Immunoglobulin Light Chains

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Paul W Sanders - One of the best experts on this subject based on the ideXlab platform.

  • The Proximal Tubule Toxicity of Immunoglobulin Light Chains
    Kidney International Reports, 2021
    Co-Authors: Christophe Sirac, Vecihi Batuman, Paul W Sanders
    Abstract:

    Abstract Plasma and B cells dyscrasias that overproduce monoclonal Immunoglobulin free Light Chains (FLC) affect the kidney frequently in various ways. The hematologic dyscrasia responsible for the production of FLCs may or may not meet the criteria for cancer, such as multiple myeloma or lymphoma, or may remain subclinical. If there is overt malignancy, the accompanying kidney disorder is called myeloma- or lymphoma-associated. If the dyscrasia is subclinical, the associated kidney disorders are grouped as monoclonal gammopathy of renal significance. Both glomeruli and tubules may be involved. The proximal tubule disorders comprise a spectrum of interesting syndromes, which range in severity. This review focuses on the recent insights gained into the patterns and the mechanisms of proximal tubule toxicity of FLCs, including subtle transport disorders, such as proximal tubule acidosis, partial or complete Fanconi syndrome, or severe acute or chronic renal failure. Histologically, there may be crystal deposition in the proximal tubule cells, acute tubule injury, interstitial inflammation, fibrosis, and tubule atrophy. Specific structural alterations in the V domain of FLCs caused by somatic hypermutations are responsible for crystal formation as well as partial or complete Fanconi syndrome. Besides crystal formation, tubulointerstitial inflammation and proximal tubulopathy can be mediated by direct activation of inflammatory pathways through cytokines and toll-like receptors due to cell stress responses induced by excessive FLC endocytosis into the proximal tubule cells. Therapy directed against the clonal source of the toxic Light chain can prevent progression to more severe lesions and may help preserve kidney function.

  • Immunoglobulin Light Chains generate pro inflammatory and pro fibrotic kidney injury
    Journal of Clinical Investigation, 2019
    Co-Authors: Weizhong Ying, Paul W Sanders, Sunil Rangarajan, Wenguang Feng, Lisa M Curtis
    Abstract:

    Because of the less-than-robust response to therapy and impact on choice of optimal chemotherapy and prognosis, chronic kidney disease has drawn attention in the treatment of multiple myeloma, a malignant hematologic disorder that can produce significant amounts of monoclonal Immunoglobulin free Light Chains (FLCs). These low-molecular-weight proteins are relatively freely filtered through the glomerulus and are reabsorbed by the proximal tubule. The present study demonstrated that during the process of metabolism of Immunoglobulin FLCs, ROS activated the STAT1 pathway in proximal tubule epithelium. STAT1 activation served as the seminal signaling molecule that produced the proinflammatory molecule IL-1β, as well as the profibrotic agent TGF-β by this portion of the nephron. These effects occurred in vivo and were produced specifically by the generation of hydrogen peroxide by the VL domain of the Light chain. To the extent that the experiments reflect the human condition, these studies offer insights into the pathogenesis of progressive kidney failure in the setting of lymphoproliferative disorders, such as multiple myeloma, that feature increased circulating levels of monoclonal Immunoglobulin fragments that require metabolism by the kidney.

  • Immunoglobulin Light Chains activate tubular epithelial cells through redox signaling
    Journal of The American Society of Nephrology, 2010
    Co-Authors: Kolitha Basnayake, Peixuan Wang, Weizhong Ying, Paul W Sanders
    Abstract:

    The renal proximal tubule metabolizes circulating low-molecular-weight proteins such as Ig free Light Chains. In the setting of plasma cell dyscrasias, the burden of filtered protein can be very high. Endocytosis of certain nephrotoxic Light Chains induces H2O2 production and monocyte chemoattractant protein-1 (MCP-1) release, leading to recruitment of inflammatory cells and interstitial fibrosis, but how these processes are linked mechanistically is not well understood. This study investigated the relationship between H2O2 generated after Light chain endocytosis by human proximal tubular (HK-2) cells and activation of c-Src, a redox-sensitive tyrosine kinase. HK-2 cells exposed to two different Light Chains upregulated c-Src activity, which increased the production of MCP-1. In parallel, we observed a time-dependent oxidation of c-Src. Inhibition of c-Src activity and silencing c-Src expression abrogated the Light chain–induced MCP-1 response, but had no effect on H2O2, indicating that production of H2O2 is upstream of c-Src in the signaling cascade. Silencing megalin and cubilin expression inhibited the MCP-1 response, whereas extracellular catalase did not, indicating that endocytosis is required and that intracellular generation of reactive oxygen species activates c-Src. These data show that intracellular H2O2 induced by endocytosis of monoclonal free Light Chains oxidizes and activates c-Src, which promotes release of MCP-1.

  • Immunoglobulin Light Chains generate hydrogen peroxide
    Journal of The American Society of Nephrology, 2007
    Co-Authors: Peixuan Wang, Paul W Sanders
    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-κB. 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.

  • mapping the binding domain of Immunoglobulin Light Chains for tamm horsfall protein
    American Journal of Pathology, 2001
    Co-Authors: Weizhong Ying, Paul W Sanders
    Abstract:

    Cast nephropathy, or myeloma kidney, is a potentially reversible cause of chronic renal failure. In this condition, filtered Light Chains bind to a common site on Tamm-Horsfall protein (THP), which is produced by cells of the thick ascending limb of the loop of Henle. Subsequent aggregation of these proteins produces casts that obstruct tubule fluid flow and results in renal failure. In the present study, we used the yeast two-hybrid system to determine the site of interaction of Light Chains with THP. The third complementarity-determining region (CDR3) of both κ and λ Light Chains interacted with THP. These findings were confirmed in a series of competition studies using a synthetic peptide that corresponded to the CDR3 region and purified THP and Light Chains. Variations in the CDR3 sequence of the Light chain affected binding. Thus, the current studies increase our understanding of the process of cast formation and provide an opportunity to develop strategies that may inhibit this interaction and prevent the clinical manifestations of myeloma kidney.

Frank A. Redegeld - One of the best experts on this subject based on the ideXlab platform.

  • effects of free Immunoglobulin Light Chains on viral myocarditis
    Circulation Research, 2010
    Co-Authors: Akira Matsumori, Miho Shimada, Xiao Jie, Hirokazu Higuchi, Tom Groot Kormelink, Frank A. Redegeld
    Abstract:

    Rationale: In recent work, we have demonstrated a crucial role of mast cells in the development of viral myocarditis. Viral infection could lead to increased synthesis of free Immunoglobulin Light Chains (FLC) and our earlier work showed that FLC can trigger mast cell activation. Objective: We studied the possible involvement of FLC in the pathogenesis of viral myocarditis, and therapeutic effects of FLC using an animal model of viral myocarditis. Methods and Results: DBA/2 mice were inoculated intraperitoneally with encephalomyocarditis (EMC) virus. Serum levels and concentrations in the heart of κ FLC on day 14 in mice inoculated with EMC virus were significantly increased compared with controls. Myocardial viral concentration was significantly inhibited, the area of myocardial lesions was smaller in mice treated with κ or λ FLC, and survival of mice given FLC significantly improved. In contrast, an FLC antagonist deteriorated myocarditis. κ and λ FLC Chains inhibited EMC viral replication in human amnion cells in vitro. λ FLC significantly increased the gene expression of interleukin-10 in the heart which was previously shown to improve viral myocarditis when given exogenously. FLC also tended to increase the gene expressions of interferon-α and -γ in the heart mice. Conclusions: FLC have antiviral and antiinflammatory effects and improved viral myocarditis in mice. FLC may be promising agents for the treatment of viral myocarditis.

  • Free Immunoglobulin Light Chains: a novel target in the therapy of inflammatory diseases
    Trends in pharmacological sciences, 2008
    Co-Authors: Marco Thio, Bart R. Blokhuis, Frans P. Nijkamp, Frank A. Redegeld
    Abstract:

    In recent years, novel therapeutic strategies have become available for the treatment of chronic inflammatory disease. Neutralizing proinflammatory mediators such as leukotrienes and TNF-α, in addition to anti-IgE therapies (Omaluzimab) that target higher in the inflammatory cascade, have shown success in the treatment of allergic or autoimmune disorders. Free Immunoglobulin Light Chains, which are produced by B lymphocytes and secreted into serum, might play a crucial role in the pathogenesis of inflammatory disease. Concentrations of free Light Chains are significantly increased under diverse pathological conditions in humans, and have been linked to the progression and severity of immune diseases. Here we discuss the importance of free Immunoglobulin Light Chains as a potential therapeutic target in the treatment of chronic inflammatory disease.

  • free Immunoglobulin Light Chains as target in the treatment of chronic inflammatory diseases
    European Journal of Pharmacology, 2006
    Co-Authors: Maurice W Van Der Heijden, Aletta D Kraneveld, Frank A. Redegeld
    Abstract:

    Immunoglobulin free Light Chains were long considered irrelevant bystander products of Immunoglobulin synthesis by B lymphocytes. To date, different studies suggest that free Light Chains may have important functional activities. For instance, it has been shown that Immunoglobulin free Light Chains can elicit mast cell-driven hypersensitivity responses leading to asthma and contact sensitivity. Free Light Chains also show other biologic actions such as anti-angiogenic and proteolytic activities or can be used as specific targeting vehicles. Levels of free Light chain levels in body fluids increase markedly in diseases such as multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus. In this review, we will focus on the unexpected biological activities of Immunoglobulin free Light Chains with special attention to its possible role in the induction of chronic inflammatory diseases.

Ingrid G. Haas - One of the best experts on this subject based on the ideXlab platform.

  • Dissociation from BiP and Retrotranslocation of Unassembled Immunoglobulin Light Chains Are Tightly Coupled to Proteasome Activity
    Molecular Biology of the Cell, 2000
    Co-Authors: Josep Chillarón, Ingrid G. Haas
    Abstract:

    Unassembled Immunoglobulin Light Chains expressed by the mouse plasmacytoma cell line NS1 (kappa(NS1)) are degraded in vivo with a half-life of 50-60 min in a way that closely resembles endoplasmic reticulum (ER)-associated degradation (). Here we show that the peptide aldehydes MG132 and PS1 and the specific proteasome inhibitor lactacystin effectively increased the half-life of kappa(NS1), arguing for a proteasome-mediated degradation pathway. Subcellular fractionation and protease protection assays have indicated an ER localization of kappa(NS1) upon proteasome inhibition. This was independently confirmed by the analysis of the folding state of kappa(NS1) and size fractionation experiments showing that the Immunoglobulin Light chain remained bound to the ER chaperone BiP when the activity of the proteasome was blocked. Moreover, kinetic studies performed in lactacystin-treated cells revealed a time-dependent increase in the physical stability of the BiP-kappa(NS1) complex, suggesting that additional proteins are present in the older complex. Together, our data support a model for ER-associated degradation in which both the release of a soluble nonglycosylated protein from BiP and its retrotranslocation out of the ER are tightly coupled with proteasome activity.

Gareth J Morgan - One of the best experts on this subject based on the ideXlab platform.

  • structural basis for the stabilization of amyloidogenic Immunoglobulin Light Chains by hydantoins
    Bioorganic & Medicinal Chemistry Letters, 2020
    Co-Authors: Nicholas L Yan, Diogo Santosmartins, Enrico Rennella, B Sanchez, Jason S Chen, Lewis E Kay, Ian A Wilson, Gareth J Morgan, Stefano Forli, Jeffery W Kelly
    Abstract:

    Misfolding and aggregation of Immunoglobulin Light Chains (LCs) leads to the degeneration of post-mitotic tissue in the disease Immunoglobulin LC amyloidosis (AL). We previously reported the discovery of small molecule kinetic stabilizers of the native dimeric structure of full-length LCs, which slow or stop the LC aggregation cascade at the outset. A predominant structural category of kinetic stabilizers emerging from the high-throughput screen are coumarins substituted at the 7-position, which bind at the interface between the two variable domains of the Light chain dimer. Here, we report the binding mode of another, more polar, LC kinetic stabilizer chemotype, 3,5-substituted hydantoins. Computational docking, solution nuclear magnetic resonance experiments, and x-ray crystallography show that the aromatic substructure emerging from the hydantoin 3-position occupies the same LC binding site as the coumarin ring. Notably, the hydantoin ring extends beyond the binding site mapped out by the coumarin hits. The hydantoin ring makes hydrogen bonds with both LC monomers simultaneously. The alkyl substructure at the hydantoin 5-position partially occupies a novel binding pocket proximal to the pocket occupied by the coumarin substructure. Overall, the hydantoin structural data suggest that a larger area of the LC variable-domain-variable-domain dimer interface is amenable to small molecule binding than previously demonstrated, which should facilitate development of more potent full-length LC kinetic stabilizers.

  • stabilization of amyloidogenic Immunoglobulin Light Chains by small molecules
    Proceedings of the National Academy of Sciences of the United States of America, 2019
    Co-Authors: Gareth J Morgan, Nicholas L Yan, Enrico Rennella, David E Mortenson, Joshua M Blundon, Ryan M Gwin, Chung Yon Lin, Robyn L Stanfield, Steven J Brown, Hugh Rosen
    Abstract:

    In Ig Light-chain (LC) amyloidosis (AL), the unique antibody LC protein that is secreted by monoclonal plasma cells in each patient misfolds and/or aggregates, a process leading to organ degeneration. As a step toward developing treatments for AL patients with substantial cardiac involvement who have difficulty tolerating existing chemotherapy regimens, we introduce small-molecule kinetic stabilizers of the native dimeric structure of full-length LCs, which can slow or stop the amyloidogenicity cascade at its origin. A protease-coupled fluorescence polarization-based high-throughput screen was employed to identify small molecules that kinetically stabilize LCs. NMR and X-ray crystallographic data demonstrate that at least one structural family of hits bind at the LC–LC dimerization interface within full-length LCs, utilizing variable-domain residues that are highly conserved in most AL patients. Stopping the amyloidogenesis cascade at the beginning is a proven strategy to ameliorate postmitotic tissue degeneration.

  • role of domain interactions in the aggregation of full length Immunoglobulin Light Chains
    Proceedings of the National Academy of Sciences of the United States of America, 2019
    Co-Authors: Enrico Rennella, Lewis E Kay, Gareth J Morgan, Jeffery W Kelly
    Abstract:

    Amyloid Light-chain (LC) amyloidosis is a protein misfolding disease in which the aggregation of an overexpressed antibody LC from a clonal plasma cell leads to organ toxicity and patient death if left untreated. While the overall dimeric architecture of LC molecules is established, with each LC composed of variable (VL) and constant (CL) domains, the relative contributions of LC domain-domain interfaces and intrinsic domain stabilities to protection against LC aggregation are not well understood. To address these topics we have engineered a number of domain-destabilized LC mutants and used solution NMR spectroscopy to characterize their structural properties and intrinsic stabilities. Moreover, we used fluorescence spectroscopy to assay their aggregation propensities. Our results point to the importance of both dimerization strength and intrinsic monomer stability in stabilizing VL domains against aggregation. Notably, in all cases considered VL domains aggregate at least 10-fold faster than full-length LCs, establishing the important protective role of CL domains. A strong protective coupling is found between VL-VL and CL-CL dimer interfaces, with destabilization of one interface adversely affecting the stability of the other. Fibril formation is observed when either the VL or CL domain in the full-length protein is severely destabilized (i.e., where domain unfolding free energies are less than 2 kcal/mol). The important role of CL domains in preventing aggregation highLights the potential of the CL-CL interface as a target for the development of drugs to stabilize the dimeric LC structure and hence prevent LC amyloidosis.

David L. Murray - One of the best experts on this subject based on the ideXlab platform.

  • using matrix assisted laser desorption ionization time of fLight mass spectrometry to detect monoclonal Immunoglobulin Light Chains in serum and urine
    Rapid Communications in Mass Spectrometry, 2015
    Co-Authors: David R. Barnidge, Thomas P. Krick, Timothy J. Griffin, David L. Murray
    Abstract:

    Rationale Use of matrix-assisted laser desorption/ionization time-of-fLight mass spectrometry (MALDI-TOFMS) to monitor serum and urine samples for endogenous monoclonal Immunoglobulins. MALDI-TOFMS is faster, fully automatable, and provides superior specificity compared to protein gel electrophoresis (PEL). Methods Samples were enriched for Immunoglobulins in 5 min using Melon Gel™ followed by reduction with dithiothreitol for 15 min to separate Immunoglobulin Light Chains and heavy Chains. Samples were then desalted using C4 ZipTips, mixed with sinapinic acid matrix, and analyzed on a Bruker Biflex III MALDI-TOF mass spectrometer. Results Monoclonal Immunoglobulin Light Chains were identified in serum and urine samples from patients with a known monoclonal gammopathy using MALDI-TOFMS with minimal sample preparation. Conclusions MALDI-TOFMS can identify a monoclonal Immunoglobulin in serum and urine samples. The molecular mass of the monoclonal Immunoglobulin Light chain is obtained providing unprecedented specificity compared to PEL. In addition, the methodology can be automated, making it a practical alternative to PEL. Copyright © 2015 John Wiley & Sons, Ltd.

  • Using matrix‐assisted laser desorption/ionization time‐of‐fLight mass spectrometry to detect monoclonal Immunoglobulin Light Chains in serum and urine
    Rapid communications in mass spectrometry : RCM, 2015
    Co-Authors: David R. Barnidge, Thomas P. Krick, Timothy J. Griffin, David L. Murray
    Abstract:

    Rationale Use of matrix-assisted laser desorption/ionization time-of-fLight mass spectrometry (MALDI-TOFMS) to monitor serum and urine samples for endogenous monoclonal Immunoglobulins. MALDI-TOFMS is faster, fully automatable, and provides superior specificity compared to protein gel electrophoresis (PEL). Methods Samples were enriched for Immunoglobulins in 5 min using Melon Gel™ followed by reduction with dithiothreitol for 15 min to separate Immunoglobulin Light Chains and heavy Chains. Samples were then desalted using C4 ZipTips, mixed with sinapinic acid matrix, and analyzed on a Bruker Biflex III MALDI-TOF mass spectrometer. Results Monoclonal Immunoglobulin Light Chains were identified in serum and urine samples from patients with a known monoclonal gammopathy using MALDI-TOFMS with minimal sample preparation. Conclusions MALDI-TOFMS can identify a monoclonal Immunoglobulin in serum and urine samples. The molecular mass of the monoclonal Immunoglobulin Light chain is obtained providing unprecedented specificity compared to PEL. In addition, the methodology can be automated, making it a practical alternative to PEL. Copyright © 2015 John Wiley & Sons, Ltd.

  • proteomic analysis of Immunoglobulin Light Chains lc in al amyloidosis shows that the sequence of clonal lc secreted by the neoplastic plasma cells is identical to the lc deposited in the amyloid plaques
    Blood, 2010
    Co-Authors: David L. Murray, Roshini S. Abraham, Marina Ramirezalvarado, Julie A Vrana, Jason D Theis, Angela Dispenzieri, Jerry A Katzmann, Ahmet Dogan
    Abstract:

    Abstract 1909 AL amyloidosis is the most common type of systemic amyloidosis. It is caused by extracellular deposition of circulating Immunoglobulin Light Chains (LC) thought to be secreted by a primarily bone marrow based clonal plasma cell proliferative disorder. Although, invariably, the type of LC secreted by the plasma cell clone is identical to the LC deposited in the amyloid plaque, a comprehensive analysis of the re-arranged clonal LC gene coding secreted LC protein, the protein sequence of the serum and urine monoclonal band and the LC protein deposited in the amyloid plaques have not been previously performed. In this study, we compared the protein sequence predicted by the clonal LC gene sequence with the protein sequence identified in the serum and urine monoclonal bands and protein plaques by mass spectrometry (MS) based proteomics. 10 cases with systemic AL amyloidosis were studied. Bone marrow samples containing the clonal plasma cells were obtained and clonal LC variable gene sequences were determined by PCR amplification, cloning and sequencing as described previously (Abraham et al, Blood 2003, 101: 3801). For protein analysis, monoclonal protein bands identified in serum and/or urine protein electrophoresis and immunofixation were isolated from archival gels. For amyloid plaque protein analysis, the plaques were microdissected from paraffin embedded tissue. To identify the protein amino acid sequence of serum and urine bands and amyloid plaques, the samples were digested into peptides by trypsin and analyzed by MS based proteomic analysis. (see Vrana et al. and Blood 2009; 114: 4957 for methods). The results for amino acid sequence predicted from the clonal LC gene sequence, determined directly by MS from the serum and/or urine monoclonal band and amyloid plaques were then aligned and compared. In all 10 cases, the LC amino acid sequences predicted by sequencing of the clonal LC gene from bone marrow plasma cells, the amino acid sequence obtained directly from the monoclonal serum and/or urine protein and the amino acid sequence obtained from the amyloid plaque were identical. In most cases, both the complete variable region and constant regions were deposited as amyloid plaques. Some amyloid plaques showed cleavage of first 16 amino acids of the variable region suggesting that this part was not required for amyloid deposition. All LC variable region gene sequences were affected by somatic hypermutation, and identical mutations were present in both the serum and urine bands and in the amyloid plaques. In conclusion, these results, for the first time, comprehensively show that the monoclonal protein secreted by the neoplastic plasma cells is the pathogenetic protein causing the amyloid deposits in AL amyloidosis. Amyloid deposits contain virtually all of the LC protein identified in the serum or urine including both variable and constant regions, suggesting that the presence of the constant region may also play a role in amyloidogenesis. The technological capability to determine the complete protein sequence of the amyloidogenic monoclonal serum and urine LC protein isolated from archived gels will create new opportunities to develop diagnostic, predictive and prognostic serum or urine based tests for amyloidosis. Disclosures: Theis: Mayo Clinic: Patents & Royalties. Vrana: Mayo Clinic: Patents & Royalties. Dogan: Mayo Clinic: Patents & Royalties.