Early anti-nucleosome autoantibodies from a single MRL+/+ mouse: fine specificity, V gene structure and pathogenicity.
In systemic lupus erythematosus, the nucleosome assumes a central role in the autoimmune response to self antigens. To gain insight into the etiology and pathogenesis of anti-nucleosome antibodies (Ab), we analyzed a panel of six IgG-secreting hybridomas derived from a single young MRL +/+ mouse at the onset of the autoimmune response. All monoclonal antibodies (mAb) bound exclusively the native nucleosome, and represented five different clonotypes that recognized diverse nucleosomal epitopes, typical of a polyclonal response. The VH-complementarity-determining region (CDR)3 regions exhibited unique stretches of charged amino acids with different polarity that may be important for the interaction with the nucleosome. These early anti-nucleosome mAb displayed striking structural differences with not only anti-DNA, but also with anti-nucleosome Ab, that appear later in disease. Two of the mAb deposited in kidney glomeruli after in vivo administration to RAG-1-deficient mice, suggesting that diverse B cell clones, possibly selected by the nucleosome itself, may play a role in the initiation of kidney damage.
Jovelin
F
F
Groupe de Recherche en Immunopathologie (Institut de Recherche Multidisciplinaire sur les Peptides, IFR 23), Faculté mixte de Médecine et de Pharmacie, Centre Hospitalier Charles Nicolle, Rouen, France.
Mostoslavsky
G
G
Amoura
Z
Z
Chabre
H
H
Gilbert
D
D
Eilat
D
D
Bach
J F
JF
Koutouzov
S
S
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000276:immunology; D001323:Autoantibodies / Q000235:genetics* / Q000276:immunology / Q000633:toxicity; D001483:Base Sequence; D000939:Epitopes; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D007668:Kidney / Q000473:pathology; D051379:Mice; D019463:Mice, Inbred MRL lpr; D008969:Molecular Sequence Data; D009707:Nucleosomes / Q000276:immunology*
D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D000939:Epitopes; D007135:Immunoglobulin Variable Region; D009707:Nucleosomes