title: β(2)-microglobulin amyloidosis.
abstract: Dialysis-related amyloidosis (DRA) is a clinical syndrome of pain, loss of function and other symptoms due to the deposition of amyloid consisting of β(2)-microglobulin (β(2)m) in the musculoskeletal system. The condition is seen in patients who suffer from chronic kidney disease and are treated with hemodialysis for a long time. Even though β(2)m easily can be manipulated to form amyloid in laboratory experiments under non-physiological conditions the precise mechanisms involved in the formation of β(2)m-amyloid in patients with DRA have been difficult to unravel. The current knowledge which is reviewed here indicates that conformational fluctuations centered around the D-strand, the DE-loop, and around the cis-configured Pro32 peptide bond are involved in β(2)m amyloidosis. Also required are highly increased concentrations of circulating β(2)m and possibly various post-translational modifications mediated by the pro-inflammatory environment in uremic blood, together with the influence of divalent metal ions (specifically Cu(2 +)), uremic toxins, and dialysis-enhanced redox-processes. It seems plausible that domain-swapped β(2)m dimers act as building blocks of β-spine cross-β -sheet fibrils consisting of otherwise globular, roughly natively folded protein. An activated complement system and cellular activation perpetuate these reactions which due to the affinity of β(2)m-amyloid for the collagen of synovial surfaces result in the DRA syndrome.
authors.affiliation: Department of Clinical Biochemistry and Immunology, Division of Microbiology and Diagnostics, Statens Serum Institut, Bldg. 85/240, Artillerivej 5, 2300, Copenhagen S, Denmark, dbcw@novonordisk.com.
authors.forename: Dorthe B
authors.initials: DB
authors.lastname: Corlin
authors.forename: Niels H H
authors.initials: NH
authors.lastname: Heegaard
mesh_terms: D000682:Amyloid / Q000737:chemistry / Q000378:metabolism; D000686:Amyloidosis / Q000097:blood / Q000209:etiology; D000818:Animals; D003167:Complement Activation; D003165:Complement System Proteins / Q000737:chemistry / Q000378:metabolism; D003300:Copper / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D017510:Protein Folding; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D006435:Renal Dialysis / Q000009:adverse effects*; D051436:Renal Insufficiency, Chronic / Q000097:blood* / Q000628:therapy; D014511:Uremia / Q000097:blood / Q000628:therapy; D001613:beta 2-Microglobulin
chemical_list: D000682:Amyloid; D001613:beta 2-Microglobulin; D003300:Copper; D003165:Complement System Proteins