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Evidence That Amyloidogenic Light Chains Undergo Antigen-Driven
Selection
Vittorio Perfetti,
Paola Ubbiali,
Maurizio Colli Vignarelli,
Marta Diegoli,
Roberta Fasani,
Monica Stoppini,
Antonella Lisa,
Palma Mangione,
Laura Obici,
Eloisa Arbustini, and
Giampaolo Merlini
From the Research Laboratories of Biotechnology and Organ
Transplantation, Clinical Immunology Unit, the Department of Internal
Medicine, Section of Internal Medicine and Medical
Oncology, and the Institutes of Human
Pathology, Biochemistry, and
CNR-IGBE, University of Pavia-IRCCS Policlinico S. Matteo,
Pavia, Italy.
AL amyloidosis is characterized by fibrillar tissue deposits
(amyloid) composed of monoclonal light chains secreted by small numbers
of indolent bone marrow plasma cells whose ontogenesis is unknown. To
address this issue and to provide insights into the processes that
accompanied pathogenic light chain formation, we isolated the complete
variable (V) regions of 14 light (VL) and 3 heavy (VH) chains secreted
by amyloid clones at diagnosis (10 Bence Jones and 4 with complete Igs,
9  and 5  ) by using an inverse polymerase chain reaction-based
approach free of primer-induced biases. Amyloid V regions were found to
be highly mutated compared with the closest germline genes in the
databases or those isolated from the patients' DNA, and mutations were
not associated with intraclonal diversification. Apparently high usage
of the III family germline gene V III.1 was observed (4 of 9 light chains). Analysis of the nature and distribution of somatic
mutations in amyloid V regions showed that there was statistical
evidence of antigen selection in 8 of 14 clones (7 in VL and 1 in VH).
These results indicate that a substantial proportion of the amyloid clones developed from B cells selected for improved antigen binding properties and that pathogenic light chains show evidence of this selection.
Blood, Vol. 91 No. 8 (April 15), 1998:
pp. 2948-2954
© 1998 by The American Society of Hematology.
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