Molecular Mechanism of Pathogenesis and Treatment Strategies for AL Amyloidosis

Abstract

In amyloid light-chain (AL) amyloidosis, small B-cell clones (mostly plasma cell clones) present in the bone marrow proliferate and secrete unstable monoclonal free light chains (FLCs), which form amyloid fibrils that deposit in the interstitial tissue, resulting in organ injury and dysfunction. AL amyloidosis progresses much faster than other types of amyloidosis, with a slight delay in diagnosis leading to a marked exacerbation of cardiomyopathy. In some cases, the resulting heart failure is so severe that chemotherapy cannot be administered, and death sometimes occurs within a few months. To date, many clinical studies have focused on therapeutics, especially chemotherapy, to treat this disease. Because it is necessary to promptly lower FLC, the causative protein of amyloid, to achieve a hematological response, various anticancer agents targeting neoplastic plasma cells are used for the treatment of this disease. In addition, many basic studies using human specimens to elucidate the pathophysiology of AL have been conducted. Gene mutations associated with AL, the characteristics of amyloidogenic LC, and the structural specificity of amyloid fibrils have been clarified. Regarding the mechanism of cellular and tissue damage, the mass effect due to amyloid deposition, as well as the toxicity of pre-fibrillar LC, is gradually being elucidated. This review outlines the pathogenesis and treatment strategies for AL amyloidosis with respect to its molecular mechanisms.

Metals Biotribology and Oral Microbiota Biocorrosion Mechanisms

“…This condition leads to a sequence of incorrect biochemical stimuli also linked to the biomaterial itself. It has been noted that the formation of amyloid-like proteins causes irreversible damage and binds the mechanisms of fibril formation [ 65 , 66 ]. In addition, metal ions bind directly or indirectly to O 2 , N, and S atoms or to negative ions in the body.…”

“…In addition, metal ions bind directly or indirectly to O 2 , N, and S atoms or to negative ions in the body. They can be one of the causes of corruption from the fact that these belong to transition metals, which according to the reactions of Fenton and Haber—Weiss are present in one of the phases of the deterioration of materials [ 66 , 67 ]. Hence, biomaterials that contain metal ions such as Fe, Ni, Ti, or Cu can initiate tissue damage.…”

Left atrium strain parameters in light chain cardiac amyloidosis and hypertensive heart disease

“…Amyloidosis is a constellation of diseases characterized by misfolded proteins deposited in target organs 1 . Cardiac involvements were thought to be very rare previously but are now understood to be underdiagnosed 2 .…”

“…Acquired monoclonal immunoglobulin light-chain (AL); hereditary, mutated transthyretin-related (ATTRm); and wild-type transthyretin-related (ATTRwt) are considered as three major types of cardiac amyloidosis 3 . Light chains cardiac amyloidosis (AL-CA) progresses much faster than other types of amyloidosis, and appropriate treatment is capable of prolonging survival time substantially 1,4 .…”

Molecular Research on Amyloidosis

“…Ikura et al [ 5 ] reviewed recent topics on the molecular mechanisms of pathogenesis and therapeutic strategies for AL amyloidosis. To elucidate the pathogenesis of AL, many basic studies using human specimens have been performed, and genetic mutations associated with AL [ 6 ], the characteristics of amyloidogenic light chains (LCs) [ 7 ], and the structural specificity of amyloid fibrils [ 8 , 9 ] have been clarified.…”