Neoantigen of the polymerized ninth component of complement. Characterization of a monoclonal antibody and immunohistochemical localization in renal disease.

Falk, Ronald J.; Dalmasso, Agustin P.; Kim, Youngki; Tsai, Cheng Han; Scheinman, Jon I.; Gewürz, Henry; Michael, Alfred F.

doi:10.1172/jci111004

Cited by 183 publications

(122 citation statements)

References 39 publications

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“…Culture supernatants were screened by ELISA (1,17) for reactivity with NHS, purified human IgG, IgA (Sigma Chemical Co., St. Louis, MO), and IgM (Silenus Laboratories, Melbourne, Australia), purified C5b-9(m) and SC5b-9 complexes (9, and see below), and purified human complement components (C3, C5, C6, C7, C8, C9) (Calbiochem-Behring Corp., La Jolla, CA).…”

Section: Methodsmentioning

confidence: 99%

SP-40,40, a newly identified normal human serum protein found in the SC5b-9 complex of complement and in the immune deposits in glomerulonephritis.

Murphy¹,

Kirszbaum²,

Walker³

et al. 1988

J. Clin. Invest.

295

178

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We report herein the isolation and initial characterization of a novel protein, termed SP-40,40, which is present at moderate levels (35-105 gg/ml) in normal human serum. SP-40,40 is deposited in the renal glomeruli of patients with glomerulonephritis but is not found in normal glomeruli. The protein is a heterodimeric structure of relative molecular mass 80 kD, both chains of which are of a similar size (40 kD). The amino-terminal sequences of both chains are unrelated to one another and possess no significant homology to any known protein sequence.The tissue distribution of SP40,40 closely resembles that of the terminal complement components and its physicochemical properties are similar to, but distinct from, those of the S protein of complement. We have identified SP-40,40 in the SC5b-9 complex of complement and have demonstrated incorporation of labeled SP-40,40 into this complex. These data suggest that SP-40,40 is an additional component of SC5b-9.

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Section: Methodsmentioning

confidence: 99%

SP-40,40, a newly identified normal human serum protein found in the SC5b-9 complex of complement and in the immune deposits in glomerulonephritis.

Murphy¹,

Kirszbaum²,

Walker³

et al. 1988

J. Clin. Invest.

295

178

View full text Add to dashboard Cite

show abstract

“…The residual cells were detached with 0.05% trypsin, combined with the respective supernatants, centrifuged at 450 Â g, washed and suspended at 10 6 /mL in 1% FBS-PBS containing 2 mM EDTA and 0.05% NaN3; then 100 mL of the suspension was incubated with 5 mg mAb against C9 neoantigen [41] for 30 min on ice and washed twice. C5b9 was assessed as previously described [8].…”

Section: Membrane Permeability Assaymentioning

confidence: 99%

IL‐4 induces protection of vascular endothelial cells against killing by complement and melittin through lipid biosynthesis

et al. 2010

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We have shown previously that cytokines IL-4 and IL-13 induce protection in porcine vascular endothelial cells (EC) against killing by the membrane attack complex (MAC) of human complement. This protection is intrinsic, not due to changes in complement regulatory proteins, and requires activation of Akt and sterol receptor element binding protein-1 (SREBP-1), which regulates fatty acid and phospholipid synthesis. Here we report that, compared to EC incubated in medium, IL-4-treated EC had a profound reduction in complement-mediated ATP loss and in killing assessed by vital dye uptake, but only a slight reduction in permeability disruption measured by calcein release. While controls exposed to complement lost mitochondrial membrane potential and subsequently died, protected EC maintained mitochondrial morphology and membrane potential, and remained alive. SREBP-1 and fatty acid synthase activation were required for protection and fatty acid and phospholipid synthesis, including cardiolipin, were increased after IL-4 stimulation, without increase in cholesterol content or cell proliferation. IL-4 also induced protection of EC from killing by the channel forming protein melittin, similar to protection observed for the MAC. We conclude that IL-4 induced activation of Akt/SREBP-1/lipid biosynthesis in EC, resulting in protection against MAC and melittin, in association with mitochondrial protection. IntroductionThe vascular endothelium has critically important physiologic functions [1] and, if injured, pathologic states such as atherosclerosis, ischemia reperfusion, and vasculopathy, as observed in vascularized allo-and xenograft rejection, may result. The vascular endothelium is directly exposed to complement, complement activation may take place in blood secondary to various physiologic and pathologic events, and activated complement may influence vascular endothelial physiology [2,3]. Among products derived from complement activation, the membrane attack complex (MAC) of human complement is known to have multiple effects on the vascular endothelium and the vasculature as a whole, including activation, production of inflammatory cytokines, expression of adhesion molecules, loss of endothelial anticoagulant properties, gain of procoagulant properties, cell retraction and detachment from the basement membrane, and cell death [2,3]. Consequently, the MAC may initiate or contribute to ischemia or to acute and chronic inflammation, becoming a major pathophysiologic mediator in vascular diseases, autoimmune diseases, and graft rejection. Cells possess at least three control mechanisms for protection against injury from the MAC. First, the membrane proteins decayaccelerating factor (CD55) and membrane cofactor protein (CD46) inhibit progression of complement activation at the C3 and C5 activation stages, and CD59 inhibits MAC assembly by blocking C9 binding to C5b-8 [4]. Second, complement proteins bound to a cell membrane may be removed from the membrane by exocytosis or endocytosis [5]. Third, nucleated cells may be in...

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“…Ultimately, glomerulosclerosis and renal failure occur in the terminal phase of disease (20). In both humans and mice with SLE, the finding of C3 and C5b-9 in association with glomerular immune deposits (21,22) and the observations that nephritogenic Abs typically are complement-fixing IgG Abs (23) support the concept that complement contributes to tissue damage and GN in human and mouse models of SLE.…”

mentioning

confidence: 94%

Transgenic Expression of a Soluble Complement Inhibitor Protects Against Renal Disease and Promotes Survival in MRL/lprMice

Bao

Haas

Boackle

et al. 2002

The Journal of Immunology

105

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To investigate the role of complement in lupus nephritis, we used MRL/lpr mice and a transgene overexpressing a soluble complement regulator, soluble CR1-related gene/protein y (sCrry), both systemically and in kidney. Production of sCrry in sera led to significant complement inhibition in Crry-transgenic mice relative to littermate transgene negative controls. This complement inhibition with sCrry conferred a survival advantage to MRL/lpr mice. In a total of 154 animals, 42.5% transgene-negative animals had impaired renal function (blood urea nitrogen > 50 mg/dl) compared with 16.4% mice with the sCrry-producing transgene (p < 0.001). In those animals that died spontaneously, MRL/lpr mice with the sCrry-producing transgene did not die of renal failure, while those without the transgene did (blood urea nitrogen values of 46.6 ± 9 and 122 ± 29 mg/dl in transgene-positive and transgene-negative animals, respectively; p < 0.001). Albuminuria was reduced in those transgenic animals in which sCrry expression was maximally stimulated (urinary albumin/creatinine = 12.4 ± 4.3 and 36.9 ± 7.7 in transgene-positive and transgene-negative animals, respectively; p < 0.001). As expected in the setting of chronic complement inhibition, there was less C3 deposition in glomeruli of sCrry-producing transgenic mice compared with transgene-negative animals. In contrast, there was no effect on glomerular IgG deposition, levels of anti-dsDNA Ab and rheumatoid factor, or spleen weights between the two groups. Thus, long-term complement inhibition reduces renal disease in MRL/lpr mice, which translates into improved survival. MRL/lpr mice in which complement is inhibited still have spontaneous mortality, yet this is not from renal disease.

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Neoantigen of the polymerized ninth component of complement. Characterization of a monoclonal antibody and immunohistochemical localization in renal disease.

Cited by 183 publications

References 39 publications

SP-40,40, a newly identified normal human serum protein found in the SC5b-9 complex of complement and in the immune deposits in glomerulonephritis.

SP-40,40, a newly identified normal human serum protein found in the SC5b-9 complex of complement and in the immune deposits in glomerulonephritis.

IL‐4 induces protection of vascular endothelial cells against killing by complement and melittin through lipid biosynthesis

Transgenic Expression of a Soluble Complement Inhibitor Protects Against Renal Disease and Promotes Survival in MRL/lprMice

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