[PDF][PDF] Toll-like receptor 7-dependent loss of B cell tolerance in pathogenic autoantibody knockin mice

R Berland, L Fernandez, E Kari, JH Han, I Lomakin… - Immunity, 2006 - cell.com
R Berland, L Fernandez, E Kari, JH Han, I Lomakin, S Akira, HH Wortis, JF Kearney, AA Ucci…
Immunity, 2006cell.com
Systemic lupus erythematosus (SLE) is characterized by the production of autoantibodies
that are frequently directed against nucleic acid-associated antigens. To better understand
how B cells reactive with such antigens are regulated, we generated a model system in
which heavy and light chain genes encoding 564 immunoglobulin have been targeted to the
heavy and light chain loci of the nonautoimmune C57BL/6 mouse strain. This antibody
recognizes RNA, single-stranded DNA, and nucleosomes. We show that B cells expressing …
Summary
Systemic lupus erythematosus (SLE) is characterized by the production of autoantibodies that are frequently directed against nucleic acid-associated antigens. To better understand how B cells reactive with such antigens are regulated, we generated a model system in which heavy and light chain genes encoding 564 immunoglobulin have been targeted to the heavy and light chain loci of the nonautoimmune C57BL/6 mouse strain. This antibody recognizes RNA, single-stranded DNA, and nucleosomes. We show that B cells expressing this immunoglobulin were activated, producing class-switched autoantibody in vivo despite the apparently normal induction of anergy. This autoantibody production was largely dependent on Toll-like receptor 7 (TLR7). We further show that production of these autoantibodies was sufficient to cause kidney pathology in these mice. These results demonstrate that the particular threat of nucleic acid-containing autoantigens lies in their ability to bind both antigen receptor and TLR7.
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