The Common Key to Class-Switch Recombination and Somatic Hypermutation: Discovery of AID and Its Role in Antibody Gene Diversification

Leeman‐Neill, Rebecca J.; Lim, Jung Hyun; Basu, Uttiya

doi:10.4049/jimmunol.1801246

Cited by 7 publications

(2 citation statements)

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“…( 38 ) Following antigen recognition, B cells undergo thymus‐dependent or ‐independent activation, affinity maturation, and class switching. ( 39 ) Activated B cells can subsequently differentiate into antibody‐secreting plasma cells and memory B cells. ( 40 ) During thymus‐dependent activation, the antigen is bound by the B‐cell receptor (BCR), internalized, and presented to follicular Th cells, which become activated and provide signals to the B cell through CD40/CD40 ligand interactions and cytokines.…”

Section: B Cells and Their Subsetsmentioning

confidence: 99%

The Emerging Role of B Cells in the Pathogenesis of NAFLD

et al. 2021

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NAFLD is one of the leading causes of abnormal liver function worldwide. NAFLD refers to a group of liver conditions ranging from nonalcoholic fatty liver to NASH, which involves inflammation, hepatocellular damage, and fibrosis. Triggering of inflammation in NASH is a key event in the progression of the disease, and identifying the factors that initiate or dysregulate this process is needed to develop strategies for its prevention or treatment. B cells have been implicated in several autoimmune and inflammatory diseases. However, their role in the pathogenesis of NAFLD and NASH is less clear. This review discusses the emerging evidence implicating intrahepatic B cells in the progression of NAFLD. We highlight the potential mechanisms of B-cell activation during NAFLD, such as increased hepatic expression of B-cell-activating factor, augmented oxidative stress, and translocation of gut-derived microbial products. We discuss the possible effector functions by which B cells promote NAFLD, including the production of proinflammatory cytokines and regulation of intrahepatic T cells and macrophages. Finally, we highlight the role of regulatory and IgA + B cells in the pathogenesis of NASH-associated HCC. In this review, we make the case that future research is needed to investigate the potential of B-cell-targeting strategies for the treatment of NAFLD. (Hepatology 2021;0:1-10). The NAFLD Inflammatory Environment at a Glance Role oF INNate IMMUNe CellSThe liver receives a constant influx of gut-derived products and acts as a firewall for the antigen-rich

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Section: B Cells and Their Subsetsmentioning

confidence: 99%

The Emerging Role of B Cells in the Pathogenesis of NAFLD

et al. 2021

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“…Mutations are generated in the variable regions of the immunoglobulin (IG) heavy (IGH) and light chain (IGK, IGL) genes by activation-induced cytidine deaminase (AID) (5,6) which acts co-transcriptionally on single-stranded DNA (ssDNA) (7)(8)(9)(10)(11). AID also acts at the IGH switch regions triggering a reaction cascade leading to class switch recombination (CSR) which yields the various antibody isotypes essential for effector functions following antigen binding (12)(13)(14)(15). In addition, SHM occurs, albeit with much lower frequency, at several transcribed non-IG genes (16)(17)(18)(19)(20).…”

Section: Introductionmentioning

confidence: 99%

Somatic hypermutation patterns in immunoglobulin variable regions are established independently of the local transcriptional landscape

Schoeberl

Fitz

Froussios

et al. 2022

Preprint

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Somatic hypermutation (SHM) of immunoglobulin variable regions in B cells modulates antibody-antigen affinity and is indispensable for adaptive immunity. Mutations are introduced by activation-induced cytidine deaminase (AID) in a co-transcriptional manner resulting in discrete mutation spectra. Current models propose that activating epigenetic marks, transcriptional pausing and convergent transcription are necessary for optimal AID recruitment. However, whether these or other transcriptional features can explain the discrete mutation spectra is unknown. To address this, we compared mutation and nascent transcription at single nucleotide resolution. Surprisingly, with this precision, SHM spectra do not correlate with any transcriptional feature at human and mouse variable regions and non-immunoglobulin AID targets. Moreover, SHM is resistant to up to four-fold reduction of both activating epigenetic marks and transcription. We propose that, following AID recruitment to its target genes, the DNA sequence flanking an AID target motif is the key determinant of mutability rather than the local transcriptional and chromatin landscape.

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