title: Differential recruitment efficacy of patient-derived amyloidogenic and myeloma light chain proteins by synthetic fibrils-A metric for predicting amyloid propensity.
abstract: BACKGROUND
  Monoclonal free light chain (LC) proteins are present in the circulation of patients with immunoproliferative disorders such as light chain (AL) amyloidosis and multiple myeloma (MM). Light chain-associated amyloid is a complex pathology composed of proteinaceous fibrils and extracellular matrix proteins found in all patients with AL and in ~10-30% of patients who presented with MM. Amyloid deposits systemically in multiple organs and tissues leading to dysfunction and ultimately death. The overall survival of patients with amyloidosis is worse than for those with early stage MM.
  
  
  RESULTS
  We have developed a sensitive binding assay quantifying the recruitment of full length, patient-derived LC proteins by synthetic amyloid fibrils, as a method for studying their amyloidogenic potential. In a survey of eight urinary LC, both AL and MM-associated proteins were recruited by synthetic amyloid fibrils; however, AL-associated LC bound significantly more efficiently (p < 0.05) than did MM LCs. The LC proteins used in this study were isolated from urine and presumed to represent a surrogate of serum free light chains.
  
  
  CONCLUSIONS
  The binding of LC to synthetic fibrils in this assay accurately differentiated LC with amyloidogenic propensity from MM LC that were not associated with clinical amyloid disease. Notably, the LC from a MM patient who subsequently developed amyloid behaved as an AL-associated protein in the assay, indicating the possibility for identifying MM patients at risk for developing amyloidosis based on the light chain recruitment efficacy. With this information, at risk patients can be monitored more closely for the development of amyloidosis, allowing timely administration of novel, amyloid-directed immunotherapies-this approach may improve the prognosis for these patients.
authors.affiliation: Department of Medicine, University of Tennessee Medical Center, Knoxville, Tennessee, United States of America.
authors.forename: Emily B
authors.initials: EB
authors.lastname: Martin
authors.affiliation: Department of Medicine, University of Tennessee Medical Center, Knoxville, Tennessee, United States of America.
authors.forename: Angela
authors.initials: A
authors.lastname: Williams
authors.affiliation: Department of Medicine, University of Tennessee Medical Center, Knoxville, Tennessee, United States of America.
authors.forename: Craig
authors.initials: C
authors.lastname: Wooliver
authors.affiliation: Department of Surgery, University of Tennessee Medical Center, Knoxville, Tennessee, United States of America.
authors.forename: R Eric
authors.initials: RE
authors.lastname: Heidel
authors.affiliation: Department of Surgery, University of Tennessee Medical Center, Knoxville, Tennessee, United States of America.
authors.forename: Sarah
authors.initials: S
authors.lastname: Adams
authors.affiliation: Microscopy Facility, University of Tennessee, Knoxville, Tennessee, United States of America.
authors.forename: John
authors.initials: J
authors.lastname: Dunlap
authors.affiliation: Department of Biochemistry and Molecular Biology, and Immunology, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Marina
authors.initials: M
authors.lastname: Ramirez-Alvarado
authors.affiliation: Department of Biochemistry and Molecular Biology, and Immunology, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Luis M
authors.initials: LM
authors.lastname: Blancas-Mejia
authors.affiliation: Department of Medicine, University of Tennessee Medical Center, Knoxville, Tennessee, United States of America.
authors.forename: Ronald H
authors.initials: RH
authors.lastname: Lands
authors.affiliation: Department of Medicine, University of Tennessee Medical Center, Knoxville, Tennessee, United States of America.|Department of Radiology, University of Tennessee Medical Center, Knoxville, Tennessee, United States of America.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Kennel
authors.affiliation: Department of Medicine, University of Tennessee Medical Center, Knoxville, Tennessee, United States of America.|Department of Radiology, University of Tennessee Medical Center, Knoxville, Tennessee, United States of America.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Wall
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000682:Amyloid / Q000276:immunology* / Q000378:metabolism / Q000648:ultrastructure; D058227:Amyloidogenic Proteins / Q000276:immunology* / Q000378:metabolism; D000686:Amyloidosis / Q000276:immunology* / Q000378:metabolism; D015153:Blotting, Western; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D006801:Humans; D007147:Immunoglobulin Light Chains / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D000075363:Immunoglobulin Light-chain Amyloidosis; D008297:Male; D016253:Microscopy, Immunoelectron; D008875:Middle Aged; D009101:Multiple Myeloma / Q000276:immunology* / Q000378:metabolism; D011379:Prognosis; D011485:Protein Binding; D055503:Protein Multimerization / Q000187:drug effects; D020349:Surface Plasmon Resonance; D013816:Thermodynamics; D014508:Urea / Q000494:pharmacology
chemical_list: D000682:Amyloid; D058227:Amyloidogenic Proteins; D007147:Immunoglobulin Light Chains; D014508:Urea