2 Role of RAG1 and RAG2 in B-cell development | 21 Receptor editing and allelic exclusion Considering the vast diversity of antibody specificities, B cells must continuously ensure the specificities against pathogens, while averting autoreactivity. Consequently, B cells undergo multiple screening checkpoints during their development to assess their autoreactivity levels. The initial screening occurs following the differentiation of pro-B cells into pre-B cells. The antigen-independent tonic pre-BCR promotes the progression of pre-B cells with non-autoreactive pre-BCR to the next developmental stage. Lack of tonic preBCR signaling leads to apoptosis. However, several studies addressing the mechanism of central tolerance have uncovered that autoreactive B cells may undergo another round of Igl chain gene recombination as an attempt to “edit” the autoreactive pre-BCR or BCR and thus escape apoptosis. This ongoing gene recombination, known as receptor editing, may change receptor specificity and this contributes to repertoire diversification24,25. At the same time, receptor editing, and the ongoing exposure of the pre-B cells to RAG1/2-recombinase, may be a potential source of genomic instability. The concept of B-cell monospecificity has long been pivotal in explaining the targeted production of antibodies against specific pathogens. Referred to as the ‘one B-cell - one antibody’ rule, this paradigm finds substantial support in numerous experimental studies. At the genetic level, the monospecificity of B cells arises from the so-called allelic exclusion, mechanism ensuring that each B cell produces antibodies with a single specificity. B cells with multiple different specificities could lead to autoimmune reactions or ineffective immune responses26,27. It has been demonstrated that successful recombination on one allele initiated signaling suppressing bi-allelic recombination by terminating RAG1 and RAG2 expression as well as the accessibility of the Ig locus. Several mechanisms have been proposed to explain how simultaneous rearrangement of both alleles is prevented. The asynchronous recombination models rely on mechanisms regulating the accessibility. These models propose two main mechanisms: the probabilistic model and the instructive model. In the probabilistic model, the chromatin (in)accessibility leads to asynchronous recombination, as the inaccessible Ig chromatin/allele leads to slow and inefficient recombinations, limiting the frequency of recombination events to one allele per cell. The instructive model is based on the asynchronous replication timing of the two alleles. The early-replicating allele is recombined first, while the late-replicating allele is recombined only if the recombination attempt on the first allele failed27,28. The stochastic model suggests that while Ig recombination is highly efficient, it typically yields only one functional Ig allele per cell. This concept implies that Ig allelic exclusion occurs due to the low probability of rearranging an allele in the correct reading frame, resulting in a functional Ig chain, compared to the higher likelihood of generating a non-functional allele. Consequently, no coordination between the two Ig alleles is deemed necessary, rendering asynchrony of allelic recombination inconsequential in this model29. On the other hand, feedback inhibition models propose that the recombination process of Ig genes is inhibited by their
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