Amyloidosis and the respiratory tract.

Amyloidosis is a generic term for a heterogeneous group of disorders associated with deposition of protein in an abnormal fibrillar form. The diverse spectrum of amyloid related diseases is now recognised to include Alzheimer’s disease, type II diabetes, and the transmissible spongiform encephalopathies. Amyloidosis can be hereditary or acquired, localised or systemic, and potentially lethal or merely an incidental finding. Amyloid deposits consist mainly of protein fibrils, the varying peptide subunits of which constitute the basis for its classification (table 1). Despite much heterogeneity among their respective precursor proteins, all amyloid fibrils have a remarkably similar adopted ultrastructure and share many physicochemical properties attributable to their acquired rich â-sheet content. Certain glycosaminoglycans (GAGs) are invariably associated with the fibrils and, in addition, all amyloid deposits contain the normal plasma protein serum amyloid P component (SAP). The specific binding interaction between SAP and all amyloid fibrils is the basis for our development of radiolabelled SAP as a diagnostic nuclear medicine tracer. 5 There have been many recent advances in amyloidosis including elucidation of the structure and properties of amyloid fibrils, the role of GAGs and SAP, and substantial improvements in clinical diagnosis and management. Although a specific generic treatment for the disease is not yet available, compelling evidence that amyloid deposits frequently regress when the supply of the respective fibril precursor protein is reduced has encouraged a much more positive approach to patient care. Pathogenesis of amyloidosis Amyloidosis is a disorder of protein folding which breaks the traditional dogma that amino acid sequence is the sole determinant of a protein’s tertiary form. Amyloid fibril proteins can evidently exist as two radically diVerent stable structures—a normal soluble form and the highly abnormal fibril conformation. The pathogenesis of amyloidosis thus centres around “oV pathway” folding of the various fibril precursor proteins into an alternative conformation rich in â-sheet structure which can form the characteristic fibrils by auto-aggregating in a highly ordered fashion. Fibril diVraction studies have confirmed that the â-strands within the â-sheets are arranged specifically, and that all amyloid fibrils share an essentially similar core structure. 8 This underlies their distinctive physicochemical properties including their ability to bind Congo red in a spatially organised manner, relative resistance to proteolysis, and capacity to bind SAP. Most fibril precursor proteins will form amyloid fibrils in vitro and in some instances the fibrils in vivo are composed of intact whole precursor molecules—for example, variants of transthyretin (TTR) and lysozyme in hereditary amyloidosis and â2-microglobulin in dialysis related amyloidosis (DRA). More often the precursor proteins undergo partial cleavage, although it is not known exactly when this occurs. 14 Although the amino acid sequence underlies the potential for a protein to form amyloid, and an essential prerequisite for its development is a sustained supply of the respective fibril precursor, little is known about the genetic or environmental factors that determine