JCI Insight (Oct 2021)

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

Journal volume & issue
Vol. 6, no. 19

Abstract

Read online

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.

Keywords