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. 2021 Oct 8;6(19):e148887. doi: 10.1172/jci.insight.148887

Figure 9. A model for autoantibody production in patients with hypomorphic RAG mutations.

Figure 9

Autoreactive immature B cells are normally eliminated by at least 3 mechanisms: deletion (apoptosis), anergy (functional inactivation), and receptor editing (48). Receptor editing is mediated by RAG1 and RAG2 and functions to remove autoreactive immature B cells by changing the specificity of the BCR. As proposed by Notarangelo et al. (4) and others (23, 49), hypomorphic RAG mutation impairs receptor editing and thus allows some autoreactive immature B cells to exit the BM and become TrB cells. Due to the B cell lymphopenic environment that causes increased levels of BAFF, autoreactive TrB cells were able to survive and become mature naive B cells. We think that these naive B cells possibly acquire the CD27–IgD– DN or memory B phenotype as a result of homeostatic proliferation. Such DN B and memory B cells can efficiently differentiate into plasma cells upon stimulation with TLR ligands and cytokines (Figure 8G) or with foreign or self-antigens, and secrete large numbers of Abs, including autoantibodies.