Tissue response to amyloidogenic light chains

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In AL amyloidosis, clonal immunoglobulin light chains form amyloid fibril deposits in tissues throughout the body. Amyloid fibril deposits occur infrequently in multiple myeloma, another clonal light chain disease, and not all in monoclonal gammopathy of unknown significance. Factors responsible for converting some monoclonal light chains to amyloid fibrils are unknown. The hypothesis of this project is that light chain modifications and a tissue response lead to fibril formation and deposition. 1) Using the deduced amino acid sequence obtained in Project 1, this project will examine amyloidogenic light chain proteins for sequence variations and post-translational modifications. Amyloid fibrils from tissue deposits of the same patients will be examined for size and proteolytic sites that may be secondary to protein modifications. 2) Proteoglycans are expected to play a key role in the physiologic mechanisms leading to amyloidogenic light chain deposition as fibrils. An increased amount of glycosaminoglycans (GAGs), particularly heparan sulfate, occurs with amyloid fibril deposition of AA (secondary) amyloidosis. Preliminary data suggests this is also true for the AL amyloidosis. Whether GAG enrichment precedes fibril deposition, is coincident with, or follows fibril deposition is not known. The influence of glycosaminoglycans on light chains in a tissue microenvironment will be tested in an in-vivo mouse model. 3) Amyloid deposition in tissues leads to organ dysfunction. The traditional explanation for this is a purely mechanical effect produced by massive infiltration of amyloid fibrils. However, clinical information and preliminary data suggest a deleterious effect of the light chain protein on tissue has been found experimentally for the beta-amyloid and transthyretin amyloidogenic proteins. The effect of circulating monoclonal light chains on organ function will be tested in an experimental model testing cardiac physiology. Correlation will be made between light chain sequence modifications and the biophysical properties observed in Project 2. Both will be correlated with the database of clinical information.