Delayed lupus onset in (NZB x NZW)F1 mice expressing a human C-reactive protein transgene.
OBJECTIVE
Human C-reactive protein (CRP) binds apoptotic cells and alters blood clearance of injected chromatin in mice. To test whether CRP participates in the pathogenesis of systemic lupus erythematosus (SLE), we examined disease development in lupus-prone (NZB x NZW)F(1) (NZB/NZW) mice expressing a human CRP transgene (hCRPtg/BW).


METHODS
Mortality was monitored, proteinuria was determined by dipstick, and serum levels of human CRP and anti-double-stranded DNA (anti-dsDNA) were determined by enzyme-linked immunosorbent assay in NZB/NZW and hCRPtg/BW mice. Thin sections of kidneys were analyzed by immunofluorescence microscopy to compare deposition of IgG, IgM, C3, and human CRP, and electron microscopy was used to reveal differences in ultrastructure. In situ hybridization was performed to detect human CRP messenger RNA expression.


RESULTS
The hCRPtg/BW mice had less proteinuria and longer survival than NZB/NZW mice. They also had lower IgM and higher IgG anti-dsDNA titers than NZB/NZW mice, although the differences were transient and small. In hCRPtg/BW mice, accumulation of IgM and IgG in the renal glomeruli was delayed, reduced, and more mesangial than in NZB/NZW mice, while end-stage accumulation of IgG, IgM, and C3 in the renal cortex was prevented. There was less glomerular podocyte fusion, basement membrane thickening, mesangial cell proliferation, and occlusion of capillary lumens in hCRPtg/BW mice, but dense deposits in the mesangium were increased. With disease progression in hCRPtg/BW mice, there was little rise in the plasma CRP level, but CRP in the kidneys became increasingly apparent due to local, disease-independent, age-related expression of the transgene.


CONCLUSIONS
In hCRPtg/BW mice, CRP protects against SLE by increasing blood and mesangial clearance of immune complexes and by preventing their accumulation in the renal cortex.
Szalai
Alexander J
AJ
The University of Alabama at Birmingham.
Weaver
Casey T
CT
McCrory
Mark A
MA
van Ginkel
Frederik W
FW
Reiman
Rachael M
RM
Kearney
John F
JF
Marion
Tony N
TN
Volanakis
John E
JE
D000818:Animals; D000974:Antibodies, Antinuclear / Q000032:analysis; D002097:C-Reactive Protein / Q000235:genetics* / Q000378:metabolism; D002196:Capillaries / Q000648:ultrastructure; D003176:Complement C3 / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D020022:Genetic Predisposition to Disease; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D007075:Immunoglobulin M / Q000378:metabolism; D007678:Kidney Glomerulus / Q000098:blood supply / Q000378:metabolism / Q000648:ultrastructure; D008136:Longevity; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008814:Mice, Inbred NZB; D008822:Mice, Transgenic; D019076:Transgenes
D000974:Antibodies, Antinuclear; D003176:Complement C3; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D002097:C-Reactive Protein