title: Alternative mechanisms of receptor editing in autoreactive B cells.
abstract: Pathogenic anti-DNA antibodies expressed in systemic lupus erythematosis bind DNA mainly through electrostatic interactions between the positively charged Arg residues of the antibody complementarity determining region (CDR) and the negatively charged phosphate groups of DNA. The importance of Arg in CDR3 for DNA binding has been shown in mice with transgenes coding for anti-DNA V(H) regions; there is also a close correlation between arginines in CDR3 of antibodies and DNA binding. Codons for Arg can readily be formed by V(D)J rearrangement; thereby, antibodies that bind DNA are part of the preimmune repertoire. Anti-DNAs in healthy mice are regulated by receptor editing, a mechanism that replaces κ light (L) chains compatible with DNA binding with κ L chains that harbor aspartic residues. This negatively charged amino acid is thought to neutralize Arg sites in the V(H). Editing by replacement is allowed at the κ locus, because the rearranged VJ is nested between unrearranged Vs and Js. However, neither λ nor heavy (H) chain loci are organized so as to allow such second rearrangements. In this study, we analyze regulation of anti-DNA H chains in mice that lack the κ locus, κ-/κ- mice. These mice show that the endogenous preimmune repertoire does indeed include a high frequency of antibodies with Arg in their CDR3s (putative anti-DNAs) and they are associated mainly with the editor L chain λx. The editing mechanisms in the case of λ-expressing B cells include L chain allelic inclusion and V(H) replacement.
authors.affiliation: Department of Pathology, Gwen Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, IL 60637.
authors.forename: Olga
authors.initials: O
authors.lastname: Kalinina
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Doyle-Cooper
authors.forename: Jennifer
authors.initials: J
authors.lastname: Miksanek
authors.forename: Wenzhao
authors.initials: W
authors.lastname: Meng
authors.forename: Eline Luning
authors.initials: EL
authors.lastname: Prak
authors.forename: Martin G
authors.initials: MG
authors.lastname: Weigert
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000235:genetics* / Q000276:immunology; D015551:Autoimmunity / Q000235:genetics* / Q000276:immunology; D001402:B-Lymphocytes; D001483:Base Sequence; D022801:Complementarity Determining Regions / Q000235:genetics* / Q000276:immunology; D015322:Gene Rearrangement, B-Lymphocyte / Q000235:genetics* / Q000276:immunology; D056426:Genetic Loci / Q000235:genetics / Q000276:immunology; D007143:Immunoglobulin Heavy Chains / Q000235:genetics / Q000276:immunology; D007147:Immunoglobulin Light Chains / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D011947:Receptors, Antigen, B-Cell / Q000235:genetics* / Q000276:immunology
chemical_list: D000974:Antibodies, Antinuclear; D022801:Complementarity Determining Regions; D007143:Immunoglobulin Heavy Chains; D007147:Immunoglobulin Light Chains; D011947:Receptors, Antigen, B-Cell