AL amyloidosis is characterized by fibrillar tissue deposits (amyloid)
composed of monoclonal light chains secreted by small numbers of indo
lent bone marrow plasma cells whose ontogenesis is unknown. To address
this issue and to provide insights into the processes that accompanie
d pathogenic light chain formation, we isolated the complete variable
(V) regions of 14 light (VL) and 3 heavy (VH) chains secreted by amylo
id clones at diagnosis (10 Bence Jones and 4 with complete Igs, 9 lamb
da and 5 kappa) by using an inverse polymerase chain reaction-based ap
proach free of primer-induced biases. Amyloid V regions were found to
be highly mutated compared with the closest germline genes in the data
bases or those isolated from the patients' DMA, and mutations were not
associated with intraclonal diversification. Apparently high usage of
the XIII family germline gene V lambda III.1 was observed (4 of 9 lam
bda light chains), Analysis of the nature and distribution of somatic
mutations in amyloid V regions showed that there was statistical evide
nce of antigen selection in 8 of 14 clones (7 in VL and 1 in VH). Thes
e results indicate that a substantial proportion of the amyloid clones
developed from B cells selected for improved antigen binding properti
es and that pathogenic light chains show evidence of this selection. (
C) 1998 by The American Society of Hematology.