| Autor: |
Atassi, M. Zouhair, Berliner, Lawrence J., Chang, Rowen Jui-Yoa, Jörnvall, Hans, Kenyon, George L., Wittman-Liebold, Brigitte, Uversky, Vladimir N., Fink, Anthony L., Ramirez-Alvarado, Marina, De Stigter, Janelle K., Baden, Elizabeth M., Sikkink, Laura A., McLaughlin, Richard W., Taboas, Anya L. |
| Zdroj: |
Protein Misfolding, Aggregation & Conformational Diseases; 2007, p183-197, 15p |
| Abstrakt: |
Light-chain amyloidosis (AL) is characterized by the clonal expansion of plasma B cells that secrete large amounts of monoclonal immunoglobulin light chains. The free light chains circulate in serum and form amyloid fibrils on vital organs such as the kidney, heart, and liver causing organ failure and eventually death. Multiple myeloma (MM) is another type of B-cell malignancy. MM results in bone lesions, hypercalcemia, renal failure, and anemia. Free light chains from MM patients are non-amyloidogenic. There is a small subset of MM patients (10-15%) that also develop light-chain amyloidosis complications. Amyloid fibrils are derived from the N-terminal region of the light-chain variable domain (VL). Due to the antigen-driven selection process, there is a large degree of mutational variability, thus each patient has a unique VL sequence. In some cases, the organ involvement has some correlation between VL subtype and germ-line donor sequence gene. To understand the amyloidogenicity of AL proteins, their thermodynamic properties have been compared with non-amyloidogenic MM proteins. Generally, AL proteins have lower thermodynamic stability than MM proteins. Current and future research is focusing on understanding the mutational diversity and organ tropism associated with AL, as well as understanding which species along the amyloid fibril formation pathway causes cellular toxicity. The current treatment for AL targets the plasma cell clone. Chemotherapy and peripheral stem cell transplantation are commonly used. Future therapies to treat this disease could involve small molecules that stabilize the folded state and inhibit amyloid fibril formation and molecules that bind to amyloid fibrils, destabilize the fibrils, thus reducing the amyloid burden. In this chapter, we discuss the structure, truncations, mutational diversity, and organ tropism of immunoglobulin light chains, thermodynamics, and fibril formation studies using AL and MM proteins and the current treatment options and also discuss directions in the study and treatment of AL. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Supplemental Index |
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