Immunoglobulin Light Chain-related Fibrils

Immunoglobulin light chain-related fibrils are amyloid fibrils formed from misfolded immunoglobulin (Ig) light chains. These fibrils are the pathological hallmark of systemic AL (amyloid light-chain) amyloidosis, a severe and often fatal protein misfolding disorder. In this disease, abnormal plasma cells produce excess monoclonal Ig light chains that circulate in the blood, misfold, and aggregate into insoluble amyloid fibrils. These deposits accumulate in various organs—most commonly the heart and kidneys—leading to progressive organ dysfunction and failure. The core of these amyloid fibrils is typically composed of a segment from the variable domain (VL) of the Ig light chain. High-resolution cryo-electron microscopy studies have revealed that these cores adopt an all-beta fold structure with significant conformational changes compared to native folded light chains. Patient-specific mutations within the VL domain can destabilize its native structure, promoting aggregation into amyloid. Efforts focus on reducing production/secretion of pathogenic free Ig light chains via chemotherapy targeting clonal plasma cells, stabilizing dimeric forms or preventing dissociation/aggregation using small molecules, and developing agents that disrupt existing deposits or enhance their clearance.

Reducing production/secretion of pathogenic free Ig light chains; Stabilizing dimeric forms or preventing dissociation/aggregation; Disrupting existing deposits or enhancing their clearance