RS rearrangement frequency as a marker of receptor editing in lupus and type 1 diabetes

The Rockefeller University Press $30.00 J. Exp. Med. Vol. 205 No. 13 2985-2994 www.jem.org/cgi/doi/10.1084/jem.20082053 2985 B cells undergo a random process of V(D)J recombination to generate the many distinct receptors needed to recognize a vast array of antigens. An inevitable consequence of this random process is the production of autoreactive B cells ( 1 ). An important mechanism for tolerizing autoreactive B cells is receptor editing ( 2 ). Receptor editing results in the alteration of B cell receptor specifi city and is achieved by ongoing Ig gene rearrangement, most commonly at the light chain loci ( 3 – 5 ). Light chain rearrangement proceeds in an ordered fashion as B cells develop in the bone marrow, with genes recombining fi rst, followed by rearrangement of the recombining sequence (RS) and ( 6, 7 ). The RS (also known as the  deleting element [KDE] in humans) is a noncoding gene segment located 25 kb downstream of C in the  locus that is rearranged during continued Ig light chain gene rearrangement ( 8, 9 ). Because of the unique structure of the locus, primary V -J rearrangements that are nonfunctional or autoreactive can be replaced via “ leap-frogging ” recombination of unrearranged upstream V and downstream J gene segments to form new  light chains ( Fig. 1 a ). Additional rearrangement attempts can be made through recombination at the second  allele or at  . Recombination of RS to upstream V gene segments or a recombination signal sequence within the J  -C intron results in the deletion or inversion of C and functional inactivation of the  locus ( Fig. 1 a ). Because RS rearrangements do not encode any functional proteins ( 10 ), monitoring RS rearrangement provides a specifi city-independent means of measuring repeated rearrangement attempts at (receptor editing). The original studies characterizing RS recombination postulated that it served to promote rearrangement by either repressing rearrangement or activating the  locus ( 7, 11 ). However, -expressing B cells can form without undergoing RS rearrangement, indicating that RS is not required for the production of  ( 12 ). When RS rearrangement is prevented in RS knockout mice, receptor editing is ineffi cient and autoreactive B cells are found among peripheral cells ( 13 ), highlighting the potential role of RS in establishing central tolerance and reducing light chain allelic and isotypic inclusion. Current clinical assays that evaluate B lymphocyte tolerance focus on serum autoantibodies, which are products of mature B cells. Because secreted autoantibodies are an end product rather than an intermediate, they do not distinguish between autoimmunity that arose CORRESPONDENCE Eline T. Luning Prak: [email protected]