RRC ID 68420
Author Min Q, Meng X, Zhou Q, Wang Y, Li Y, Lai N, Xiong E, Wang W, Yasuda S, Yu M, Zhang H, Sun J, Wang X, Wang JY.
Title RAG1 splicing mutation causes enhanced B cell differentiation and autoantibody production.
Journal JCI Insight
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.
Volume 6(19)
Published 2021-10-8
DOI 10.1172/jci.insight.148887
PII 148887
PMID 34622798
PMC PMC8525647
MeSH Autoantibodies / immunology* Autoimmune Diseases / genetics* Autoimmune Diseases / immunology Autoimmune Diseases / therapy B-Lymphocytes / immunology* Child Cord Blood Stem Cell Transplantation Fatal Outcome Granuloma / genetics* Granuloma / immunology Granuloma / therapy Homeodomain Proteins / genetics* Homeodomain Proteins / metabolism Homozygote Humans Immunoglobulin G / immunology Immunoglobulin M / immunology Immunologic Deficiency Syndromes / genetics* Immunologic Deficiency Syndromes / immunology Immunologic Deficiency Syndromes / therapy Immunologic Memory / immunology Lymphopenia / genetics Lymphopenia / immunology Lymphopoiesis / genetics* Lymphopoiesis / immunology Male Plasma Cells / immunology RNA Splice Sites / genetics Receptors, Antigen, B-Cell / immunology* V(D)J Recombination / genetics
IF 6.205
Human and Animal Cells NALM-6(RCB1933)