RAG1 splicing mutation causes enhanced B cell differentiation and autoantibody production.
JCI Insight
; 6(19)2021 10 08.
Article
en En
| MEDLINE
| ID: mdl-34622798
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Autoanticuerpos
/
Enfermedades Autoinmunes
/
Linfocitos B
/
Receptores de Antígenos de Linfocitos B
/
Proteínas de Homeodominio
/
Linfopoyesis
/
Granuloma
/
Síndromes de Inmunodeficiencia
Tipo de estudio:
Etiology_studies
Límite:
Child
/
Humans
/
Male
Idioma:
En
Revista:
JCI Insight
Año:
2021
Tipo del documento:
Article
País de afiliación:
China