RAG1 splicing mutation causes enhanced B cell differentiation and autoantibody production
Qing Min, Xin Meng, Qinhua Zhou, Ying Wang, Yaxuan Li, Nannan Lai, Ermeng Xiong, Wenjie Wang, Shoya Yasuda, Meiping Yu, Hai Zhang, Jinqiao Sun, Xiaochuan Wang, Ji-Yang Wang
Qing Min, Xin Meng, Qinhua Zhou, Ying Wang, Yaxuan Li, Nannan Lai, Ermeng Xiong, Wenjie Wang, Shoya Yasuda, Meiping Yu, Hai Zhang, Jinqiao Sun, Xiaochuan Wang, Ji-Yang Wang
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Research Article Immunology

RAG1 splicing mutation causes enhanced B cell differentiation and autoantibody production

Abstract

Hypomorphic RAG1 or RAG2 mutations cause primary immunodeficiencies and can lead to autoimmunity, but the underlying mechanisms are elusive. We report here a patient carrying a c.116+2T>G homozygous splice site mutation in the first intron of RAG1, which led to aberrant splicing and greatly reduced RAG1 protein expression. B cell development was blocked at both the pro-B to pre-B transition and the pre-B to immature B cell differentiation step. The patient B cells had reduced B cell receptor repertoire diversity and decreased complementarity determining region 3 lengths. Despite B cell lymphopenia, the patient had abundant plasma cells in the BM and produced large quantities of IgM and IgG Abs, including autoantibodies. The proportion of naive B cells was reduced while the frequency of IgD–CD27– double-negative (DN) B cells, which quickly differentiated into Ab-secreting plasma cells upon stimulation, was greatly increased. Immune phenotype analysis of 52 patients with primary immunodeficiency revealed a strong association of the increased proportion of DN B and memory B cells with decreased number and proportion of naive B cells. These results suggest that the lymphopenic environment triggered naive B cell differentiation into DN B and memory B cells, leading to increased Ab production.

Authors

Qing Min, Xin Meng, Qinhua Zhou, Ying Wang, Yaxuan Li, Nannan Lai, Ermeng Xiong, Wenjie Wang, Shoya Yasuda, Meiping Yu, Hai Zhang, Jinqiao Sun, Xiaochuan Wang, Ji-Yang Wang

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Figure 9

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

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A model for autoantibody production in patients with hypomorphic RAG mut...
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.