Pneumocystis jirovecii pneumonia, and gastrointestinal issues, often requiring immunoglobulin replacement therapy and prophylactic antibiotics.^[44] Similarly, mutations in uracil-DNA glycosylase (UNG), which processes AID-induced uracils during SHM, cause hyper-IgM syndrome type 5 (HIGM5), with comparable defects in SHM and CSR, manifesting as recurrent infections and lymphoid hyperplasia.^[45] Off-target SHM activity, where AID mutates non-immunoglobulin genes, can contribute to autoimmunity by generating self-reactive B cells or disrupting immune regulation. In systemic lupus erythematosus (SLE), somatic mutations in B cell receptor genes drive the emergence of autoreactive clones that produce anti-nuclear antibodies, with studies showing that the majority of such autoreactive B cells arise via SHM-like processes.^[46] These mutations can enhance B cell survival and affinity for self-antigens, exacerbating disease pathogenesis. In rheumatoid arthritis (RA), aberrant SHM in B cells within ectopic germinal centers promotes the production of rheumatoid factor and anti-citrullinated protein antibodies, further linking off-target mutagenesis to chronic inflammation.^[47] Specific non-Ig targets like inducible T-cell costimulator ligand (ICOSL) have been implicated in T-B cell interactions that amplify autoimmune responses.^[48] In oncology, off-target SHM by AID drives oncogenic transformation in B cell malignancies, particularly through mutations in proto-oncogenes. In follicular lymphoma (FL), AID aberrantly targets genes such as PIM1, a serine/threonine kinase, with mutations observed in approximately 30% of cases, often clustered in patterns resembling SHM hotspots.^[49] These mutations, including point substitutions and insertions/deletions, promote cell survival and proliferation, contributing to lymphomagenesis and disease progression, especially in high-risk FL subsets that harbor elevated somatic mutation burdens.^[50] Similar AID off-target effects are seen in other B cell lymphomas, underscoring SHM's dual role in adaptive immunity and cancer initiation.^[51] Therapeutic strategies targeting SHM dysregulation hold promise for mitigating these pathologies. Small-molecule inhibitors of AID have been developed to suppress off-target mutagenesis, potentially reducing autoantibody production in autoimmune diseases like SLE while preserving baseline immune function.^[52] In B cell cancers, modulating error-prone DNA polymerases involved in SHM repair pathways, such as polymerase eta, is an emerging approach; preclinical studies suggest their inhibition could limit mutation accumulation in chronic lymphocytic leukemia (CLL), where SHM contributes to clonal evolution, though dedicated clinical trials remain in early phases as of 2025.^[53]

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We herein report mutations in the human counterpart of AID in patients with the autosomal recessive form of hyper-IgM syndrome (HIGM2).
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Mutations of the Activation-Induced Cytidine Deaminase (AID) gene have been found in patients with autosomal recessive hyper-IgM (HIGM) syndrome type 2.
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