Reduced receptor editing in lupus-prone MRL/lpr mice.
The initial B cell repertoire contains a considerable proportion of autoreactive specificities. The first major B cell tolerance checkpoint is at the stage of the immature B cell, where receptor editing is the primary mode of eliminating self-reactivity. The cells that emigrate from the bone marrow have a second tolerance checkpoint in the transitional compartment in the spleen. Although it is known that the second checkpoint is defective in lupus, it is not clear whether there is any breakdown in central B cell tolerance in the bone marrow. We demonstrate that receptor editing is less efficient in the lupus-prone strain MRL/lpr. In an in vitro system, when receptor-editing signals are given to bone marrow immature B cells by antiidiotype antibody or after in vivo exposure to membrane-bound self-antigen, MRL/lpr 3-83 transgenic immature B cells undergo less endogenous rearrangement and up-regulate recombination activating gene messenger RNA to a lesser extent than B10 transgenic cells. CD19, along with immunoglobulin M, is down-regulated in the bone marrow upon receptor editing, but the extent of down-regulation is fivefold less in MRL/lpr mice. Less efficient receptor editing could allow some autoreactive cells to escape from the bone marrow in lupus-prone mice, thus predisposing to autoimmunity.
Lamoureux
Jennifer L
JL
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Watson
Lisa C
LC
Cherrier
Marie
M
Skog
Patrick
P
Nemazee
David
D
Feeney
Ann J
AJ
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D001854:Bone Marrow Cells / Q000276:immunology / Q000502:physiology; D002478:Cells, Cultured; D020022:Genetic Predisposition to Disease; D015851:Interleukin-7 / Q000502:physiology; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D051379:Mice; D019463:Mice, Inbred MRL lpr; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction; D017393:RNA Editing / Q000235:genetics*; D011947:Receptors, Antigen, B-Cell / Q000235:genetics* / Q000502:physiology
D015851:Interleukin-7; D011947:Receptors, Antigen, B-Cell