Review: Immunoglobulin light chain amyloidosis - The archetype of structural and pathogenic variability

AL amyloidosis is caused by deposition in target tissue of amyloid fibrils constituted by monoclonal immunoglobulin light chains. The amyloidogenic pl asma cells derive from a transformed memory B cell that can be identified b y anti-idiotype monoclonal antibodies. Comparison of the primary structures of amyloidogenic and nonamyloidogenic light chains does not show any commo n structural motif in the amyloidogenic variants but reveals peculiar repla cements which can destabilize the folding state. Reduced folding stability now appears to be a unifying property of amyloidogenic light chains. The te ndency of these proteins to populate a partially unfolded intermediate stat e is a key event in the self-association that progresses to the formation o f oligomers and fibrils. The mechanism of organ damage caused by AL amyloid deposition is not known, but clinical findings suggest that the process of amyloid fibril formation itself exerts tissue toxic effects independently of the amount of amyloid deposited. Since the disease is caused by the neop lastic expansion of the plasma cell population synthesizing the amyloidogen ic light chains, the clone represents the prime therapeutic target of conve ntional chemotherapy and experimental immunotherapy. In common with other t ypes of amyloidosis the therapeutic strategy can take advantage of drugs ab le to improve the reabsorption of the amyloid deposits or able to bind and stabilize the light chain in the native-like folded state. (C) 2000 Academi c Press.