Immunoglobulin Light Chains Generate Hydrogen Peroxide

Abstract

As low molecular weight proteins, restriction from glomerular filtration is minimized, permitting significant amounts of Ig light chains to be endocytosed into the proximal tubule epithelium, particularly in plasma cell dyscrasias. Recent studies have shown that this effect of concentrating light chains within the proximal tubule alters cell function. This study demonstrated that light chains belonged to a class of proteins that are capable of catalyzing the formation of hydrogen peroxide. Sufficient amounts of hydrogen peroxide were produced in HK-2 cells to stimulate the production of monocyte chemoattractant protein-1 (MCP-1), a key chemokine involved in monocyte/macrophage migration and activation of the proximal tubule, and to increase lactate dehydrogenase release into the medium. The light chain-mediated effect on MCP-1 production was inhibited by co-incubation with 1,3-dimethyl-2-thiourea, which also inhibited lactate dehydrogenase release, and by pyrrolidine dithiocarbamate, an inhibitor of NF-B. The amount of light chain that stimulated an intracellular redox-signaling pathway in the proximal tubule cells was well within levels that are seen in patients who have plasma cell dyscrasias. The conclusion is that light chains possess a unique property that permits the development of intracellular oxidative stress that in turn promotes activation of the proximal tubule and elaboration of MCP-1.

Quantitative Assessment of Serum and Urinary Polyclonal Free Light Chains in Patients with Chronic Kidney Disease

“…Thus, as nephrons are lost, the remaining nephrons are exposed to increasing concentrations of polyclonal FLC. Recent studies demonstrated that monoclonal FLC promote proximal tubular injury by increasing intracellular oxidative stress with the subsequent production of monocyte chemoattractant protein 1 (28). Further work has shown that FLC induce epithelial-mesangial transition (29) and activate mesangial cells to proliferate and increase production of matrix proteins (30).…”

Kidney Disease and Multiple Myeloma

“…Light chains that are degraded induce proinflammatory cytokines, such as monocyte chemoattractant protein-1 and IL-6 and -8 (32,33). These light chains also seem to catalyze the production of reactive oxygen species, which in turn, results in inflammatory cell infiltration, matrix deposition, and fibrosis, and it may contribute to epithelial-mesenchymal transformation of renal tubular epithelial cells (34). Both the mitogen-activated kinase and NF-kB pathways mediate the proinflammatory cascade (32,33).…”

Tubular injury in multiple myeloma

“…Recently, it has been established that monoclonal FLCs, but not polyclonal light chains, may generate intracellular oxidative stress, particularly hydrogen peroxide (53). These molecules promote redox-signaling events that result in production of chemokines and cytokines, but also in apoptosis of the proximal tubular cells (53)(54)(55)(56).…”

“…These molecules promote redox-signaling events that result in production of chemokines and cytokines, but also in apoptosis of the proximal tubular cells (53)(54)(55)(56).…”