Expression and reexpression of recombination activating genes: relevance to the development of autoimmune states.
Like all antibodies, autoreactive antibodies are generated in developing B cells in the bone marrow by variable (V), diversity (D), and joining (J) recombination under the regulation of recombination activating gene (RAG) 1 and RAG2 proteins. Deletion, anergy, and receptor edition prevent the emergence of autoreactive B cells. In the periphery, somatic hypermutation during the course of germinal center responses can lead to the emergence of autoreactive and low-affinity antibody-producing B cells. Deletion and receptor revision regulate autoreactive and inappropriate B cells. Defects in central or peripheral tolerance mechanisms associated with RAG expression could contribute to the appearance of autoreactive B cells. We demonstrate the presence of RAG(+) B cells in CD5-expressing cells outside germinal centers. Our data suggest that receptor revision in the periphery also may occur in unusual sites when B cells are induced to express CD5. This revision may correspond to a novel regulation checkpoint in which impaired control of RAG expression could generate autoreactive B cells and lead to autoimmune states.
Hillion
Sophie
S
Laboratory of Immunology, Brest University Medical School Hospital, BP824, F29609 Brest, France.
Rochas
Caroline
C
Youinou
Pierre
P
Jamin
Christophe
C
D000818:Animals; D015551:Autoimmunity / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology* / Q000502:physiology; D018956:CD5 Antigens / Q000276:immunology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology*; D005786:Gene Expression Regulation / Q000276:immunology*; D016654:Genes, RAG-1; D018398:Homeodomain Proteins / Q000235:genetics / Q000276:immunology*; D006801:Humans; D018448:Models, Immunological; D009687:Nuclear Proteins; D011995:Recombination, Genetic
D018956:CD5 Antigens; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; C499311:RAG2 protein, human; C064655:V(D)J recombination activating protein 2; C064658:RAG-1 protein