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
• Journal: JCI insight (JCI Insight) Vol. 6 Issue 19 (10 08 2021) ISSN: 2379-3708 [Electronic] United States
• PMID: 34622798 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Autoantibodies
• Homeodomain Proteins
• Immunoglobulin G
• Immunoglobulin M
• RNA Splice Sites
• Receptors, Antigen, B-Cell
• RAG-1 protein

Topics

• Autoantibodies (immunology)
• Autoimmune Diseases (genetics, immunology, therapy)
• B-Lymphocytes (immunology)
• Child
• Cord Blood Stem Cell Transplantation
• Fatal Outcome
• Granuloma (genetics, immunology, therapy)
• Homeodomain Proteins (genetics, metabolism)
• Homozygote
• Humans
• Immunoglobulin G (immunology)
• Immunoglobulin M (immunology)
• Immunologic Deficiency Syndromes (genetics, immunology, therapy)
• Immunologic Memory (immunology)
• Lymphopenia (genetics, immunology)
• Lymphopoiesis (genetics, immunology)
• Male
• Plasma Cells (immunology)
• RNA Splice Sites (genetics)
• Receptors, Antigen, B-Cell (immunology)
• V(D)J Recombination (genetics)