Journal
JOURNAL OF IMMUNOLOGY
Volume 177, Issue 9, Pages 6504-6516Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.177.9.6504
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Funding
- Canadian Institutes of Health Research [42391, 67101] Funding Source: Medline
- NHLBI NIH HHS [HL 69722] Funding Source: Medline
- NIDDK NIH HHS [DK 59793, R01 DK059793] Funding Source: Medline
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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 ss(2)-glycoprotein I, an apoptotic cell-binding protein, in the presence of LPS induces a long-lived, potent response to ss(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.
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