Funding sources Mitchell Center for Neurodegenerative Diseases.
Formation of immunoglobulin light chain amyloid oligomers in primary cutaneous nodular amyloidosis
Article first published online: 17 OCT 2011
© 2011 The Authors. BJD © 2011 British Association of Dermatologists 2011
British Journal of Dermatology
Volume 165, Issue 6, pages 1349–1354, December 2011
How to Cite
Clos, A.L., Lasagna-Reeves, C.A., Castillo-Carranza, D.L., Sengupta, U., Jackson, G.R., Kelly, B., Beachkofsky, T.M. and Kayed, R. (2011), Formation of immunoglobulin light chain amyloid oligomers in primary cutaneous nodular amyloidosis. British Journal of Dermatology, 165: 1349–1354. doi: 10.1111/j.1365-2133.2011.10508.x
Conflicts of interest None declared.
- Issue published online: 24 NOV 2011
- Article first published online: 17 OCT 2011
- Accepted manuscript online: 5 JUL 2011 01:06PM EST
- Accepted for publication 26 June 2011
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.
Objectives 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.