Alternative mechanisms of receptor editing in autoreactive B cells

作者：Kalinina Olga; Doyle Cooper Colleen M; Miksanek Jennifer; Meng Wenzhao; Prak Eline Luning; Weigert Martin G^*

来源：Proceedings of the National Academy of Sciences of the United States of America, 2011, 108(17): 7125-7130.

DOI：10.1073/pnas.1019389108

• autoimmunity
• tolerance

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 kappa light (L) chains compatible with DNA binding with kappa L chains that harbor aspartic residues. This negatively charged amino acid is thought to neutralize Arg sites in the VH. Editing by replacement is allowed at the kappa locus, because the rearranged VJ is nested between unrearranged Vs and Js. However, neither lambda 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 kappa locus, kappa-/kappa- 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 lambda x. The editing mechanisms in the case of lambda-expressing B cells include L chain allelic inclusion and V(H) replacement.

• 出版日期2011-4-26