title: Ig knock-in mice producing anti-carbohydrate antibodies: breakthrough of B cells producing low affinity anti-self antibodies.
abstract: Natural Abs specific for the carbohydrate Ag Galalpha1-3Galbeta1-4GlcNAc-R (alphaGal) play an important role in providing protective host immunity to various pathogens; yet little is known about how production of these or other anti-carbohydrate natural Abs is regulated. In this study, we describe the generation of Ig knock-in mice carrying functionally rearranged H chain and L chain variable region genes isolated from a B cell hybridoma producing alphaGal-specific IgM Ab that make it possible to examine the development of B cells producing anti-carbohydrate natural Abs in the presence or absence of alphaGal as a self-Ag. Knock-in mice on a alphaGal-deficient background spontaneously developed alphaGal-specific IgM Abs of a sufficiently high titer to mediate rejection of alphaGal expressing cardiac transplants. In the spleen of these mice, B cells expressing alphaGal-specific IgM are located in the marginal zone. In knock-in mice that express alphaGal, B cells expressing the knocked in BCR undergo negative selection via receptor editing. Interestingly, production of low affinity alphaGal-specific Ab was observed in mice that express alphaGal that carry two copies of the knocked in H chain. We suggest that in these mice, receptor editing functioned to lower the affinity for self-Ag below a threshold that would result in overt pathology, while allowing development of low affinity anti-self Abs.
authors.affiliation: Transplantation Research Center, Brigham and Women's Hospital, Children's Hospital Boston and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Benatuil
authors.forename: Joel
authors.initials: J
authors.lastname: Kaye
authors.forename: Nathalie
authors.initials: N
authors.lastname: Cretin
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Godwin
authors.forename: Annaiah
authors.initials: A
authors.lastname: Cariappa
authors.forename: Shiv
authors.initials: S
authors.lastname: Pillai
authors.forename: John
authors.initials: J
authors.lastname: Iacomini
mesh_terms: D000818:Animals; D000918:Antibody Specificity; D001323:Autoantibodies / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D016175:B-Lymphocyte Subsets / Q000166:cytology* / Q000201:enzymology / Q000276:immunology*; D001666:Binding Sites, Antibody / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D005700:Galactosyltransferases / Q000235:genetics / Q000276:immunology*; D006825:Hybridomas; D007143:Immunoglobulin Heavy Chains / Q000096:biosynthesis / Q000235:genetics; D007147:Immunoglobulin Light Chains / Q000096:biosynthesis / Q000235:genetics; D007075:Immunoglobulin M / Q000096:biosynthesis; D007135:Immunoglobulin Variable Region / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D014312:Trisaccharides / Q000235:genetics / Q000276:immunology*
chemical_list: D001323:Autoantibodies; D007143:Immunoglobulin Heavy Chains; D007147:Immunoglobulin Light Chains; D007075:Immunoglobulin M; D007135:Immunoglobulin Variable Region; D014312:Trisaccharides; C076569:alpha-galactosyl epitope; D005700:Galactosyltransferases; C047006:N-acetyllactosaminide alpha-1,3-galactosyltransferase