Metabolic studies of radioiodinated serum amyloid P component in normal subjects and patients with systemic amyloidosis.

Hawkins, Philip N.; Wootton, R; Pepys, Mark B.

doi:10.1172/jci114917

Cited by 83 publications

(51 citation statements)

References 40 publications

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“…Doxycycline-induced overexpression of SAA is thus totally independent of inflammation. Doubletransgenic mice exposed to drinking water containing 2 mg/mL doxycycline developed major systemic amyloid deposits after a median of 5 wk (range, 4-16 wk) as shown by massive whole body retention of i.v.-administered 125 I-human SAP ( 125 I-hSAP), a validated, specific, quantitative in vivo tracer for systemic amyloid deposits in mice (14,15) and humans (16)(17)(18). Heavy AA amyloid deposits were confirmed histologically in the spleen and liver, correlating closely with the major organ localization of 125 I-hSAP.…”

Section: Resultsmentioning

confidence: 99%

Pathogenetic mechanisms of amyloid A amyloidosis

Simons

Al‐Shawi

Ellmerich

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Systemic amyloid A (AA) amyloidosis is a serious complication of chronic inflammation. Serum AA protein (SAA), an acute phase plasma protein, is deposited extracellularly as insoluble amyloid fibrils that damage tissue structure and function. Clinical AA amyloidosis is typically preceded by many years of active inflammation before presenting, most commonly with renal involvement. Using dose-dependent, doxycycline-inducible transgenic expression of SAA in mice, we show that AA amyloid deposition can occur independently of inflammation and that the time before amyloid deposition is determined by the circulating SAA concentration. High level SAA expression induced amyloidosis in all mice after a short, slightly variable delay. SAA was rapidly incorporated into amyloid, acutely reducing circulating SAA concentrations by up to 90%. Prolonged modest SAA overexpression occasionally produced amyloidosis after long delays and primed most mice for explosive amyloidosis when SAA production subsequently increased. Endogenous priming and bulk amyloid deposition are thus separable events, each sensitive to plasma SAA concentration. Amyloid deposits slowly regressed with restoration of normal SAA production after doxycycline withdrawal. Reinduction of SAA overproduction revealed that, following amyloid regression, all mice were primed, especially for rapid glomerular amyloid deposition leading to renal failure, closely resembling the rapid onset of renal failure in clinical AA amyloidosis following acute exacerbation of inflammation. Clinical AA amyloidosis rarely involves the heart, but amyloidotic SAA transgenic mice consistently had minor cardiac amyloid deposits, enabling us to extend to the heart the demonstrable efficacy of our unique antibody therapy for elimination of visceral amyloid.

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Section: Resultsmentioning

confidence: 99%

Pathogenetic mechanisms of amyloid A amyloidosis

Simons

Al‐Shawi

Ellmerich

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…The most exquisitely sensitive test for protein integrity, namely its turnover after intravenous injection in vivo, is absolutely normal for SAP isolated from serum heated in that way (17).…”

Section: Discussionmentioning

confidence: 99%

Normal circulating serum amyloid P component concentration in systemic sclerosis

Tennent¹,

Dziadzio²,

Triantafillidou³

et al. 2007

Arthritis & Rheumatism

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Objective. The observation of reduced circulating concentrations of the constitutive plasma pentraxin protein, serum amyloid P component (SAP), in serum samples obtained from a small number of patients with systemic sclerosis (SSc) has been reported as confirmation of an antifibrotic role of this protein. Because neither sustained SAP depletion in humans nor SAP deficiency in mice is associated with fibrosis, we sought to establish rigorously the serum SAP concentration in well-characterized patients with SSc.Methods. Serum concentrations of SAP were measured by electroimmunoassay in a cross-sectional cohort of 20 patients with diffuse cutaneous SSc and 12 patients with limited cutaneous SSc, and in a separate 12-month longitudinal cohort of 13 patients with diffuse disease and 37 patients with limited disease. The extent and severity of disease were characterized in detail at the time of serum sampling. Serum concentrations of the classic acute-phase reactants, C-reactive protein and serum amyloid A protein, were measured by immunonephelometric assays.Results. SAP values were entirely within the normal range, regardless of the extent and severity of disease, apart from a very few isolated raised values associated with acute intercurrent complications causing major acute-phase responses.Conclusion. We observed no reduced circulating concentrations of SAP in patients with SSc, nor any evidence of an association between SAP levels and the extent or severity of fibrosis.

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“…However, before the widespread recognition of the association between cerebral amyloidosis and Alzheimer's disease, systemic amyloidosis was of no interest to pharmaceutical companies. Our subsequent clinical work with radiolabelled tracer SAP, coupled with precise characterization of SAP from blood and tissues, demonstrated that SAP in amyloid is indistinguishable from its plasma precursor, that SAP persists in the deposits for prolonged periods, and that SAP is not catabolized at all in the deposits but only when it reenters the blood and is then taken up by hepatocytes (Hawkins et al 1990b;). These observations supported the concept that SAP may provide a normal, autologous protein coat masking the abnormal amyloid ¢brils from the scavenging processes that usually so e¤ciently clear the tissues of abnormal material.…”

Section: (C) Inhibition Of ¢Brillogenesismentioning

confidence: 99%

Pathogenesis, diagnosis and treatment of systemic amyloidosis

Pepys

2001

Phil. Trans. R. Soc. Lond. B

201

156

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Amyloidosis is a disorder of protein folding in which normally soluble proteins are deposited as abnormal, insoluble ¢brils that disrupt tissue structure and cause disease. Although about 20 di¡erent unrelated proteins can form amyloid ¢brils in vivo, all such ¢brils share a common cross-b core structure. Some natural wild-type proteins are inherently amyloidogenic, form ¢brils and cause amyloidosis in old age or if present for long periods at abnormally high concentration. Other amyloidogenic proteins are acquired or inherited variants, containing amino-acid substitutions that render them unstable so that they populate partly unfolded states under physiological conditions, and these intermediates then aggregate in the stable amyloid fold. In addition to the ¢brils, amyloid deposits always contain the non-¢brillar pentraxin plasma protein, serum amyloid P component (SAP), because it undergoes speci¢c calcium-dependent binding to amyloid ¢brils. SAP contributes to amyloidogenesis, probably by stabilizing amyloid ¢brils and retarding their clearance. Radiolabelled SAP is an extremely useful, safe, speci¢c, non-invasive, quantitative tracer for scintigraphic imaging of systemic amyloid deposits. Its use has demonstrated that elimination of the supply of amyloid ¢bril precursor proteins leads to regression of amyloid deposits with clinical bene¢t. Current treatment of amyloidosis comprises careful maintenance of impaired organ function, replacement of end-stage organ failure by dialysis or transplantation, and vigorous e¡orts to control underlying conditions responsible for production of ¢bril precursors. New approaches under development include drugs for stabilization of the native fold of precursor proteins, inhibition of ¢brillogenesis, reversion of the amyloid to the native fold, and dissociation of SAP to accelerate amyloid ¢bril clearance in vivo.

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Metabolic studies of radioiodinated serum amyloid P component in normal subjects and patients with systemic amyloidosis.

Cited by 83 publications

References 40 publications

Pathogenetic mechanisms of amyloid A amyloidosis

Pathogenetic mechanisms of amyloid A amyloidosis

Normal circulating serum amyloid P component concentration in systemic sclerosis

Pathogenesis, diagnosis and treatment of systemic amyloidosis

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