Do V_L genes have prognostic relevance?

Primary or light chain–associated amyloidosis (AL), a monoclonal plasma cell dyscrasia, is characterized by the deposition of light chain–related proteins, principally of λ-type, as fibrils in vital organs (eg, heart, kidney, and liver) and other body tissues (eg, nerves and intestine), and results in morbidity and eventually, death. There are 2 remarkable features of this disease: first, for each patient, only one of these anatomic sites (at least initially) is the principal target of this pathologic process and, second, κ light chains deposit as amyloid less commonly then do λ light chains. Whether protein properties, host factors, or both are responsible for these phenomena are as yet unknown.

In this issue, Abraham and colleagues (page 3801) have confirmed and extended earlier reports (Comenzo et al, Blood. 2001;98:714-720; Perfetti et al, Blood. 2002;100:948-953) indicating that the products of certain light chain–variable region (V_L) genes are especially amyloidogenic and seem to deposit preferentially in particular locations, as exemplified by the association of V_λ2, V_λ6, and V_λ3 proteins with cardiac, renal, and soft-tissue deposits, respectively. Not unexpectedly, patients with heart involvement and those with more overt plasma cell proliferation (ie, multiple myeloma) fare poorly.

In AL amyloidosis, what accounts for the selection of a particular organ as the target of fibril deposition? One may speculate that in this clonal proliferative disorder, B cells respond to an antigenic stimulus by using (fortuitously) those V_L germ line genes that encode for potentially amyloidogenic light chains (ie, those that have primary structural features that render them intrinsically unstable) or, more likely, have destabilizing amino acid substitutions caused by somatic mutation. Since light chain dimers structurally resemble complete antibodies (Edmundson et al, Biochemistry. 1974;13:3816-3827), these molecules could bind to organ- or tissue-specific extracellular matrix proteins and, as a result of these interactions, form amyloid fibrils in situ.

For patients with AL amyloidosis, the recognition that there is a relationship between V_L genes, fibrillogenic light chains, and tissue affinity would have not only prognostic implications but also could provide the basis of new therapeutic strategies for this ultimately fatal disease.