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. 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.

[1]  A. Szalai The antimicrobial activity of C-reactive protein. , 2002, Microbes and infection.

[2]  M. Nagata,et al.  C-reactive protein frequently localizes in the kidney in glomerular diseases. , 2001, Clinical nephrology.

[3]  N. Brot,et al.  C-Reactive Protein Binds to Apoptotic Cells, Protects the Cells from Assembly of the Terminal Complement Components, and Sustains an Antiinflammatory Innate Immune Response , 2000, The Journal of experimental medicine.

[4]  C. Mold,et al.  C-Reactive Protein Binding to Murine Leukocytes Requires Fcγ Receptors1 , 2000, The Journal of Immunology.

[5]  H. Colten,et al.  Modulation of Renal Disease in MRL/lpr Mice Genetically Deficient in the Alternative Complement Pathway Factor B1 , 2000, The Journal of Immunology.

[6]  D. Bharadwaj,et al.  The Major Receptor for C-Reactive Protein on Leukocytes Is Fcγ Receptor II , 1999 .

[7]  P. Butler,et al.  Serum amyloid P component controls chromatin degradation and prevents antinuclear autoimmunity , 1999, Nature Medicine.

[8]  L. Klein,et al.  CD4 T Cell Tolerance to Human C-reactive Protein, an Inducible Serum Protein, Is Mediated by Medullary Thymic Epithelium , 1998, The Journal of experimental medicine.

[9]  J. Volanakis,et al.  Testosterone and IL-6 requirements for human C-reactive protein gene expression in transgenic mice. , 1998, Journal of immunology.

[10]  J. Ravetch,et al.  Uncoupling of immune complex formation and kidney damage in autoimmune glomerulonephritis. , 1998, Science.

[11]  T. D. Du Clos,et al.  The effect of acute phase proteins on clearance of chromatin from the circulation of normal mice. , 1996, Journal of immunology.

[12]  M. Daha,et al.  Both IgG- and C1q-receptors play a role in the enhanced binding of IgG complexes to human mesangial cells. , 1996, Journal of the American Society of Nephrology : JASN.

[13]  J. Volanakis,et al.  Human C-reactive protein is protective against fatal Streptococcus pneumoniae infection in transgenic mice. , 1995, Journal of immunology.

[14]  L. Marnell,et al.  C-reactive protein binds to Fc gamma RI in transfected COS cells. , 1995, Journal of immunology.

[15]  T. Lint,et al.  Structure and function of the pentraxins. , 1995, Current opinion in immunology.

[16]  H. Colten,et al.  Cellular specificity of murine renal C3 expression in two models of inflammation. , 1994, Immunology.

[17]  T. Vischer,et al.  Absence of correlation between interleukin 6 and C-reactive protein blood levels in systemic lupus erythematosus compared with rheumatoid arthritis. , 1993, The Journal of rheumatology.

[18]  Y. Yazaki,et al.  Interrelationship between autoepitope, DNA-binding domain, and CRP-binding domain on a histone H1 molecule. , 1993, Clinical immunology and immunopathology.

[19]  H. Colten,et al.  Complement gene expression in hepatic and extrahepatic tissues of NZB and NZB x W (F1) mouse strains. , 1990, Immunology.

[20]  P. Butler,et al.  Pentraxin-chromatin interactions: serum amyloid P component specifically displaces H1-type histones and solubilizes native long chromatin , 1990, The Journal of experimental medicine.

[21]  C. Dinarello,et al.  Cytokines, Acute Phase Proteins, and Tissue Injury , 1990, Annals of the New York Academy of Sciences.

[22]  T. D. Du Clos,et al.  C-reactive protein reacts with the U1 small nuclear ribonucleoprotein. , 1989, Journal of immunology.

[23]  M. Pepys,et al.  Serum amyloid P component binds to cell nuclei in vitro and to in vivo deposits of extracellular chromatin in systemic lupus erythematosus , 1989, The Journal of experimental medicine.

[24]  T. D. Du Clos,et al.  Analysis of the binding of C-reactive protein to histones and chromatin. , 1988, Journal of immunology.

[25]  H. Colten,et al.  Local extrahepatic expression of complement genes C3, factor B, C2, and C4 is increased in murine lupus nephritis. , 1988, The Journal of clinical investigation.

[26]  M. Pepys,et al.  Amyloid P component binds to keratin bodies in human skin and to isolated keratin filament aggregates in vitro. , 1988, The Journal of investigative dermatology.

[27]  E. Wagner,et al.  Inducible and tissue‐specific expression of human C‐reactive protein in transgenic mice. , 1987, The EMBO journal.

[28]  A. Steinberg,et al.  C-reactive protein mediates the solubilization of nuclear DNA by complement in vitro , 1985, The Journal of experimental medicine.

[29]  C. Mold,et al.  C-reactive protein inhibits pneumococcal activation of the alternative pathway by increasing the interaction between factor H and C3b. , 1984, Journal of immunology.

[30]  J. Kearney,et al.  Demonstration of calcium-induced conformational change(s) in C-reactive protein by using monoclonal antibodies. , 1982, Molecular immunology.

[31]  M. Pepys,et al.  C-reactive protein in SLE. , 1982, Clinics in rheumatic diseases.

[32]  J. Schifferli,et al.  Complement-mediated inhibition of immune precipitation. I. Role of the classical and alternative pathways. , 1982, Clinical and experimental immunology.

[33]  J. Kearney,et al.  Anti-DNA autoantibodies in (NZB X NZW)F1 mice are clonally heterogeneous, but the majority share a common idiotype. , 1982, Journal of immunology.

[34]  G. Hughes,et al.  C-reactive protein levels in systemic lupus erythematosus: a classification criterion? , 1980, Arthritis and rheumatism.

[35]  V. Nussenzweig,et al.  Requirements for the solubilization of immune aggregates by complement. The role of the classical pathway. , 1978, The Journal of clinical investigation.

[36]  R. Siboo,et al.  Isolation of mouse C-reactive protein from liver and serum. , 1977, Journal of immunology.

[37]  M. Steward,et al.  Changes in immunoglobulin class and subclass of anti-DNA antibodies with increasing age in N/ZBW F1 hybrid mice. , 1976, Clinical and experimental immunology.

[38]  J. Volanakis,et al.  Interaction of C-reactive protein complexes with the complement system. I. Consumption of human complement associated with the reaction of C-reactive protein with pneumococcal C-polysaccharide and with the choline phosphatides, lecithin and sphingomyelin. , 1974, Journal of immunology.

[39]  B. J. Helyer,et al.  Renal Disease associated with Positive Lupus Erythematosus Tests in a Crossbred Strain of Mice , 1963, Nature.

[40]  A. Teppo,et al.  Serum C-reactive protein is rarely lost into urine in patients with secondary amyloidosis and proteinuria , 2005, Clinical Rheumatology.

[41]  C. Jacob,et al.  Definition of microsatellite size variants forTnfa andHsp70 in autoimmune and nonautoimmune mouse strains , 2004, Immunogenetics.

[42]  G. Appel,et al.  Advances in the treatment of lupus nephritis. , 2001, Annual review of medicine.

[43]  T. Vyse,et al.  Genetic susceptibility to systemic lupus erythematosus. , 1998, Annual review of immunology.

[44]  C. Mold,et al.  Decreased autoantibody levels and enhanced survival of (NZB x NZW) F1 mice treated with C-reactive protein. , 1994, Clinical immunology and immunopathology.

[45]  C. Mold,et al.  C-reactive protein and the acute phase response. , 1982, Advances in internal medicine.