Contribution of Polyclonal Free Light Chain Deposition to Tubular Injury

Parasuraman, Ravi; Wolforth, Stacy C.; Wiesend, Wendy N.; Dumler, Francis; Rooney, Michelle Nayahamui; Li, Wei; Zhang, Ping L.

doi:10.1159/000356557

Cited by 8 publications

(3 citation statements)

References 53 publications

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“…FLCs may also contribute to tubular injury in patients with CKD(29). Thus, the present work by Ying et al is important, because it substantially expands upon previous knowledge related to the pathogenic role of monoclonal FLCs within the kidney that may ultimately provide insight for the development of novel therapeutics.…”

mentioning

confidence: 73%

Freedom isn’t always free: immunoglobulin free light chains promote renal fibrosis

Taylor

Ryan

2019

Journal of Clinical Investigation

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Renal injury in multiple myeloma Clonal plasma cell dyscrasias, including monoclonal gammopathy of undetermined significance (MGUS), solitary plasmacytoma, immunoglobulin-mediated amy loidosis, and multiple myeloma (MM), are relatively common disorders, with 2% to 3% of patients over the age of 50 affected by premalignant MGUS. MGUS can progress to MM, which accounts for 12% to 13% of all hematologic malignancies in the United States (1). The complications of MM include hypercalcemia, anemia, bone disease, such as lytic lesions and/or severe osteopenia, and renal insufficiency. MM is the most common malignancy associated with end-stage renal disease (2), and, depending on the diagnostic criteria (serum creatinine level), 20% to 50% of patients have renal failure at diagnosis (3). Because of the high prevalence of renal involvement in MM and its documented importance as a prognostic indicator (4),

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mentioning

confidence: 73%

Freedom isn’t always free: immunoglobulin free light chains promote renal fibrosis

Taylor

Ryan

2019

Journal of Clinical Investigation

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“…Then, the endosomes in the proximal tubules catabolize the internalized LCs, returning the amino acids to circulation. Due to the low concentration and structural heterogeneity of polyclonal free LCs circulating in the blood of normal individuals, tissue deposition rarely occurs ( 304 ).…”

Section: Diseases Caused By Immunoglobulin Light Chains Misfolding An...mentioning

confidence: 99%

Role of the mechanisms for antibody repertoire diversification in monoclonal light chain deposition disorders: when a friend becomes foe

et al. 2023

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The adaptive immune system of jawed vertebrates generates a highly diverse repertoire of antibodies to meet the antigenic challenges of a constantly evolving biological ecosystem. Most of the diversity is generated by two mechanisms: V(D)J gene recombination and somatic hypermutation (SHM). SHM introduces changes in the variable domain of antibodies, mostly in the regions that form the paratope, yielding antibodies with higher antigen binding affinity. However, antigen recognition is only possible if the antibody folds into a stable functional conformation. Therefore, a key force determining the survival of B cell clones undergoing somatic hypermutation is the ability of the mutated heavy and light chains to efficiently fold and assemble into a functional antibody. The antibody is the structural context where the selection of the somatic mutations occurs, and where both the heavy and light chains benefit from protective mechanisms that counteract the potentially deleterious impact of the changes. However, in patients with monoclonal gammopathies, the proliferating plasma cell clone may overproduce the light chain, which is then secreted into the bloodstream. This places the light chain out of the protective context provided by the quaternary structure of the antibody, increasing the risk of misfolding and aggregation due to destabilizing somatic mutations. Light chain-derived (AL) amyloidosis, light chain deposition disease (LCDD), Fanconi syndrome, and myeloma (cast) nephropathy are a diverse group of diseases derived from the pathologic aggregation of light chains, in which somatic mutations are recognized to play a role. In this review, we address the mechanisms by which somatic mutations promote the misfolding and pathological aggregation of the light chains, with an emphasis on AL amyloidosis. We also analyze the contribution of the variable domain (VL) gene segments and somatic mutations on light chain cytotoxicity, organ tropism, and structure of the AL fibrils. Finally, we analyze the most recent advances in the development of computational algorithms to predict the role of somatic mutations in the cardiotoxicity of amyloidogenic light chains and discuss the challenges and perspectives that this approach faces.

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“…Finally, the monoclonal light chains can randomly distribute along proximal tubules, which can be identified by immunofluorescent staining, but there is no specific appearance by electron microscopy, thus called monoclonal proximal tubulopathy without cytoplasmic inclusions. The monoclonal proximal tubules can also coexist with other variants of paraprotein‐associated kidney diseases such as monoclonal cast nephropathy or monoclonal light chain deposition disease (Parasuraman et al, 2013).…”

Section: Evs In Monoclonal Protein Associated Renal Diseasesmentioning

confidence: 99%

Extracellular vesicles mediate cellular interactions in renal diseases—Novel views of intercellular communications in the kidney

Zhang

Liu

2021

Journal Cellular Physiology

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The kidney is a complicated and important internal organ receiving approximately 20% of the cardiac output and mediates numerous pathophysiologic actions. These include selectively filtering macromolecules of the blood, exquisite reclaimation of electrolyctes, urine concentration via an elegant osmotic mechanism, and excretion of an acid load. In addition, the renal tubules carry out secretory functions and produce hormones and cytokines. The kidney receives innervation and hormonal regulation. Therefore, dysfunction of the kidney leads to retention of metabolic waste products, and/or significant proteinuria and hematuria. In the past several decades, the role of extracellular vesicles (EVs) in intercellular communications, and the uptake of EVs by recipient cells through phagocytosis and endocytosis have been elucidated. The new knowledge on EVs expands over the classical mechanisms of cellular interaction, and may change our way of thinking of renal pathophysiology in the subcellular scale. Based on some ultrastructural discoveries in the kidney, this review will focus on the role of EVs in intercellular communications, their internalization by recipient cells, and their relationship to renal pathology.

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Contribution of Polyclonal Free Light Chain Deposition to Tubular Injury

Cited by 8 publications

References 53 publications

Freedom isn’t always free: immunoglobulin free light chains promote renal fibrosis

Freedom isn’t always free: immunoglobulin free light chains promote renal fibrosis

Role of the mechanisms for antibody repertoire diversification in monoclonal light chain deposition disorders: when a friend becomes foe

Extracellular vesicles mediate cellular interactions in renal diseases—Novel views of intercellular communications in the kidney

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