Immunoglobulin class-switch recombination: Mechanism, regulation, and related diseases

Abstract

Maturation of the secondary antibody repertoire requires class-switch recombination (CSR), which switches IgM to other immunoglobulins (Igs), and somatic hypermutation, which promotes the production of high-affinity antibodies. Following immune response or infection within the body, activation of T cell-dependent and T cell-independent antigens triggers the activation of activation-induced cytidine deaminase, initiating the CSR process. CSR has the capacity to modify the functional properties of antibodies, thereby contributing to the adaptive immune response in the organism. Ig CSR defects, characterized by an abnormal relative frequency of Ig isotypes, represent a rare form of primary immunodeficiency. Elucidating the molecular basis of Ig diversification is essential for a better understanding of diseases related to Ig CSR defects and could provide clues for clinical diagnosis and therapeutic approaches. Here, we review the most recent insights on the diversification of five Ig isotypes and choose several classic diseases, including hyper-IgM syndrome, Waldenström macroglobulinemia, hyper-IgD syndrome, selective IgA deficiency, hyper-IgE syndrome, multiple myeloma, and Burkitt lymphoma, to illustrate the mechanism of Ig CSR deficiency. The investigation into the underlying mechanism of Ig CSR holds significant potential for the advancement of increasingly precise diagnostic and therapeutic approaches.

Keywords: B cell development; antibody diversification; genetic defects; immunodeficiency; isotype switching.

FIGURE 1

Pathogenesis of CSR deficiencies. CD40 interacts with CD40L and then activates downstream NEMO. NEMO removes the inhibitory subunits IκBα and releases reactive NF‐κB. NF‐κB is localized to the cell nucleus and regulates Ig production and CSR. The binding of TLR and MYD88 initiates two independent pathways, IRAK and BTK pathways. the former recruits IRAK1–4 and the later recruits PLCγ, DAG, and CARD11–BCL10–MALT1 complex, both pathways ultimately activate NEMO. Cytokines also affect Ig CSR. Upon binding with IL‐6R, IL‐6 initiates the JAK–PI3K–AKT signaling pathway, which then activates NEMO and contributes to Ig CSR. IL‐6 and IL‐21 both can activate STAT3 and enter the cell nucleus to regulate gene expression. Besides, IL‐4 has a JAK–STAT6 signaling pathway and exhibits a similar function as IL‐6 and IL‐21. TGF‐β activates SAMD2/3 and recruits SAMD4 to exert its function (Figure 2B). Schematic diagram of DNA breakage in the S region and the following genetic events including CSR, repairment, mutation, and translocation. AID initiates the deamination of cytosine to uracil in the S and IgV region, then UNG removes mismatched uracil and APE creates single‐stranded breaks (SSBs). When these SSBs escape from DNA repair, CSR, point mutation, and translocation happen. IKK, IκB kinase; TLR, toll‐like receptor; MYD, myeloid differentiation primary response protein; IRAK, interlukin‐1 receptor‐associated kinase; TRAF, TNF receptor‐associated factor; TAK, TGF‐activated kinase; BTK, Bruton's tyrosine kinase; PLC, phospholipase C; DAG, diacylglycerol; CARD, caspase recruitment domain‐ containing protein; MALT1, mucosa‐associated lymphoid tissue lymphoma translocation gene 1; JAK, Janus kinase; PI3K, phosphatidylinositol 3‐kinase; STAT, signal transducer and activator of transcription protein; SMAD, small mother against decapentaplegic protein; AID, activation‐induced deaminase; UNG, uracil DNA glycosylase; APE, apurinic/apyrimidinic endonuclease.

FIGURE 2

The dysregulation of AID can result in an increased mutational burden, translocation events, genomic instability, and the development of lymphoma. It also exhibits a certain inhibitory effect on polyreactive B cells.

FIGURE 3

AID enzyme generates uracil, which then undergoes the base excision repair (BER) pathway, or is recognized as U:G mismatch and subsequently enters the mismatch repair (MMR) pathway. During the repair of uracil residues, single‐strand DNA breaks (SSB) are generated, which then convert to double‐strand DNA breaks (DSB), and these DSBs are repaired through classical nonhomologous end joining (c‐NHEJ) to generate diverse BCR genomic repertoire.

FIGURE 4

The partial mechanisms of CSR involvement in the antiviral process are illustrated in the diagram. Viral proteins bind to the BCRs of follicular B cells, while viral RNA binds to TLR7. Viral infection can also induce the production of IFN γ through interaction with different cell types binding to B cell IFN γ R.

FIGURE 5

Production of IgM⁻IgD⁺ B cells and IgD antibody. IgM⁻IgD⁺ B cells are produced through TI and TD pathways with the help of DC cells, IL‐2, IL‐15, IL‐21, BAFF, APRIL, and so on, to perform their antibacterial function in mucosal immunity. BAFF, B cell activating factor; APRIL, a proliferation‐inducing ligand; MVK, mevalonate kinase.