title: Formation of immunoglobulin light chain amyloid oligomers in primary cutaneous nodular amyloidosis.
abstract: BACKGROUND
  Primary cutaneous nodular amyloidosis (PCNA) is thought to be a plasma cell dyscrasia. The amyloid deposits are found in the dermis and subcutis, and they contain clonal immunoglobulin light chains, produced by a local proliferation of plasma cells. New insights into amyloid diseases have revealed that the pathology is due more to the presence of small, misfolded protein species termed oligomers than to the deposition of fibrillar material.
  
  
  OBJECTIVE
  To demonstrate the presence of amyloid oligomers in PCNA and to provide evidence that cutaneous amyloid diseases share a common pathogenic pathway similar to other amyloid diseases.
  
  
  METHODS
  Immunohistochemical staining with conformation-specific and sequence-specific antibodies was used to localize different amyloid species of light chain immunoglobulins in a case of PCNA. Additionally, in vitro characterization of immunoglobulin oligomers and fibrils was performed to determine, through toxicity studies in a human keratinocyte cell line, which amyloidogenic form of the immunoglobulin is toxic in PCNA.
  
  
  RESULTS
  Amyloid oligomers were identified in PCNA. Oligomers were mainly formed by lambda light chain immunoglobulins, and kappa light chain oligomers were detected in lesser amounts. Amyloid species were detected intra- and extracellularly. In addition, amyloid oligomers and fibrils, derived from unknown protein sources, were detected. This finding suggests that immunoglobulin amyloids can act as seeds capable of inducing the aggregation of heterogeneous proteins in the skin. Furthermore, cytotoxicity studies demonstrated that immunoglobulin oligomers, but not monomers or fibrils, are toxic to human keratinocytes.
  
  
  CONCLUSIONS
  These data indicate that PCNA has common pathways with other amyloid diseases with respect to protein misfolding and pathogenesis. Immunoglobulin oligomers may prove to be targets for the treatment of PCNA.
authors: Department of Internal Medicine, The George P. and Cynthia Woods Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, Galveston, TX 77555-1045, USA.
authors: A L
authors: AL
authors: Clos
authors: C A
authors: CA
authors: Lasagna-Reeves
authors: D L
authors: DL
authors: Castillo-Carranza
authors: U
authors: U
authors: Sengupta
authors: G R
authors: GR
authors: Jackson
authors: B
authors: B
authors: Kelly
authors: T M
authors: TM
authors: Beachkofsky
authors: R
authors: R
authors: Kayed
mesh_terms: D000682:Amyloid / Q000276:immunology* / Q000378:metabolism; D000686:Amyloidosis / Q000276:immunology*; D006801:Humans; D007147:Immunoglobulin Light Chains / Q000096:biosynthesis*; D000075363:Immunoglobulin Light-chain Amyloidosis; D007145:Immunoglobulin kappa-Chains / Q000378:metabolism; D007146:Immunoglobulin lambda-Chains / Q000378:metabolism; D007150:Immunohistochemistry; D015603:Keratinocytes / Q000276:immunology; D008853:Microscopy; D012871:Skin Diseases / Q000276:immunology*
chemical_list: D000682:Amyloid; D007147:Immunoglobulin Light Chains; D007145:Immunoglobulin kappa-Chains; D007146:Immunoglobulin lambda-Chains