Delayed lupus onset in (NZB × NZW)F₁ mice expressing a human C‐reactive protein transgene

Abstract

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 lupusprone (NZB ؋ 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.Conclusion. 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.

Neointimal formation is reduced after arterial injury in human crp transgenic mice

“…CRP suppresses neutrophil chemotaxis [39] and superoxide generation [40] that are associated with neointimal formation. CRP confers protection against autoimmune diseases: CRPtg are relatively insensitive to murine systemic lupus [41], and experimental allergic encephalomyelitis [42]. Furthermore, CRP upregulated the expression of complement inhibitory factors on endothelial cells [43], suggesting that CRP may protect from complement-mediated vascular injury implicated in intimal hyperplasia [44].…”

Transgenic human C-reactive protein is not proatherogenic in apolipoprotein E-deficient mice

“…In addition, there may be different regulation of the human transgene compared with autologous murine SAP and C3, which showed no increased production. It is known, for example, that the transgene is aberrantly expressed in this model, with abundant CRP production in the kidney and other tissues, whereas CRP in humans is produced in significant amounts only by the liver (49). Baseline CRP concentration in humans shows a strong positive relationship with obesity (50)(51)(52), and, although at 1 yr the weights of the apoE Ϫ/Ϫ mice were only Ϸ6% greater than those of the apoE ϩ/ϩ animals, a difference that was not statistically significant, there may perhaps be differences in their adipose tissue.…”

C-reactive protein, immunoglobulin G and complement co-localize in renal immune deposits of proliferative lupus nephritis

“…Furthermore, in 2 murine lupus models, subcutaneous CRP injections delayed the disease onset, reversed nephritis, and prolonged the survival of the animals [18,19].…”