he enormous diversity of immunoglobulin (Ig) specificities is the product of combinatorial joining of a relatively limited number of germline genes, and the subsequent somatic hypermutation of the rearranged genes. The resulting diversity comes at a price. First, self-reactive antibodies are generated and need to be deleted from the repertoire. Second, structurally compromised Ig chains are generated at considerable frequency during diversification. Normally, these do not pose a significant health problem, indicating that the immune system has built-in mechanisms to detect and, if necessary, eliminate the expression of such dysfunctional molecules. Occasionally, however, expression of a given Ig light chain (LC) has pathological consequences: LCs are involved in a group of human diseases, affecting a large number of people, whose common denominator is LC aggregation.
Light chain diseases
The Ig LC has a range of actions in diseases 1 , from benign high-level production of a soluble LC to pathological deposition of LCs, which disrupts organ function. Many B-cell neoplasms are accompanied by secretion of LCs, often detected as Bence-Jones proteins in the urine, soluble even at high protein concentrations. Other LCs aggregate and are deposited, with various morphologies, in a number of organs. In LC-deposition disease (LCDD), punctate deposits are seen in the basement membranes of the glomerulus and other tissues 2,3 . Tubular cast formation involves aggregation of Bence-Jones proteins in the renal tubules 4 . Intracellular LC deposits in bone marrow plasma cells and in renal tubular cells are characteristic of acquired Fanconi's syndrome 5 . Finally, LCs are frequently involved in amyloidosis, forming birefringent, unbranched fibrils of 5-10 nm in diameter, which become deposited in interstitial tissues, arterial walls and basement membranes [2][3][4] .
In all these diseases, the deposits can contain either whole LC or LC fragments. Tubular cast nephropathy and the systemic forms of LC amyloidosis and LCDD are evidently consequences of LCs that are secreted from plasma cells, and are therefore soluble (at least transiently). However, other LC pathologies are attributable to proteins that are either not secreted, or self-associate and aggregate intracellularly. Extensive amyloid formation in the rough endoplasmic reticulum (ER) of plasma cells has been described 6 . Aggregation of overproduced proteins as inclusion bodies in recombinant expression systems is a common occurrence, and a human analog of this phenomenon is the large Ig-derived occlusions found in some plasma cells, known as Mott cells 7 .