Autoreactive B cells escape clonal deletion by expressing multiple antigen receptors.
IgH and L chain transgenes encoding a phosphocholine (PC)-specific Ig receptor were introduced into recombinase-activating gene (Rag-2-/-) knockout mice. The PC-specific B cells that developed behaved like known autoreactive lymphocytes. They were 1) developmentally arrested in the bone marrow, 2) unable to secrete Ab, 3) able to escape clonal deletion and develop into B1 B cells in the peritoneal cavity, and 4) rescued by overexpression of bcl-2. A second IgL chain was genetically introduced into Rag-2-/- knockout mice expressing the autoreactive PC-specific Ig receptor. These dual L chain-expressing mice had B cells in peripheral lymphoid organs that coexpressed both anti-PC Ab as well as Ab employing the second available L chain that does not generate an autoreactive PC-specific receptor. Coexpression of the additional Ig molecules rescued the autoreactive anti-PC B cells and relieved the functional anergy of the anti-PC-specific B cells, as demonstrated by detection of circulating autoreactive anti-PC-Abs. We call this novel mechanism by which autoreactive B cells can persist by compromising allelic exclusion receptor dilution. Rescue of autoreactive PC-specific B cells would be beneficial to the host because these Abs are vital for protection against pathogens such as Streptococcus pneumoniae.
Kenny
J J
JJ
Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA. kennyj@grc.nia.nih.gov
Rezanka
L J
LJ
Lustig
A
A
Fischer
R T
RT
Yoder
J
J
Marshall
S
S
Longo
D L
DL
D000818:Animals; D016175:B-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D017635:Clonal Anergy / Q000235:genetics; D017637:Clonal Deletion / Q000235:genetics* / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D018985:Epitopes, B-Lymphocyte / Q000378:metabolism; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007145:Immunoglobulin kappa-Chains / Q000235:genetics; D007136:Immunoglobulins / Q000096:biosynthesis / Q000097:blood; D008213:Lymphocyte Activation / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010529:Peritoneal Cavity / Q000166:cytology; D010767:Phosphorylcholine / Q000276:immunology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000502:physiology; D011947:Receptors, Antigen, B-Cell / Q000096:biosynthesis* / Q000378:metabolism / Q000502:physiology; D019076:Transgenes / Q000276:immunology
D004268:DNA-Binding Proteins; D018985:Epitopes, B-Lymphocyte; D007143:Immunoglobulin Heavy Chains; D007145:Immunoglobulin kappa-Chains; D007136:Immunoglobulins; D019253:Proto-Oncogene Proteins c-bcl-2; C499308:Rag2 protein, mouse; D011947:Receptors, Antigen, B-Cell; C064655:V(D)J recombination activating protein 2; D010767:Phosphorylcholine