Aggressive Light Chain Amyloidosis Cases have Unstable Immunoglobulin Light Chains

In Ig light-chain (LC) amyloidosis (AL), the unique antibody LC protein that is secreted by monoclonal plasma cells in each patient misfolds and/or aggregates, a process leading to organ degeneration. As a step toward developing treatments for AL patients with substantial cardiac involvement who have difficulty tolerating existing chemotherapy regimens, we introduce small-molecule kinetic stabilizers of the native dimeric structure of full-length LCs, which can slow or stop the amyloidogenicity cascade at its origin. A protease-coupled fluorescence polarization-based high-throughput screen was employed to identify small molecules that kinetically stabilize LCs. NMR and X-ray crystallographic data demonstrate that at least one structural family of hits bind at the LC–LC dimerization interface within full-length LCs, utilizing variable-domain residues that are highly conserved in most AL patients. Stopping the amyloidogenesis cascade at the beginning is a proven strategy to ameliorate postmitotic tissue degeneration.

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Immunoglobulin light chain alters mesangial cell calcium homeostasis

AJP Renal Physiology ◽

10.1152/ajprenal.1997.272.3.f319 ◽

1997 ◽

Vol 272 (3) ◽

pp. F319-F324 ◽

Cited By ~ 3

Author(s):

L. Zhu ◽

G. A. Herrera ◽

C. R. White ◽

P. W. Sanders

Keyword(s):

Calcium Homeostasis ◽

Light Chain ◽

Mesangial Cell ◽

Mesangial Cells ◽

Calcium Influx ◽

Light Chains ◽

Kappa Light Chain ◽

Immunoglobulin Light Chains ◽

Acetoxymethyl Ester ◽

Cell Calcium

This study examined the hypothesis that certain immunoglobulin light chains directly altered mesangial cell calcium homeostasis. Intracellular Ca2+ concentration (intracellular [Ca2+]) signaling was determined in suspensions of rat mesangial cells using the acetoxymethyl ester of fura 2 with a calcium removal/replacement protocol. Pretreatment of cultured rat mesangial cells with a glomerulopathic kappa-light chain (gle) produced reversible dose- and time-dependent attenuation of ATP- and thrombin-evoked [Ca2+] transients (189 +/- 24 vs. 126 +/- 10 nM, P < 0.05 with ATP; 198 +/- 5 vs. 117 +/- 3 nM, P < 0.05 with thrombin) and capacitative calcium influx (199 +/- 14 vs. 142 +/- 17 nM, P < 0.05 for ATP; 252 +/- 19 vs. 198 +/- 18 nM, P < 0.05 for thrombin). Mesangial cells treated with gle and supplemented with myo-inositol (450 microM) did not demonstrate the attenuation of the ATP-evoked [Ca2+] transient and capacitative calcium influx. Gle also decreased mean [Ca2+] transient (80 +/- 7 vs. 56 +/- 1 nM, P < 0.05) and capacitative calcium influx (306 +/- 10 vs. 241 +/- 4 nM, P < 0.05) in response to thapsigargin, a Ca2+-adenosinetriphosphatase inhibitor. This inhibition was not reversed by exogenous myo-inositol. Another kappa-light chain (10 microg/ml) did not affect mesangial cell calcium signaling. Deranged mesangial cell calcium homeostasis by certain light chains may play a central pathogenetic role in glomerulosclerosis associated with deposition of immunoglobulin light chains.

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IgD myeloma protein with "unreactive" light chain determinants.

Clinical Chemistry ◽

10.1093/clinchem/25.8.1495 ◽

1979 ◽

Vol 25 (8) ◽

pp. 1495-1498 ◽

Cited By ~ 12

Author(s):

J Cejka ◽

K Kithier

Keyword(s):

Multiple Myeloma ◽

Light Chain ◽

Light Chains ◽

Precipitation Reaction ◽

Immunoglobulin Light Chains ◽

Myeloma Protein ◽

Monoclonal Protein ◽

Immunofixation Electrophoresis ◽

Intact Molecule

Abstract Serum from a patient with multiple myeloma showed a monoclonal protein, classified by immunoelectrophoresis as IgD. Immunofixation electrophoresis and immunoelectrophoresis failed to demonstrate a precipitation reaction between the paraprotein and antisera to immunoglobulin light chains. The light chains of the monoclonal protein, immunologically inaccessible in the intact molecule, reacted with anti-lambda chain antisera only after reduction and alkylation of the paraprotein. Moreover, interpretation of the immunoelectrophoretic patterns was hampered by the presence in patient's serum of free lambda chains having about the same mobility as that of the paraprotein.

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Complete primary sequences of three λ immunoglobulin light chains in myelomas with light chain deposition disease

Immunology Letters ◽

10.1016/s0165-2478(97)88164-3 ◽

1997 ◽

Vol 56 (1-3) ◽

pp. 328

Author(s):

C Decourt

Keyword(s):

Light Chain ◽

Light Chains ◽

Immunoglobulin Light Chains ◽

Light Chain Deposition Disease ◽

Deposition Disease ◽

Light Chain Deposition

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Clinical presentation and outcomes in light chain amyloidosis patients with non-evaluable serum free light chains

Leukemia ◽

10.1038/leu.2017.286 ◽

2017 ◽

Vol 32 (3) ◽

pp. 729-735 ◽

Cited By ~ 32

Author(s):

S Sidana ◽

N Tandon ◽

A Dispenzieri ◽

M A Gertz ◽

F K Buadi ◽

...

Keyword(s):

Light Chain ◽

Clinical Presentation ◽

Light Chains ◽

Free Light Chains ◽

Serum Free ◽

Light Chain Amyloidosis ◽

Serum Free Light Chains

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Light chain proximal tubulopathy with cast nephropathy in monoclonal gammopathy of renal significance

BMJ Case Reports ◽

10.1136/bcr-2020-234361 ◽

2020 ◽

Vol 13 (6) ◽

pp. e234361

Author(s):

Rebaika Chopra ◽

Rosalba Santana de Roberts ◽

Ibrahim Batal ◽

Sachin Batra ◽

Belinda Jim

Keyword(s):

Light Chain ◽

Monoclonal Gammopathy ◽

Fanconi Syndrome ◽

Cell Damage ◽

Biochemical Properties ◽

Light Chains ◽

Immunoglobulin Light Chains ◽

Cast Nephropathy ◽

Proximal Tubulopathy ◽

Light Chain Proximal Tubulopathy

Kidney tubular disorders due to monoclonal immunoglobulin light chains are common manifestations of B-cell neoplasm. Cast nephropathy (CN) is the most frequent type of these disorders and may present with acute kidney injury (AKI) due to the presence of excess light chains in the distal tubules. Light chain proximal tubulopathy (LCPT) is an uncommon form of renal disease and may present as Fanconi syndrome due to proximal tubular cell damage by intracellular deposition of light chains. The concomitant disorder of both CN and LCPT is rare given the inherent differences in the biochemical properties of the immunoglobulin light chains of each disorder. We report a 64-year-old man who presented with AKI and Fanconi syndrome who was discovered to have both CN and LCPT due to the underlying disorder of monoclonal gammopathy of renal significance and who has responded favourably with conventional chemotherapy. We also review the existing literature on this interesting subject.

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Pediatric and Perinatal Reference Intervals for Immunoglobulin Light Chains Kappa and Lambda

Clinical Chemistry ◽

10.1093/clinchem/38.4.548 ◽

1992 ◽

Vol 38 (4) ◽

pp. 548-550 ◽

Cited By ~ 4

Author(s):

K R Herkner ◽

H Salzer ◽

A Böck ◽

A Mühl ◽

T Tsaka ◽

...

Keyword(s):

Light Chain ◽

Reference Intervals ◽

Linear Increase ◽

Light Chains ◽

Serum Concentrations ◽

Immunoglobulin Light Chains ◽

Adult Type ◽

Mean Values ◽

Age Related ◽

Chain Analysis

Abstract In routine analysis for immunoglobulin light chains in pediatric diagnostics, the age-related reference intervals for serum kappa (kappa) and lambda (lambda) light chains were evaluated in 1543 healthy subjects (newborns to age 16 years, including 168 premature infants). Light-chain analysis was performed by rate nephelometry. IgG, IgA, and IgM were measured simultaneously, and heavy- and light-chain differences were calculated for control purposes. Results for IgG, IgA, and IgM generally agreed with reference intervals reported in the literature. kappa showed age-related changes comparable with changes in IgG concentrations, whereas lambda showed moderate fluctuations. The kappa/lambda ratio showed an almost linear increase with age, starting with 0.97 at four months and reaching the highest value of 2.21 at 15 years (mean values). Preterm infants presented with markedly low serum concentrations of IgG and corresponding light chains but with adult-type kappa/lambda ratios because of the maternal-origin IgG.

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