Toll-like receptor 7-dependent loss of B cell tolerance in pathogenic autoantibody knockin mice.
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.
Berland
Robert
R
Department of Pathology, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
Fernandez
Luis
L
Kari
Elina
E
Han
Jin-Hwan
JH
Lomakin
Ina
I
Akira
Shizuo
S
Wortis
Henry H
HH
Kearney
John F
JF
Ucci
Angelo A
AA
Imanishi-Kari
Thereza
T
D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis* / Q000502:physiology; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D051199:Toll-Like Receptor 7 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D001323:Autoantibodies; D008562:Membrane Glycoproteins; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7