Recombinant versus natural human 111In-β2-microglobulin for scintigraphic detection of Aβ2m amyloid in dialysis patients

Schäffer, Jürgen; Burchert, Wolfgang; Floege, Jürgen; Gielow, P.; Kionka, Christine; Linke, Reinhold P.; Weiß, Elisabeth H.; Shaldon, Stanley; Koch, K. M.

doi:10.1046/j.1523-1755.2000.00237.x

Cited by 16 publications

(14 citation statements)

References 22 publications

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“…As a consequence of renal failure, the concentration of circulating ␤ 2 m increases by up to 60-fold (21). Through a mechanism that is not fully understood, the full-length, wild-type, disulfide oxidized protein then self-assembles to form amyloid fibrils that typically deposit in and around osteoarticular sites (22,23). Despite the identification of ␤ 2 m as the causative agent of DRA more than 20 years ago (17), there are currently no therapies for the disorder other than organ transplantation or other surgical procedures (24), an option that is only available for a minority of patients.…”

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confidence: 99%

Production and Characterization of RNA Aptamers Specific for Amyloid Fibril Epitopes

Bunka

Mantle

Morten

et al. 2007

Journal of Biological Chemistry

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One of the most fascinating features of amyloid fibrils is their generic cross-␤ architecture that can be formed from many different and completely unrelated proteins. Nonetheless, amyloid fibrils with diverse structural and phenotypic properties can form, both in vivo and in vitro, from the same protein sequence. Here, we have exploited the power of RNA selection techniques to isolate small, structured, single-stranded RNA molecules known as aptamers that were targeted specifically to amyloidlike fibrils formed in vitro from ␤ 2 -microglobulin (␤ 2 m), the amyloid fibril protein associated with dialysis-related amyloidosis. The aptamers bind with high affinity (apparent K D ϳ nM) to ␤ 2 m fibrils with diverse morphologies generated under different conditions in vitro, as well as to amyloid fibrils isolated from tissues of dialysis-related amyloidosis patients, demonstrating that they can detect conserved epitopes between different fibrillar species of ␤ 2 m. Interestingly, the aptamers also recognize some other, but not all, amyloid fibrils generated in vitro or isolated from ex vivo sources. Based on these observations, we have shown that although amyloid fibrils share many common structural properties, they also have features that are unique to individual fibril types.A number of proteins and peptides undergo specific aggregation in vivo, leading to a range of pathological disorders, collectively known as amyloidoses (1, 2). These diseases are characterized by the deposition of normally soluble proteins or peptides into insoluble fibrillar arrays with a cross-␤ architecture (1, 2). About 30 different proteins have been identified as the fibrillar component of human amyloid deposits to date, although studies have shown that amyloid-like fibrils can be generated in vitro from virtually any protein sequence under suitable experimental conditions (3, 4). Remarkably, although amyloid and amyloid-like fibrils are formed from diverse precursor proteins with unrelated primary sequences and tertiary folds, they all adopt a cross-␤ molecular architecture, identified by x-ray fiber diffraction (5, 6) and bind a number of histological dyes, such as thioflavin T (ThT) and Congo Red (7,8), the latter showing a characteristic optical anisotropy with apple-green birefringence when viewed using cross-polarized light (9). The ubiquitous ability of amyloid fibrils to bind serum amyloid P component (10, 11), glycosaminoglycans and apolipoprotein E (12), together with the finding that antibodies (e.g. WO1) raised against A␤-(1-40) amyloid fibrils are also able to recognize amyloid fibrils formed from a wide variety of proteins and peptides, unrelated in sequence and structure (13), reinforces the view that amyloid fibrils possess a common core structure. Despite the immense interest in this field (1, 14), the mechanism of how normally soluble proteins or peptides are transformed into the ordered cross-␤ structure of amyloid is largely unknown, although partial denaturation of the native protein, or folding of disordered states to...

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confidence: 99%

Production and Characterization of RNA Aptamers Specific for Amyloid Fibril Epitopes

Bunka

Mantle

Morten

et al. 2007

Journal of Biological Chemistry

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“…It has been recently shown that scintigraphy in which the radioactive tracer (iodine 131 or indium 111) is labeled to the amyloid precursor protein ␤ 2 -microglobulin is superior to MRI in demonstrating deposition of ␤ 2 -microglobulin amyloid in dialysis patients. 13,14 This is particularly so when recombinant human ␤ 2 -microglobulin is used as the labeling agent. 14…”

Section: Discussionmentioning

confidence: 99%

Rapid Progression of Destructive Spondyloarthropathy

Chow¹,

Griffith²,

Fung³

et al. 2005

Spine

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Study Design. A case of destructive spondyloarthropathy was reported.Objectives. To describe the rapid destruction of intervertebral disc and vertebral body as a consequence of destructive spondyloarthropathy in a patients with endstage renal disease receiving hemodialysis.Summary of Background Data. An important facet of this case is that the serial radiographs provide key information about the rapid nature of dialysis associated destructive spondyloarthropathy, a condition which has been increasingly recognized over the last 2 decades.Methods. The clinical and radiologic features of a 55-year-old dialysis patient with destructive spondyloarthropathy are herein detailed. Her serial radiographs and magnetic resonance images have implications both for our understanding of the underlying destructive process and its clinical evaluation.Results. Serial lateral lumbar spines illustrated that the destructive process started at the leading edge of the endplate of vertebral body, closely followed by adjacent intervertebral disc destruction that appeared in parallel with vertebral body bone resorption.Conclusions. A case of dialysis-associated destructive spondyloarthropathy was reported, with key information about its rapid nature being provided by serial radiographs.

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“…This also includes the uptake in the spleen and liver which is also observed in other In‐labeled proteins. Thus, this new tracer is as specific for organs containing Aβ 2 m‐amyloid as natural β 2 m as no tracer was fixed in organs lacking amyloid and no fixation above background has been noted in patients without amyloidosis [21].…”

Section: Discussionmentioning

confidence: 99%

Production of recombinant human β₂‐microglobulin for scintigraphic diagnosis of amyloidosis in uremia and hemodialysis

Linke

Schaeffer²,

Gielow³

et al. 2000

European Journal of Biochemistry

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Amyloid of b 2 -microglobulin (b 2 m) origin can be diagnosed using 131 I-radiolabelled-b 2 m scintigraphy in patients with uremia and hemodialysis treatment. As the tracer b 2 m is isolated from another patient, it carries the common risks, including viral infections such as Hepatitis B, C and HIV, which are associated with human plasma products.In order to exclude these risks we have produced recombinant human b 2 m (rhb 2 m) in Escherichia coli. The expression vector pASK40DLb 2 m(His) 5 contains a C-terminal (His) 5 -tag for purification via immobilized metal ion affinity chromatography (IMAC). Size exclusion chromatography on a Superose 12 column represents the second step of purification.The isolated rhb 2 mH 5 reacted in an immunochemically identical manner to native human b 2 m, and showed a single band of < 11.8 kDa in Western blot analysis and revealed a single spot in two-dimensional gel electrophoresis. Mass spectrometry analysis revealed a single peak at the expected molecular mass of 12 415.8 Da. Uniformity was further proven by crystallization and N-terminal amino-acid sequence analysis.The rhb 2 mH 5 protein was then produced under conditions that allow the intravenous use in humans. Intraveneously applied indium-111-labelled rhb 2 mH 5 was monitored in hemodialysed patients with and without known b 2 m-amyloidosis. The tracer was localized specifically to particular areas known to contain amyloid.Thus, this rhb 2 mH 5 preparation is suitable for detecting amyloid-containing organs of the b 2 m-class in vivo and fulfils the requirements of a tracer for common use. Finally, the use of indium-111 instead of iodine-131 has reduced the radioactive load and resulted in higher resolution.Keywords: amyloidosis; recombinant b 2 -microglobulin; scintigraphy; indium-111; whole-body diagnosis.Amyloidosis of b 2 -macroglobulin (b 2 m) origin is a serious disease in patients with long-standing uremia and hemodialysis treatment. It is seen to occur with increasing prevalence with the duration of dialysis, with age of the patient and with the kind of dialyzer used [1±3]. As this class of amyloidosis causes severe osteo-articular symptoms with carpal tunnel syndrome and bone erosions which lead to pathologic bone fractures, early diagnosis is needed in order to achieve a timely therapeutic intervention.As early bioptic diagnosis has not yet been established, minimal invasive scintigraphic diagnosis has been reported using 131 I-labelled b 2 m [4] which was confirmed by others [5±7]. However, the tracer b 2 m in all studies was isolated from urine or uremic ultrafiltrate of other patients. Although these selected donor patients had been carefully scrutinized for any possible transmissible disease, there still remains a risk, including viral infections such as Hepatitis B, C and HIV, inherent in all human plasma products.As such a tracer may only be applicable in a limited and strictly controlled setting, it cannot be commonly applied and its commercial distribution is not feasible due to the remaining risks. The ...

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Recombinant versus natural human 111In-β2-microglobulin for scintigraphic detection of Aβ2m amyloid in dialysis patients

Abstract: Scintigraphy for Abeta2m with 111In-labeled rhbeta2m provides a homogenous and safe recombinant protein source and leads to enhanced sensitivity and lower radiation exposure.

Cited by 16 publications

References 22 publications

Production and Characterization of RNA Aptamers Specific for Amyloid Fibril Epitopes

Production and Characterization of RNA Aptamers Specific for Amyloid Fibril Epitopes

Rapid Progression of Destructive Spondyloarthropathy

Production of recombinant human β₂‐microglobulin for scintigraphic diagnosis of amyloidosis in uremia and hemodialysis

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Recombinant versus natural human 111In-β2-microglobulin for scintigraphic detection of Aβ2m amyloid in dialysis patients

Abstract: Scintigraphy for Abeta2m with 111In-labeled rhbeta2m provides a homogenous and safe recombinant protein source and leads to enhanced sensitivity and lower radiation exposure.

Cited by 16 publications

References 22 publications

Production and Characterization of RNA Aptamers Specific for Amyloid Fibril Epitopes

Production and Characterization of RNA Aptamers Specific for Amyloid Fibril Epitopes

Rapid Progression of Destructive Spondyloarthropathy

Production of recombinant human β2‐microglobulin for scintigraphic diagnosis of amyloidosis in uremia and hemodialysis

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Product

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Production of recombinant human β₂‐microglobulin for scintigraphic diagnosis of amyloidosis in uremia and hemodialysis