Immunization with an apoptotic cell-binding protein recapitulates the nephritis and sequential autoantibody emergence of systemic lupus erythematosus.
The initial events predisposing to loss of tolerance in patients with systemic lupus erythematosus (SLE) are largely unknown, as are the events that precipitate the transition from preclinical to overt disease. We hypothesized that induction of murine SLE would require tipping the balance between tolerance and immunity in two ways: 1) an immunogen that could take advantage of apoptotic cells as a scaffold for epitope spread, and 2) an immune activator that would generate a strong and persistent T cell response to the inciting immunogen. We show that immunization of C57BL/6 and BALB/c mice with human beta(2)-glycoprotein I, an apoptotic cell-binding protein, in the presence of LPS induces a long-lived, potent response to beta(2)-glycoprotein I that results in epitope spread to multiple SLE autoantigens. SLE-specific autoantibodies emerged in a sequential manner that recapitulated the order seen in human SLE. Moreover, immunized mice developed overt glomerulonephritis closely resembling human lupus nephritis.
Levine
Jerrold S
JS
Section of Nephrology, Department of Medicine, The University of Illinois, Chicago, IL 60612, USA.
Subang
Rebecca
R
Nasr
Samih H
SH
Fournier
Sylvie
S
Lajoie
Ginette
G
Wither
Joan
J
Rauch
Joyce
J
D000818:Animals; D017152:Antibodies, Antiphospholipid / Q000096:biosynthesis; D017209:Apoptosis / Q000276:immunology; D001323:Autoantibodies / Q000096:biosynthesis / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology; D018106:CD28 Antigens / Q000276:immunology; D004195:Disease Models, Animal; D007108:Immune Tolerance; D007114:Immunization; D016056:Immunodominant Epitopes / Q000276:immunology; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000276:immunology; D007075:Immunoglobulin M / Q000096:biosynthesis / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000473:pathology; D008181:Lupus Nephritis / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D017634:Self Tolerance / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D017152:Antibodies, Antiphospholipid; D001323:Autoantibodies; D001324:Autoantigens; D018106:CD28 Antigens; D016056:Immunodominant Epitopes; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha