Central and peripheral RAG protein re-expression: underestimate mechanisms of tolerance?
The generation of developing B cells in the bone marrow is regulated by recombination activating genes RAG1 and RAG2 proteins. They contribute to the synthesis of functional antibodies (Abs) that can present self-reactivities following V(D)J (V, variable; D, diversity and J, joining) recombination. The emergence of autoreactive B cells is prevented by deletion through apoptosis, by stimulation blockade through anergy, or by synthesis of a new B-cell receptor through receptor edition. In the periphery, somatic hypermutation during the course of germinal centre (GC) responses can lead to the appearance of autoreactive and low-affinity Ab-producing B cells. Apoptotic deletion and receptor revision regulate these autoreactive and inappropriate B cells. Moreover, the presence of RAG-positive B cells outside GCs suggest that still uncharacterized regulation checkpoint, associated with secondary V(D)J recombination, also contribute to the regulation of autoreactivities. Failure in central and/or peripheral tolerance mechanisms associated with RAG expression could contribute to the terminal differentiation of autoreactive B cells leading to autoimmune states.
Hillion
S
S
Laboratory of Immunology, Brest University Medical School Hospital, F-29609 Brest, France.
Rochas
C
C
Devauchelle
V
V
Youinou
P
P
Jamin
C
C
D000818:Animals; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D001853:Bone Marrow / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D018858:Germinal Center / Q000502:physiology; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D007108:Immune Tolerance; D051379:Mice; D018448:Models, Immunological
D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C064655:V(D)J recombination activating protein 2; C064658:RAG-1 protein