Autoimmune NZB/NZW F1 mice utilize B cell receptor editing for generating high-affinity anti-dsDNA autoantibodies from low-affinity precursors.
We have previously constructed knock-in (C57BL/6xBALB/c) F1 mice, each expressing an anti-DNA heavy (H) chain (D42), combined with one of three different light (L) chains, namely Vkappa1-Jkappa1, Vkappa4-Jkappa4 or Vkappa8-Jkappa5. All of these H/L chain combinations bind DNA with similar affinity and fine specificity. However, while mice carrying Vkappa1-Jkappa1-transgenic L chain were tolerized almost exclusively by L chain receptor editing, the mice expressing Vkappa8-Jkappa5 L chains utilized clonal anergy as their principal mechanism of B cell tolerance. Vkappa4-Jkappa4 targeted mice exhibited an intermediate phenotype. In the present study, these three H/L chain combinations were backcrossed onto the autoimmune NZB/NZW F1 mice. We find that the mechanism of clonal anergy is abrogated in these mice, but that receptor editing is maintained. Moreover, diseased NZB/NZW mice utilize L chain secondary rearrangements for the generation of high-affinity, anti-dsDNA-producing B cells from low-affinity precursors. The edited B cell clones are not deleted or anergized in the autoimmune animal; rather they are selected for activation, class-switching and affinity maturation by somatic mutation. These results suggest that B cell receptor editing plays an important role not only in tolerance induction, but also in generating high-affinity autoreactive B cells in autoimmune diseases.
Yachimovich-Cohen
Nurit
N
Department of Medicine, Hadassah University Hospital, Faculty of Medicine, Hebrew University, Jerusalem, Israel.
Fischel
Ruth
R
Bachar
Neta
N
Yarkoni
Yuval
Y
Eilat
Dan
D
D000818:Animals; D000917:Antibody Formation / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology*; D001483:Base Sequence; D004247:DNA / Q000276:immunology* / Q000378:metabolism; D007143:Immunoglobulin Heavy Chains / Q000235:genetics / Q000276:immunology; D051379:Mice; D008814:Mice, Inbred NZB; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D011947:Receptors, Antigen, B-Cell / Q000276:immunology*
D001323:Autoantibodies; D007143:Immunoglobulin Heavy Chains; D011947:Receptors, Antigen, B-Cell; D004247:DNA