Local extrahepatic expression of complement genes C3, factor B, C2, and C4 is increased in murine lupus nephritis.

Passwell, J H; Schreiner, George F.; Nonaka, Manabu; Beuscher, H U; Colten, Harvey R.

doi:10.1172/jci113780

Cited by 150 publications

(93 citation statements)

References 32 publications

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“…However, we do know that in hCRPtg/BW mice, there is a virtual absence of immune complex deposition in the renal cortex and an increased accumulation of dense deposits in the glomerular mesangium, and we think this is informative. As we demonstrated here for C3, other complement proteins are also expressed by the renal epithelium in murine lupus nephritis (33)(34)(35). CRP is known to activate complement via the classical pathway (14), and the classical pathway plays an important physiologic role by preventing the formation of immune complexes (36).…”

Section: Discussionsupporting

confidence: 57%

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: 57%

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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“…Our earlier studies with Crry demonstrated that complement activation was critical for the pathology in lupus cerebritis [5]. Furthermore, fB, an important component of the alternative pathway, was increased in MRL/lpr mice [8], suggesting a role for this protein in lupus. Therefore, we examined the role of the alternative pathway in lupus cerebritis by studying MRL/lpr mice in the presence and absence of fB.…”

Section: Discussionmentioning

confidence: 92%

“…Complement can be activated through classical, alternative and lectin pathways. Complement factor B (fB) is a key protein required for the activation of the alternative pathway [6] and is increased in circulation and in tissues of lupus mice [7][8][9]. In addition, fB solubilizes immune complexes, inhibits proliferation, acts as a B cell growth factor and activates monocytes 15].…”

Section: Introductionmentioning

confidence: 99%

Absence of functional alternative complement pathway alleviates lupus cerebritis

et al. 2007

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The complement inhibitor, Crry, which blocks both the classical and alternative pathways, alleviates CNS disease in the lupus model, MRL/MpJ-Tnfrsf6lpr (MRL/lpr) mice. To understand the role of the alternative pathway, we studied mice deficient in a key alternative pathway protein, complement factor B (fB). Immune deposits (IgG and C3) were reduced in the brains of MRL/lpr fB-deficient (fB -/-MRL/lpr) compared to fBsufficient (MRL/lpr) mice, indicating reduced complement activation. Reduced neutrophil infiltration (22% of MRL/lpr mice) and apoptosis (caspase-3 activity was reduced to 33% of MRL/lpr mice) in these mice indicates that the absence of the alternative pathway was neuroprotective. Furthermore, expression of phospho (p)-Akt (0.16 AE 0.02 vs. 0.35 AE 0.13, p <0.03) was increased, while expression of p-PTEN (0.40 AE 0.06 vs. 0.11 AE 0.07, p <0.05) was decreased in fB -/-MRL/lpr mice compared to their MRL/lpr counterparts. The expression of fibronectin, laminin and collagen IV was significantly decreased in fB -/-MRL/lpr mice compared to MRL/lpr mice, indicating that in the lupus setting, tissue integrity was maintained in the absence of the alternative pathway. Absence of fB reduced behavioral alterations in MRL/lpr mice. Our results suggest that in lupus, the alternative pathway may be the key mechanism through which complement activation occurs in brain, and therefore it might serve as a therapeutic target for lupus cerebritis. IntroductionSystemic lupus erythematosus (SLE) is an autoimmune disease, with central nervous system (CNS) involvement occurring in 20-70% of patients. Complement activation is believed to play a key role in the pathogenesis of SLE [1]. The relevance of complement in lupus cerebritis is supported by enhanced C3 and C4 index values in the cerebrospinal fluid of patients [2] and increased levels of the anaphylatoxins, C3a and C5a, which correlate with the CNS flares [3]. This is also true in experimental lupus cerebritis, and is supported by our recent studies, in which systemic inhibition of the C3/C5 convertases reduced pathological alterations in the CNS of the lupus mouse model, MRL/MpJ-Tnfrsf6lpr (MRL/lpr) mice [4,5]. Complement can be activated through classical, alternative and lectin pathways. Complement factor B (fB) is a key protein required for the activation of the alternative pathway [6] and is increased in circulation and in tissues of lupus mice [7][8][9]. In addition, fB solubilizes immune complexes, inhibits proliferation, acts as a B cell growth factor and activates monocytes 15]. Mice with targeted deletion of the fB gene (fB -/-) were protected from lupus nephritis and ischemiareperfusion injury [7,16]. However, the role of fB in the pathogenesis of lupus cerebritis has not been defined. Bb, one of the split products of fB, can induce apoptosis [17], which is a key feature in the brains of MRL/lpr mice [5,18]. Apoptosis can also be induced by several other factors such as nitric oxide (NO), edema, and the extracellular matrix (ECM) proteins through integrin si...

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“…It is now recognized that the kidney itself is a significant source of complement components. 5 Recent experimental work has suggested that such local synthesis of complement has great influence on local tissue injury in the transplanted kidney 6 and that local production in the kidney, for example of the pivotal component C3, which links the activation and terminal cascades of complement, is increased in response to I/R injury. 7 In addition, ischemia/reperfusion injury and its contributory factors have a serious negative impact on acute rejection and the long-term results in clinical transplantation.…”

mentioning

confidence: 99%

Nontransgenic Hyperexpression of a Complement Regulator in Donor Kidney Modulates Transplant Ischemia/Reperfusion Damage, Acute Rejection, and Chronic Nephropathy

Pratt

Jones

Dong

et al. 2003

The American Journal of Pathology

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Complement activation during ischemia and reperfusion contributes to the development of tissue injury with severe negative impact on outcomes in transplantation. To counter the effect of complement, we present a strategy to deliver a novel complement regulator stabilized on cell surfaces within donor organs. The membrane-bound complement regulator is able to inhibit complement activation when the donor organ is revascularized and exposed to host-circulating complement. Application of this construct to donor kidneys protected transplanted tissues from ischemia/reperfusion injury and reduced the deposition of activated complement and histological signs of damage under conditions in which a nontargeted control construct was ineffective. Treatment of donor organs in this way improved graft performance in the short and long term. An analysis of the immune response in allograft recipients showed that reducing graft damage at the time of transplantation through complement regulation also modulated the alloresponse. Additionally, the results of perfusion studies with human kidneys demonstrated the feasibility of targeting endothelial and epithelial surfaces with this construct, to allow investigation in clinical transplantation.

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Local extrahepatic expression of complement genes C3, factor B, C2, and C4 is increased in murine lupus nephritis.

Cited by 150 publications

References 32 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

Absence of functional alternative complement pathway alleviates lupus cerebritis

Nontransgenic Hyperexpression of a Complement Regulator in Donor Kidney Modulates Transplant Ischemia/Reperfusion Damage, Acute Rejection, and Chronic Nephropathy

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Local extrahepatic expression of complement genes C3, factor B, C2, and C4 is increased in murine lupus nephritis.

Cited by 150 publications

References 32 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

Absence of functional alternative complement pathway alleviates lupus cerebritis

Nontransgenic Hyperexpression of a Complement Regulator in Donor Kidney Modulates Transplant Ischemia/Reperfusion Damage, Acute Rejection, and Chronic Nephropathy

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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