Decreased Autoantibody Levels and Enhanced Survival of (NZB × NZW) F1 Mice Treated with C-Reactive Protein

Clos, Terry W. Du; Zlock, Lorna; Hicks, Phillip; Mold, Carolyn

doi:10.1006/clin.1994.1005

Cited by 75 publications

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“…This finding confirms and extends earlier observations made by Du Clos et al (21), who showed that 26-week-old NZB/NZW mice injected repeatedly with chromatincoated latex beads pretreated with human CRP lived longer than age-matched animals injected with untreated chromatin-coated beads. In those experiments, CRP did not alter the IgM and IgG anti-DNA response, the beneficial effect of CRP was short-lived, and protection was not observed in 19-week-old mice.…”

Section: Discussionsupporting

confidence: 92%

“…In comparison, we found that in our transgenic NZB/NZW mice, expression of human CRP was associated with slight and transient, but significant, lowering of IgM anti-dsDNA autoantibody titers, and slight and transient elevation of IgG1, IgG2a, and IgG2b anti-dsDNA titers. Precisely how human CRP changes the tempo and repertoire of the anti-dsDNA response in NZB/NZW mice is not known with certainty, but the data from both our study and that by Du Clos et al are consistent with the proposal by Du Clos and colleagues (21) that this is a consequence of altered clearance and/or processing of autoantigens by circulating CRP. Such a process could hasten the isotype switch and might also explain the apparent discordance in the IgM and IgG results.…”

Section: Discussionsupporting

confidence: 89%

“…In those experiments, CRP did not alter the IgM and IgG anti-DNA response, the beneficial effect of CRP was short-lived, and protection was not observed in 19-week-old mice. The transient nature of the CRP protective effect was attributed to development of anti-CRP responses in mice given human CRP (21). In comparison, we found that in our transgenic NZB/NZW mice, expression of human CRP was associated with slight and transient, but significant, lowering of IgM anti-dsDNA autoantibody titers, and slight and transient elevation of IgG1, IgG2a, and IgG2b anti-dsDNA titers.…”

Section: Discussionmentioning

confidence: 54%

“…Furthermore, in SLE, and probably in other diseases, CRP can potentially mediate an immunoregulatory effect by binding and opsonizing apoptotic cells (18). Importantly in mice, where CRP is not an acutephase protein and is only a trace serum component (19), injected human CRP alters the clearance of administered chromatin (20) and offers transient protection against murine lupus in the NZB/NZW strain (21).…”

mentioning

confidence: 99%

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

Szalai

Weaver

McCrory

et al. 2003

Arthritis & Rheumatism

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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.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 54%

mentioning

confidence: 99%

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

Szalai

Weaver

McCrory

et al. 2003

Arthritis & Rheumatism

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“…CRP may inhibit antibody (Ab) responses to antigens by epitope blocking, a possible mechanism for inhibition of the immune responses to self-antigens [11]. CRP may be protective against the development of autoimmunity [12] and anti-inflammation [13] in mice, however human CRP does not protect mice against lipopolysaccharide (LPS) lethality [14]. Additionally, CRP has been shown to be protective against bacterial infections [15], a variety of inflammatory conditions and various mediators of inflammation [16].…”

Section: Introductionmentioning

confidence: 99%

C‐reactive protein impairs human CD14⁺ monocyte‐derived dendritic cell differentiation, maturation and function

Zhang¹,

Becnel

Li³

et al. 2006

Eur J Immunol

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C-reactive protein (CRP) is an acute phase reactant protein considered to be the prototypic marker for inflammation and its associated diseases. However, little is known about how CRP affects the immune system. In this study, we investigated the effect of CRP on dendritic cell (DC) differentiation, activation and biological functions. CD14 + monocytes were purified from PBMC and differentiated into DC in vitro. CRP (10 lg/ mL) substantially down-regulated expression of DC-SIGN (CD209) and the costimulatory molecules CD40 and CD86 during DC differentiation. This inhibitory effect was more pronounced when CRP was added at the early stage (0-2 days) of DC differentiation. The inhibitory effect of CRP could be specifically blocked by an anti-CD32 Ab. In addition, CRP dramatically down-regulated expression of the antigenuptake molecules CD205 and CD206, resulting in reduced DC endocytosis. Furthermore, CRP down-regulated expression of the costimulatory molecules CD40, CD80 and CD86 as well as the DC maturation marker CD83 after lipopolysaccharideinduced DC maturation. CRP-treated DC also showed an inhibitory effect on allogeneic T cell proliferation in a mixed leukocyte reaction. CRP treatment of activated DC preferentially decreased production of the proinflammatory and inflammatory cytokines IL-6, IL-8, IL-12, TNF-a, MIP-1a, MIP-1b and MCP-1. This work reveals a new role for CRP in modulating the immune system by inhibiting DC differentiation, maturation and functions mainly through FccRIIa/CD32.

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Pentraxins

Mold

Sun

Clos

2012

Encyclopedia of Life Sciences

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The pentraxin family of proteins is characterised by sequence and structural homology and calcium‐dependent ligand binding. The human pentraxins are C‐reactive protein (CRP) and serum amyloid P component (SAP), the former of which is a strong acute phase protein. The activities of CRP and SAP are mediated through the classical complement pathway and through activation of Fc receptors (FcRs). Pentraxins are pattern recognition molecules that play important roles in host defence and control of inflammation. Measurement of CRP in blood has been used to monitor inflammation and infection and more recently to predict cardiovascular disease. Recent studies suggest that each of the pentraxins plays a role in the regulation of inflammation and tissue fibrosis. Knockout and transgenic models suggest that these effects are due to interaction with FcRs on macrophages and dendritic cells. Ongoing laboratory studies and clinical trials suggest that pentraxins may have therapeutic benefits. Key Concepts: Pentraxins form a family of proteins based on structural homology and calcium‐dependent ligand binding. Pentraxins are serum proteins that are important in host defence and regulation of the inflammatory response. The functional activities of CRP and SAP are mediated by complement activation and by interaction with Fc receptors on leucocytes. Structurally pentraxins are planar pentamers with five calcium‐dependent ligand‐binding sites on one face and a binding site for a single Fc receptor on the opposite face. CRP and SAP are the two members of the pentraxin family found in most animals. Human CRP is a strong acute phase reactant made in the liver in response to tissue injury or infection. CRP is often used to monitor inflammation or infection because of its rapid synthesis and clearance. CRP has anti‐inflammatory activity mediated through Fcγ receptors in a number of mouse autoimmune models and in endotoxin shock. SAP inhibits fibrocyte differentiation and prevents fibrosis in pulmonary and renal models. Genetic polymorphisms in noncoding regions of the CRP gene determine baseline levels of CRP and are the risk factors for systemic lupus erythematosus, but not cardiovascular disease.

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Decreased Autoantibody Levels and Enhanced Survival of (NZB × NZW) F1 Mice Treated with C-Reactive Protein

Cited by 75 publications

References 0 publications

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

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

C‐reactive protein impairs human CD14⁺ monocyte‐derived dendritic cell differentiation, maturation and function

Pentraxins

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Decreased Autoantibody Levels and Enhanced Survival of (NZB × NZW) F1 Mice Treated with C-Reactive Protein

Cited by 75 publications

References 0 publications

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

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

C‐reactive protein impairs human CD14+ monocyte‐derived dendritic cell differentiation, maturation and function

Pentraxins

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Product

Resources

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

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

C‐reactive protein impairs human CD14⁺ monocyte‐derived dendritic cell differentiation, maturation and function