Pathogenic potential of human monoclonal immunoglobulin light chains: relationship of in vitro aggregation to in vivo organ deposition.

Abstract

The deposition of certain Bence Jones proteins as tubular casts, basement membrane precipitates, or amyloid fibrils results in the human light-chain-associated renal and systemic dis -myeloma (cast) nephropathy, light-chain deposition disease, and immunocyte-derived (primary or AL) amyloidosis. To determine if light-chain nephrotoxicity or amyloidogenicity is related to the propensity of these components to form high molecular weight aggregates under physiological conditions, we used a size-exclusion chromatographic system to study 40 different Bence Jones proteins. Each sample was tested over a wide range of protein concentration in three different buffers varying in pH, osmolality, and the presence or absence oflow concentrations ofurea. Thirty-three of the 35 proteins found clinically and/or experimentally to form in vivo pathologic light-chain deposits were shown to undergo high-order self-association and form hh molecular weight aggregates. In contrast, of five nonpathologic proteins, one showed polymerization under the chromatographic conditions used. The correlation between the in vitro results achieved by size-exclusion chromatography and that found in vivo provides (i) a rapid dlagnostic method to identify potential nephrotoxic or amyloidogenic Bence Jones proteins and (ii) an experimental means to gain new insight into the physicochemical basis of light-chain aggregtion and the treatment of those invariably fatal disorders associated with pathologic lightchain deposition.The human light-chain-related renal and systemic diseasesmyeloma (cast) nephropathy, light-chain deposition disease, and immunocyte-derived (primary or AL) amyloidosisresult from the pathologic deposition of monoclonal light chains (i.e., Bence Jones proteins) in the form of casts, basement membrane precipitates, or fibrils, respectively (1). These light-chain deposits ultimately result in the impairment ofrenal and other organ function and account for much ofthe morbidity and mortality found in patients with these disorders. The fact that pathologic light-chain deposits are not an invariant accompaniment of clinical or experimental (1) Bence Jones proteinuria and are not necessarily directly related to the amount of monoclonal light chain synthesized or excreted implies that certain light chains are inherently nephrotoxic or amyloidogenic.Several in vitro and in vivo models have been devised that provide an experimental means to assess the pathologic potential of Bence Jones proteins (2-5). For example, in one model we demonstrated that the injection into mice ofcertain Bence Jones proteins resulted in the deposition in the mouse kidney of the human proteins in the form of tubular casts, basement membrane precipitates, crystals, or amyloid fibrils (6). Through studies involving >40 different Bence Jones proteins, we found that the renal lesions induced experimentally were comparable to those of patients from whom the proteins were derived and that the experimental mouse model was capable of differentiating "nephrotoxic" from "...

Counteracting Effects of Renal Solutes on Amyloid Fibril Formation by Immunoglobulin Light Chains

“…The recombinant V L protein LEN has the same sequence as a V L isolated from the urine of a patient (LEN) with multiple myeloma who, despite excretion of up to 50 g of this protein daily, had no renal dysfunction or evidence of amyloidosis (9,10). Both proteins were products of same germline gene family IV (10).…”

“…Other constituents of amyloid fibrils such as proteoglycans and apolipoprotein-E may also be relevant (3,9,26). Thus, different behaviors could be seen with the same protein, depending on individual-specific factors.…”

“…In vitro there is a strong inverse relationship between the intrinsic thermodynamic stability of light chains and their propensity to form fibrils (2,(5)(6)(7)(8). Furthermore, thermodynamic stability and propensity to form fibrils have been modulated extrinsically by employing solutes such as urea and sucrose (6,8,9).…”

Pitfalls of Molecular Replacement: the Structure Determination of an Immunoglobulin Light-Chain Dimer

“…The Bence-Jones protein from patient Cle was characterized serologically and by its aminoacid sequence as a 211I light chain with Mcg-Kern-Ozconstant region (Eulitz, Murphy, Weiss & Solomon, 1991). It was excreted as the covalent dimer, and Cle protein formed casts in the kidney tubules of the patient (Myatt et al, 1994). Light chains of the 2Ill subgroup represent about 43% of human )~ chains (Solomon & Weiss, 1995).…”

Lambda light chain deposition disease presenting as sicca syndrome

“…The different physicochemical properties of light chains and the tissue environment are responsible for the pattern of pathologic organ deposition (4). Light chain deposits, usually of kappa isotype, localize preferentially in kidney, liver, and myocardium.…”