Influence of Genes and Post-translational Modifications in the Pathogenesis of Light Chain Amyloidosis

Abstract: Amyloid is formed when a normally soluble protein undergoes conformational changes that results in self-aggregation. The pathogenic protein in light chain amyloidosis is an immunoglobulin light chain produced by a plasma cell clone mainly in the bone marrow. The light chain is transported via the circulation to various organs and tissues but deposits only in certain locations. The disease is very heterogenous and every patient can be considered to have their own disease, since symptoms and outcome vary enormously. In this thesis I have tried to elucidate some factors involved in the pathogenesis of light chain amyloidosis. Firstly, we investigated the impact of the germ line origin for tissue affinity and found out that even though it is important other factors like posttranslational modifications are also of relevance. Secondly we describe familial-like light chain amyloidosis in Sweden, affecting a father and son. The inheritance is hard to explain but we believe that genetic factors that might be involved in the rearrangement of light chain genes or that familial immunopathies predispose certain families for development of light chain amyloidosis. Thirdly, we wanted to study if cleavage of the light chain occurs before or after deposition, since purified light chain amyloid contains full-length, and N- and C-terminal fragments of the protein. The cleavage pattern in 1-5 organs from 6 patients was analyzed by Western blot with three antisera directed against one epitope in the N-terminal and two epitopes in the N- and C-terminal part of the protein. By using these antisera we could determine to which part of the light chain molecule the fragment belonged. We found fragments that could be aligned to compose the whole light chain. The finding indicates that cleavage occurs after deposition. Finally, we wanted to investigate if lambda amyloid fibrils contain small C-terminal fragments from the constant domain, earlier been detected in patients with kappa light chain amyloidosis. In concordance, we identified the same fragments in lambda patients and could demonstrate that these fragments made fibrils in vitro. The role of the small C-terminal peptides for the development of light chain amyloidosis must be further investigated.