Phospholipid-binding proteins differ in their capacity to induce autoantibodies and murine systemic lupus erythematosus.
We have previously shown that immunization of nonautoimmune mice with the phospholipid-binding protein β2-glycoprotein I (β2GPI), in combination with lipopolysaccharide (LPS), induces a murine model of systemic lupus erythematosus (SLE), with sequential emergence of autoantibodies and glomerulonephritis. Here, we determine whether the paradigm for induction of murine SLE extends to other phospholipid-binding proteins. Mice were immunized with a phospholipid-binding protein (prothrombin (PT), protein S, or β2GPI), or a nonphospholipid-binding protein (glu-plasminogen), in the presence of LPS. The breadth and degree of the autoantibody response, and the frequency of glomerulonephritis, varied among the three proteins, with β2GPI being the most effective in inducing SLE-like disease. The phospholipid-binding proteins also differed in the pattern of serum cytokines they elicited. The most apparent difference between β2GPI and the other phospholipid-binding proteins was in their ability to bind to LPS: β2GPI bound to LPS, while PT and protein S did not. Our data suggest that binding to phospholipid(s) is a necessary, but not sufficient, condition for full induction of murine SLE. We propose that other properties, such as physiologic function, avidity for anionic phospholipids, and degree of interaction with other cell surface and/or circulating molecules (particularly LPS) may determine the range and severity of disease.
Section of Nephrology, Department of Medicine, University of Illinois at Chicago, and Section of Nephrology, Department of Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, IL, USA.
J S
JS
Levine
Division of Rheumatology, Department of Medicine, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada.
R
R
Subang
Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA.
S
S
Setty
Department of Pathology, Advocate Lutheran General Hospital, Park Ridge, IL, USA.
J
J
Cabrera
Division of Rheumatology, Department of Medicine, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada.
P
P
Laplante
Departments of Medicine and Biochemistry & Molecular Biology, University of Calgary, Calgary, Alberta, Canada.
M J
MJ
Fritzler
Division of Rheumatology, Department of Medicine, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada joyce.rauch@mcgill.ca.
J
J
Rauch
D000818:Animals; D001323:Autoantibodies / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011516:Prothrombin / Q000502:physiology*; D053482:beta 2-Glycoprotein I / Q000502:physiology*
D001323:Autoantibodies; D053482:beta 2-Glycoprotein I; D011516:Prothrombin
antiphospholipid antibodies; murine models; phospholipid-binding proteins; systemic lupus erythematosus; β2-glycoprotein I