Heterogeneity and clinical significance of glomerular-binding antibodies in systemic lupus erythematosus.
We used an ELISA employing extracts of human glomerular basement membrane (GBM) to detect, characterize, and evaluate the clinical significance of glomerular-binding IgG in patients with SLE nephritis. Most patients with SLE nephritis exhibited GBM-binding IgG, although many patients with active nonrenal SLE or symptomatic, drug-induced lupus had similar reactivity, albeit at lower levels. IgG binding to GBM in SLE nephritis patients was decreased by DNase pretreatment of GBM, restored after DNase with nuclear antigens (most notably with nucleosomes), inhibited by exogenous nuclear antigens (particularly nucleosomes), but unaffected by exposure of serum to DNase/high ionic strength. The characteristics of IgG binding to GBM largely paralleled the patients' underlying autoimmune response, which was dominated either by antibodies to DNA/nucleosomes or to nucleosomes alone. Binding of lupus sera to nonrenal extracellular matrix (even with nucleosomes) was not equivalent to GBM. Collagenase pretreatment of GBM variably decreased IgG binding, depending on the level and type of binding. SLE nephritis patients with high levels of GBM-binding IgG exhibited more severe disease clinically, but the same renal histopathology, as patients with lower levels. The level of GBM-binding IgG at presentation did not predict the therapeutic response, but decreased in responders to therapy. In sum, glomerular-binding IgG in lupus nephritis binds to epitopes on chromatin, which adheres to GBM in part via collagen. These autoantibodies appear necessary, but not sufficient, for the development of nephritis, and correlate with clinical rather than histopathologic parameters of disease activity.
Lefkowith
J B
JB
Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA. jlefkowith@imgate.wustl.edu
Kiehl
M
M
Rubenstein
J
J
DiValerio
R
R
Bernstein
K
K
Kahl
L
L
Rubin
R L
RL
Gourley
M
M
D015551:Autoimmunity; D001485:Basement Membrane / Q000737:chemistry / Q000187:drug effects / Q000276:immunology; D001666:Binding Sites, Antibody / Q000187:drug effects; D002843:Chromatin / Q000276:immunology; D017364:Collagenases / Q000494:pharmacology; D004247:DNA / Q000276:immunology; D003851:Deoxyribonucleases / Q000494:pharmacology; D000939:Epitopes / Q000276:immunology; D005109:Extracellular Matrix / Q000276:immunology; D005921:Glomerulonephritis / Q000097:blood / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology*; D007678:Kidney Glomerulus / Q000276:immunology*; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000276:immunology*; D009707:Nucleosomes / Q000235:genetics / Q000276:immunology; D014020:Tissue Extracts / Q000276:immunology
D002843:Chromatin; D000939:Epitopes; D007074:Immunoglobulin G; D009707:Nucleosomes; D014020:Tissue Extracts; D004247:DNA; D003851:Deoxyribonucleases; D017364:Collagenases