Ea. Myatt et al., PATHOGENIC POTENTIAL OF HUMAN MONOCLONAL IMMUNOGLOBULIN LIGHT-CHAINS - RELATIONSHIP OF IN-VITRO AGGREGATION TO IN-VIVO ORGAN DEPOSITION, Proceedings of the National Academy of Sciences of the United Statesof America, 91(8), 1994, pp. 3034-3038
The deposition of certain Bence Jones proteins as tubular casts, basem
ent membrane precipitates, or amyloid fibrils results in the human fig
ht-chain-associated renal and systemic diseases-myeloma (cast) nephrop
athy, light-chain deposition disease, and immunocyte-derived (primary
Gr AL) amyloidosis. To determine if light-chain nephrotoxicity or amyl
oidogenicity is related to the propensity of these components to form
high molecular weight aggregates under physiological conditions, we us
ed a size-exclusion chromatographic system to study 40 different Bence
Jones proteins. Each sample was tested over a wide range of protein c
oncentration in three different buffers varying in pH, osmolality, and
the presence or absence of low concentrations of urea. Thirty-three o
f the 35 proteins found clinically and/or experimentally to form in vi
vo pathologic light-chain deposits were shown to undergo high-order se
lf-association and form high molecular weight aggregates. In contrast,
of five nonpathologic proteins, one showed polymerization under the c
hromatographic conditions used. The correlation between the in vitro r
esults achieved by size-exclusion chromatography and that found in viv
o provides (i) a rapid diagnostic method to identify potential nephrot
oxic or amyloidogenic Bence Jones proteins and (ii) an experimental me
ans to gain new insight into the physicochemical basis of light-chain
aggregation and the treatment of those invariably fatal disorders asso
ciated with pathologic light-chain deposition.