Amyloid formation from Immunoglobulin chains

Abstract

Amyloid 1 was first discovered during the examination of tissue by Rudolf Virchow in 1854.Because it could be stained in a similar manner as starch with iodine in Lugol's solution it was named "amyloid" by Virchow [1]. The deposition of this substance occurs extracellularly in small blood vessels and various organs. Examination under the light microscope reveals a homogeneous eosinophilic substance with hyaline appearance. Nowadays the diagnosis of amyloidosis still depends mainly on the examination of bioptic material from involved organs. Main criteria are the staining of amyloid with Congo red [2] and a characteristic green birefringence in polarized light.The formation of amyloid is associated with many different disorders and impairs the normal organ function when the deposits are severe. There have been controversial discussions about the nature of this substance for more than one hundred years. The observation by electron microscopy that the deposited material is composed of fibrils was a first step toward the unraveling of the mysteries of this disease [3]. A further major breakthrough happened when it became possible to extract amyloid fibrils from the tissue [4]. It was proven by serological and chemical methods that proteins are the main constituents of extracted amyloid fibrils and not, as supposed for a long time, starchlike polysaccharides. Particularly amino acid sequence analysis was applied successfully to identify the individual proteins which participate in the formation of amyloid deposits. These studies revealed that amyloidosis is not a single entity but is connected to a still growing range of various disorders and diseases. The current state of research in this field has been summarized by an international nomenclature committee at the Vlth International Symposium on Amyloidosis [5], which was held in Oslo in 1990.Because several excellent reviews on amyloidosis have been published [6-10], this paper concentrates only on amyloid formation from immunoglobulin chains. Magnus-Levy (in 1931 [11]) and Apitz (in 1940 [12]) were the first authors to report on correlations between multiple myeloma 1 Abbreviations: Protein A = amyloid associated protein; apoSAA = serum precursor of protein AA; AL-type = amyloid derived from immunoglobulin light chains; VHjjj = V-regions of immunoglobulin heavy (H) chains, subgroup III; CH = constant regions of H-chains

Mass spectrometry characterization of light chain fragmentation sites in cardiac AL amyloidosis: insights into the timing of proteolysis

“…In fact, whereas fragmentation sites in VL are rare or, as in the case of AL-H7, concentrated in the N-terminal portion of the molecule, fragmentation in the CL is scattered along the sequence. The truncation points identified in the N-terminal portion of the CL (around positions 124–133) in these two samples are largely concordant with those previously reported in other studies ( 25 ). The more distal truncation points in the CL, however, are mostly novel and suggest an intense degradation activity on this portion of the molecule.…”

“…This task is especially challenging in AL given the complexity of the fragmentation pattern. Past studies, based on biochemical investigations, amino acid analysis, and protein sequencing, detected fragmentation points that, across the various LCs, were located in the N-terminal part of the constant region (around amino acids 110, 130, and 150) ( 21 , 25 ). These studies, however, could not map the primary sequences of all the fragments but rather of the most abundant ones.…”

Recombinant immunoglobulin variable domains generated from synthetic genes provide a system for in vitro characterization of light‐chain amyloid proteins

“…In the case of light-chain-associated amyloidosis, the deposits contain a monoclonal Ig light chain (Glenner et al, 1971) or, more often, a light-chain fragment that consists of the variable domain (VL) and varying amounts of the constant domain (CL), or a mixture of fragment and full-length light chain. However, the presence of monoclonal light chains is not invariably associated with amyloid deposition; these proteins can be deposited in vivo in other pathologic forms, or, in some cases, they do not form deposits at all (Solomon, 1986;Buxbaum, 1992;Eulitz, 1992). Considerable effort has been devoted to determining the sequences of amyloid-associated Ig light chains in order to identify specific V-region residues responsible for fibril formation.…”

Dissecting the Molecular Features of Systemic Light Chain (AL) Amyloidosis: Contributions from Proteomics

“…Proteomic typing offers important advantages that have been extensively reviewed elsewhere [61,82]; however, AL amyloidosis also poses unique challenges to this approach. In fact, the above-discussed uniqueness of sequence in the V L translates in the fact that protein databases cannot contain the full sequence of each monoclonal LC, and therefore peptide ions from the variable domain, which forms the structured core of the fibrils, may not be matched [21,28,83]. In some instances, this may qualitatively and quantitatively affect protein identification and impair typing.…”