Experimental Model of Human Light-Chain-Associated Disease

Solomon, Alan; Weiss, Deborah; Williams, T

doi:10.1007/978-3-642-77633-5_32

Cited by 9 publications

(5 citation statements)

References 9 publications

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“…This technique is valuable for rapid assessment of the deposition patterns, especially of amyloidogenic proteins. Following a single injection of 200-300 mg of a Bence-Jones protein, lesions typical of myeloma (cast) nephropathy begin to appear within 48 h (Solomon et al, 1992b). The injected protein may also form crystals in the casts and precipitates in the basement membranes.…”

Section: Experimental Evaluation Of the Deposition Of L Chainsmentioning

confidence: 99%

Binding of nascent collagen by amyloidogenic light chains and amyloid fibrillogenesis in monolayers of human fibrocytes

et al. 2000

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Light (L) chain dimers expressed by multiple myeloma cells and collected as Bence‐Jones proteins from the urine of human subjects were tested for their ability to form deposits in fibroblast monolayer cell cultures. Bence‐Jones proteins from subjects with primary amyloidosis associated with L chains were shown to form fibrillar deposits by the in vitro assay introduced in this report. Filaments interspersed with nascent collagen could be detected after only 48 h. Deposition of L chains continued over a period of 72 h culminating in the appearance of dense fibrils with widths of 80–100 Å and a variety of lengths. Formation of amyloid‐like fibrils was accompanied by interference with the maturation of the collagen produced by the fibroblast cells. Fibrils composed of the Mcg λ‐type L chain were deposited between collagen fibers, thus expanding them laterally and leading to their partial disintegration. Mature collagen was completely missing from fibroblast monolayers exposed to the Sea λ chain and the Jen κ chain. Collagen with the characteristic striped pattern matured normally in control samples, such as those not dosed with amyloid precursors or those treated with a non‐amyloidogenic Bence‐Jones protein (e.g., the Hud λ chain dimer). By immunochemical techniques using fluorescein‐ and gold‐labeled anti‐L chain antibodies, amyloidogenic L chains were shown to decorate the strands of nascent collagen. This observation suggests that amyloidogenic L chains are concentrated in the extracellular matrix by monovalent antigen–antibody type reactions. The capacity of the Mcg L chain dimer to bind collagen‐derived sequences was tested by soaking crystals with a collagenase substrate, PZ‐Pro‐Leu‐Gly‐Pro‐D‐Arg. Difference Fourier analysis at 2.7 Å resolution indicated that the PZ‐peptide is a site‐filling ligand. It could not be removed from the active site by perfusion of the crystal with ammonium sulfate crystallizing media. Similar experiments with the collagen‐derived peptide (Pro‐Pro‐Gly)5 showed substantial hysteresis effects extending from one end of the Mcg dimer to the other. After the ligand was withdrawn, the active site of the Mcg dimer could no longer bind the PZ‐peptide. However, if the active site was first blocked by the PZ‐peptide and subsequently exposed to the (Pro‐Pro‐Gly)5 peptide, the difference Fourier map was indistinguishable from that obtained with the PZ‐peptide alone. We concluded that amyloidogenic L chains such as the Mcg dimer could be concentrated in the perivascular space by binding to normal tissue constituents. These components include nascent collagen, which can be deterred from maturing as a result of this binding. Participation in such pathological activity is also self‐destructive to the amyloidogenic L chains, which lose their binding capabilities for collagen‐derived peptides and also become susceptible to irreversible conversion to amyloid fibrils. All of these events may be prevented by prior treatment of the amyloidogenic L chains with site‐filling ligands. Copyright © 20...

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Section: Experimental Evaluation Of the Deposition Of L Chainsmentioning

confidence: 99%

Binding of nascent collagen by amyloidogenic light chains and amyloid fibrillogenesis in monolayers of human fibrocytes

et al. 2000

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“…Furthermore, experimental designs have shown that injection of monoclonal proteins derived from patients with a MCN, a MIDD, or an AL into animals induced renal damage reminiscent of the renal disease of the human donor. It was consequently concluded that structural abnormalities of the monoclonal molecules are responsible for the specific forms of renal manifestation [9][10][11][12] . Although modern biopsy techniques such as ultrasound guidance and semiautomatic biopsy guns have been established, the risk of bleeding exists in MM because thrombocytopenia is frequently present, and abnormalities of the coagulation system exist due to the nephrotic syndrome and high levels of paraproteins [13] .…”

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confidence: 99%

Screening and Differential Diagnosis of Renal Light Chain-Associated Diseases

Gerth¹,

Sachse

Busch

et al. 2011

Kidney Blood Press Res

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Background: Renal involvement in the light chain-associated diseases multiple myeloma (MM), amyloidosis (AL) and monoclonal immune position disease (MIDD) is common and differential diagnosis usually requires renal biopsy. The aim of this study was to investigate if noninvasive methods are viable to identify and differentiate between the various types of kidney diseases. Patients and Methods: All patients with a light chain-associated disease admitted to our center from 1996 to 2008 were retrospectively evaluated. Renal biopsy data were correlated with proteinuria findings. Results: Only the ratio of free ĸ/λ light chains showed a good sensitivity for myeloma cast nephropathy (MCN), AL and MIDD. The λ light chain was characteristic for AL, the ĸ light chain dominated in MIDD. Renal function at the time of diagnosis was worst in MIDD. MCN presented with a proteinuria of >3.5 g/g creatinine. In contrast, a higher proteinuria was found in AL or MIDD. Whereas the ĸ/λ ratio in the urine was pathological for all three diseases, extremely high or low ratios indicated the presence of MCN. However, in AL or MIDD, the ratio was only moderately elevated. Conclusion: A noninvasive differentiation between MCN and other forms of renal light chain disease is possible.

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“…However, sequencing of light chains that formed amyloid or other pathological deposits never revealed the equivalent of the glutamic acid to valine substitution at position six in the ␤ chain of hemoglobin that sufficiently alters the physicochemical properties of the normal protein to generate sickle cell hemoglobin. Nevertheless, a linkage of pathological properties to primary structure of the light chain, rather than a outcome of patient-specific factors, was provided by Solomon et al [82,83], who demonstrated that infusion of human Bence Jones proteins into mice revealed that the pathological character of the protein that was observed in the patient was reprised in the mouse. Thus, the pathologenic nature of a particular light chain was neither patient, nor species, dependent.…”

Section: Light Chain Diversitymentioning

confidence: 98%

Diversity and Diversification of Light Chains in Myeloma:The Specter of Amyloidogenesis by Proxy

Wilton

Stevens³

2006

Contributions to Nephrology

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The plasma cell dyscrasias including myeloma, lymphoma, leukemia, and monoclonal gammopathy of undetermined significance are usually monoclonal diseases; however, the light chains produced are not homogeneous. Thus, the pathological risk for the patient may change during the course of the illness. Mutation rates in light chains observed during clonal diversification parallel mutations occurring in all genes in the malignant cells and could be a clinically useful biomarker.

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Experimental Model of Human Light-Chain-Associated Disease

Cited by 9 publications

References 9 publications

Binding of nascent collagen by amyloidogenic light chains and amyloid fibrillogenesis in monolayers of human fibrocytes

Binding of nascent collagen by amyloidogenic light chains and amyloid fibrillogenesis in monolayers of human fibrocytes

Screening and Differential Diagnosis of Renal Light Chain-Associated Diseases

Diversity and Diversification of Light Chains in Myeloma:The Specter of Amyloidogenesis by Proxy

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