Immunoglobulin light chains, glycosaminoglycans, and amyloid

Immunoglobulin light chains are the precursor proteins for fibrils that are formed during primary amyloidosis and in amyloidosis associated with multi ple myeloma. As found for the approximately 20 currently described forms of focal, localized, or systemic amyloidoses, light chain-related fibrils ext racted from physiological deposits are invariably associated with glycosami noglycans, predominantly heparan sulfate. Other amyloid-related proteins ar e either structurally normal, such as beta 2-microglobulin and islet amyloi d polypeptide, fragments of normal proteins such as serum amyloid A protein or the precursor protein of the beta peptide involved in Alzheimer's disea se, or are inherited forms of single amino acid variants of a normal protei n such as found in the familial forms of amyloid associated with transthyre tin. In contrast, the primary structures of light chains involved in fibril formation exhibit extensive mutational diversity rendering some proteins h ighly amyloidogenic and others non-pathological. The interactions between l ight chains and glycosaminoglycans are also affected by amino acid variatio n and may influence the clinical course of disease by enhancing fibril stab ility and contributing to resistance to protease degradation. Relatively li ttle is currently known about the mechanisms by which glycosaminoglycans in teract with light chains and light-chain fibrils. It is probable that futur e studies of this uniquely diverse family of proteins will continue to shed light on the processes of amyloidosis, and contribute as well to a greater understanding of the normal physiological roles of glycosaminoglycans.