Kappa editing rescues autoreactive B cells destined for deletion in mice transgenic for a dual specific anti-laminin Ig.
We explored mechanisms involved in B cell self-tolerance in a double- and triple-transgenic mouse model bearing the LamH-C mu Ig H chain conventional transgene and a gene-targeted replacement for a functional V kappa 8J kappa 5 L chain gene. Whereas the H chain is known to generate anti-laminin Ig in combination with multiple L chains, the H + L Ig binds ssDNA in addition to laminin. Immune phenotyping indicates that H + L transgenic B cells are regulated by clonal deletion, receptor editing via secondary rearrangements at the nontargeted kappa allele, and anergy. Collectively, the data suggest that multiple receptor-tolerogen interactions regulate autoreactive cells in the H + L double-transgenic mice. Generation of H + LL triple-transgenic mice homozygous for the targeted L chain to exclude secondary kappa rearrangements resulted in profound B cell depletion with absence of mature B cells in the bone marrow. We propose that the primary tolerogen of dual reactive B cells in this model is not ssDNA, but a strongly cross-linking tolerogen, presumably basement membrane laminin, that triggers recombination-activating gene activity, L chain editing, and deletion.
Brady
Graham F
GF
Department of Medicine, Duke University and Durham Veterans Administration Medical Centers, Durham, NC 27710, USA.
Congdon
Kendra L
KL
Clark
Amy G
AG
Sackey
Faustina N A
FN
Rudolph
Earl H
EH
Radic
Marko Z
MZ
Foster
Mary H
MH
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000235:genetics; D000918:Antibody Specificity / Q000235:genetics*; D001323:Autoantibodies / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D017637:Clonal Deletion / Q000235:genetics*; D015328:Gene Rearrangement, B-Lymphocyte, Light Chain; D007127:Immunoglobulin Constant Regions / Q000235:genetics; D007143:Immunoglobulin Heavy Chains / Q000096:biosynthesis / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D007145:Immunoglobulin kappa-Chains / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D007148:Immunoglobulin mu-Chains / Q000096:biosynthesis; D007797:Laminin / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017393:RNA Editing / Q000276:immunology; D017634:Self Tolerance / Q000235:genetics*; D013154:Spleen / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014162:Transfection
D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D007127:Immunoglobulin Constant Regions; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D007145:Immunoglobulin kappa-Chains; D007148:Immunoglobulin mu-Chains; D007797:Laminin