22 | Chapter 2 products or intermediates. In the classical feedback inhibition model, successful Ig gene rearrangements activate signals through pre-BCRs or B-cell receptors (BCRs), leading to the suppression of further allelic recombination30,31. This model explains the observed ratios of peripheral B cells with Igh and Igl loci in different configurations32. A more recent study proposes a mechanistic explanation based on the fact that only the mRNA transcripts from productively rearranged Igh allele are stable, whereas the non-productive Igh mRNA transcripts carry multiple stop-codons and are degraded by nonsense-mediated mRNA decay. Therefore, it was hypothesized that it is the stable mRNA transcript of productively rearranged Igh is responsible for the allelic exclusion33. However, a more detailed investigation of this mechanism provided compelling evidence showing that the Igh mRNA actually does not play a role in allelic exclusion, and that it is the Igh protein complex that enforces the allelic exclusion and drives B cell development34. In addition, the RAG2 C-terminus and ataxia-telangiectasia mutated (ATM) were shown to prevent the bi-allelic gene recombination35. In fact, the double-stranded DNA breaks (DSBs) arising from the RAG1/2 activity, which activate the DNA damage sensor ATM, have been proposed to trigger a negative feedback loop limiting the RAG expression. Inhibition or deletion of ATM resulted in bi-allelic recombinations and an increase in genomic instability in developing B cells36. From mature B-cell to plasma cell Immature B cells exit the bone marrow and travel to the spleen, where they complete their early development by differentiating into naïve, follicular, or marginal zone (MZ) B cells. In secondary lymphoid organs, mature B cells encounter antigens presented by antigen-presenting cells (APCs), such as dendritic cells. Upon recognition of specific antigens by their BCRs, B cells become activated and undergo clonal expansion. Activated B cells that receive appropriate signals from helper T cells differentiate into plasma cells. Plasma cells are specialized for antibody production and secrete large quantities of antibodies. A subset of activated B cells differentiates into memory B cells, which persist long-term and provide a rapid and robust secondary immune response upon re-exposure to the same antigen37. The first antibodies produced in a humoral immune response are always of the IgM isotype. However, mature B cells may undergo so-called class-switch recombination (CSR) changing the antibody isotype. There are 5 antibody isotypes: IgG (subclasses IgG1, IgG2, IgG3, and IgG4), IgA (subclasses IgA1 and IgA2), IgM, IgD, and IgE. Exons that encode for these antibody classes are named g (g1, g2, g3, and g4), a (a1 and a2), m, d, and e. Different isotypes have adapted to function in different body compartments, for instance, IgA is predominantly present in secretions such as saliva, digestive tract, or nasal secretions, while IgG is primarily present in the blood serum38. In addition to CSR, the affinity and other biological properties of the immunoglobulins can be further modified without changing their specificity in a process termed somatic hypermutation (SHM). Both CSR and SHM are
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