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Moderer T, Puşcalău-Gîrţu I, Haupt C, Baur J, Rodríguez-Alfonso A, Wiese S, Schmidt CQ, Malešević M, Forssmann WG, Ständker L, Fändrich M. Human lysozyme inhibits the fibrillation of serum amyloid a protein from systemic AA amyloidosis. Amyloid 2023; 30:424-433. [PMID: 37431668 DOI: 10.1080/13506129.2023.2232518] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Accepted: 06/28/2023] [Indexed: 07/12/2023]
Abstract
BACKGROUND Systemic AA amyloidosis is a world-wide occurring protein misfolding disease in humans and animals that arises from the formation of amyloid fibrils from serum amyloid A (SAA) protein and their deposition in multiple organs. OBJECTIVE To identify new agents that prevent fibril formation from SAA protein and to determine their mode of action. MATERIALS AND METHODS We used a cell model for the formation of amyloid deposits from SAA protein to screen a library of peptides and small proteins, which were purified from human hemofiltrate. To clarify the inhibitory mechanism the obtained inhibitors were characterised in cell-free fibril formation assays and other biochemical methods. RESULTS We identified lysozyme as an inhibitor of SAA fibril formation. Lysozyme antagonised fibril formation both in the cell model as well as in cell-free fibril formation assays. The protein binds SAA with a dissociation constant of 16.5 ± 0.6 µM, while the binding site on SAA is formed by segments of positively charged amino acids. CONCLUSION Our data imply that lysozyme acts in a chaperone-like fashion and prevents the aggregation of SAA protein through direct, physical interactions.
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Affiliation(s)
- Tim Moderer
- Institute of Protein Biochemistry, Ulm University, Ulm, Germany
| | | | - Christian Haupt
- Institute of Protein Biochemistry, Ulm University, Ulm, Germany
| | - Julian Baur
- Institute of Protein Biochemistry, Ulm University, Ulm, Germany
| | - Armando Rodríguez-Alfonso
- Core Facility for Functional Peptidomics, Ulm University Medical Center, Ulm, Germany
- Core Unit Mass Spectrometry and Proteomics, Ulm University Medical Center, Ulm, Germany
| | - Sebastian Wiese
- Core Unit Mass Spectrometry and Proteomics, Ulm University Medical Center, Ulm, Germany
| | - Christoph Q Schmidt
- Institute of Experimental and Clinical Pharmacology, Toxicology and Pharmacology of Natural Products, University of Ulm Medical Center, Ulm, Germany
| | - Miroslav Malešević
- Max Planck Research Unit for Enzymology of Protein Folding, Halle, Germany
| | | | - Ludger Ständker
- Core Facility for Functional Peptidomics, Ulm University Medical Center, Ulm, Germany
| | - Marcus Fändrich
- Institute of Protein Biochemistry, Ulm University, Ulm, Germany
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2
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Dolkar T, Mann H, Salahuddin M, Spitalewitz S, Shein L. Renal Amyloid-Associated (AA) Amyloidosis in a Sickle Cell Patient: A Case Report and Literature Review. Cureus 2023; 15:e36608. [PMID: 37102016 PMCID: PMC10123223 DOI: 10.7759/cureus.36608] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/23/2023] [Indexed: 04/28/2023] Open
Abstract
Renal amyloid-associated (AA) amyloidosis is a rare occurrence in sickle cell disease (SCD). Very little literature is available on renal AA amyloidosis in sickle cell disease. Nephrotic range proteinuria is associated with higher mortality among patients with SCD. We present a case of a young reproductive-age African American woman who presented with massive nephrotic range proteinuria. Other more common causes of AA amyloidosis such as immunologic and infectious etiologies were ruled out by history, physical examination, radiologic investigation, and serology. Renal biopsy showed mesangial expansion with Congo red-positive material. Staining for immunoglobulins was negative. Electron microscopy showed nonbranching fibrils. These findings were consistent with AA amyloidosis. This case report adds to the rare findings of renal AA amyloidosis in sickle cell disease. The patient refused any intervention to decrease her Glomerular Filtration Rate (GFR) in the hopes of potentially reversing the disabling proteinuria. We report sickle cell disease presenting with nephrotic syndrome secondary to AA amyloid.
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Affiliation(s)
- Tsering Dolkar
- Internal Medicine, One Brooklyn Health (OBH) Interfaith Medical Center, Brooklyn, USA
| | - Henry Mann
- Internal Medicine, One Brooklyn Health (OBH) Interfaith Medical Center, Brooklyn, USA
| | - Mohammad Salahuddin
- Nephrology, One Brooklyn Health (OBH) Brookdale University Hospital Medical Center, Brooklyn, USA
| | - Samuel Spitalewitz
- Nephrology, One Brooklyn Health (OBH) Brookdale University Hospital Medical Center, Brooklyn, USA
| | - Leon Shein
- Nephrology, One Brooklyn Health (OBH) Interfaith Medical Center, Brooklyn, USA
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3
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Wang F, Chen M, Ma J, Wang C, Wang J, Xia H, Zhang D, Yao S. Integrating bulk and single-cell sequencing reveals the phenotype-associated cell subpopulations in sepsis-induced acute lung injury. Front Immunol 2022; 13:981784. [PMID: 36405762 PMCID: PMC9666384 DOI: 10.3389/fimmu.2022.981784] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 10/21/2022] [Indexed: 01/25/2023] Open
Abstract
The dysfunctional immune response and multiple organ injury in sepsis is a recurrent theme impacting prognosis and mortality, while the lung is the first organ invaded by sepsis. To systematically elucidate the transcriptomic changes in the main constituent cells of sepsis-injured lung tissue, we applied single-cell RNA sequencing to the lung tissue samples from septic and control mice and created a comprehensive cellular landscape with 25044 cells, including 11317 immune and 13727 non-immune cells. Sepsis alters the composition of all cellular compartments, particularly neutrophils, monocytes, T cells, endothelial, and fibroblasts populations. Our study firstly provides a single-cell view of cellular changes in septic lung injury. Furthermore, by integrating bulk sequencing data and single-cell data with the Scissors-method, we identified the cell subpopulations that are most associated with septic lung injury phenotype. The phenotypic-related cell subpopulations identified by Scissors-method were consistent with the cell subpopulations with significant composition changes. The function analysis of the differentially expressed genes (DEGs) and the cell-cell interaction analysis further reveal the important role of these phenotype-related subpopulations in septic lung injury. Our research provides a rich resource for understanding cellular changes and provides insights into the contributions of specific cell types to the biological processes that take place during sepsis-induced lung injury.
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Affiliation(s)
- Fuquan Wang
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,Department of Anesthesiology, Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ming Chen
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,Department of Anesthesiology, Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiamin Ma
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,Department of Anesthesiology, Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chenchen Wang
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,Department of Anesthesiology, Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jingxu Wang
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,Department of Anesthesiology, Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Haifa Xia
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,Department of Anesthesiology, Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dingyu Zhang
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,Department of Anesthesiology, Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,Wuhan Jinyintan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,*Correspondence: Dingyu Zhang, ; Shanglong Yao,
| | - Shanglong Yao
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,Department of Anesthesiology, Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,*Correspondence: Dingyu Zhang, ; Shanglong Yao,
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4
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Seth P, Sarkar N. A comprehensive mini-review on amyloidogenesis of different SARS-CoV-2 proteins and its effect on amyloid formation in various host proteins. 3 Biotech 2022; 12:322. [PMID: 36254263 PMCID: PMC9558030 DOI: 10.1007/s13205-022-03390-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Accepted: 09/30/2022] [Indexed: 11/21/2022] Open
Abstract
Amyloidogenesis is the inherent ability of proteins to change their conformation from native state to cross β-sheet rich fibrillar structures called amyloids which result in a wide range of diseases like Parkinson's disease, Alzheimer's disease, Finnish familial amyloidosis, ATTR amyloidosis, British and Danish dementia, etc. COVID-19, on the other hand is seen to have many similarities in symptoms with other amyloidogenic diseases and the overlap of these morbidities and symptoms led to the proposition whether SARS-CoV-2 proteins are undergoing amyloidogenesis and whether it is resulting in or aggravating amyloidogenesis of any human host protein. Thus the SARS-CoV-2 proteins in infected cells, i.e., Spike (S) protein, Nucleocapsid (N) protein, and Envelope (E) protein were tested via different machinery and amyloidogenesis in them were proven. In this review, we will analyze the pathway of amyloid formation in S-protein, N-protein, E-protein along with the effect that SARS-CoV-2 is creating on various host proteins leading to the unexpected onset of many morbidities like COVID-induced Acute Respiratory Distress Syndrome (ARDS), Parkinsonism in young COVID patients, formation of fibrin microthrombi in heart, etc., and their future implications.
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Affiliation(s)
- Prakriti Seth
- Department of Biotechnology and Medical Engineering, National Institute of Technology Rourkela, Rourkela, Odisha 769008 India
| | - Nandini Sarkar
- Department of Biotechnology and Medical Engineering, National Institute of Technology Rourkela, Rourkela, Odisha 769008 India
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Yasar F, Sheridan MS, Hansmann UHE. Interconversion between Serum Amyloid A Native and Fibril Conformations. ACS OMEGA 2022; 7:12186-12192. [PMID: 35449919 PMCID: PMC9016813 DOI: 10.1021/acsomega.2c00566] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Accepted: 03/15/2022] [Indexed: 06/14/2023]
Abstract
Overexpression of serum amyloid A (SAA) can lead to a form of amyloidosis where the fibrils are made of SAA fragments, most often SAA1-76. Using Replica Exchange with Tunneling, we study the conversion of a SAA1-76 chain between the folded conformation and a fibril conformation. We find that the basins in the free energy landscape corresponding to the two motifs are separated by barriers of only about 2-3 k B T. Crucial for the assembly into the fibril structure is the salt bridge 26E-34K that provides a scaffold for forming the fibril conformation.
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Affiliation(s)
| | - Miranda S. Sheridan
- Department of Chemistry &
Biochemistry, University of Oklahoma, Norman, Oklahoma 73019, United States
| | - Ulrich H. E. Hansmann
- Department of Chemistry &
Biochemistry, University of Oklahoma, Norman, Oklahoma 73019, United States
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Kamiya S, Shimizu K, Okada A, Inoshima Y. Induction of Serum Amyloid A3 in Mouse Mammary Epithelial Cells Stimulated with Lipopolysaccharide and Lipoteichoic Acid. Animals (Basel) 2021; 11:ani11061548. [PMID: 34070499 PMCID: PMC8230092 DOI: 10.3390/ani11061548] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 05/15/2021] [Accepted: 05/23/2021] [Indexed: 12/04/2022] Open
Abstract
Simple Summary Serum amyloid A (SAA) is an acute phase protein present in mammals and birds. Based on the amino acid sequence, SAA has been classified into isoforms SAA1–4 in mice. Previously, it was reported that after the stimulation with bacterial antigens, the expression of the Saa3 mRNA was induced more strongly than that of the Saa1 mRNA in mouse epithelia, including colonic and alveolar epithelial cells, indicating that SAA3 plays a role in the local response. However, the contribution of SAA3 to the local response in mouse mammary epithelium, where mastitis occurs due to bacterial infection, has not been completely determined yet. In this study, to clarify whether mouse SAA3 has a role in the defense against bacterial infection in mouse mammary epithelium, normal murine mammary gland (NMuMG) epithelial cells were stimulated with lipopolysaccharide (LPS) and lipoteichoic acid (LTA). LPS and LTA significantly enhanced mRNA expression level of the Saa3 gene but not that of Saa1. Furthermore, LPS induced SAA3 protein expression more strongly than LTA. Our data indicate that SAA3 expression in mouse mammary epithelial cells was increased by the stimulation with bacterial antigens, suggesting that SAA3 is involved in the defense against bacterial infection in mouse mammary epithelium. Abstract In this study, to establish whether serum amyloid A (SAA) 3 plays a role in the defense against bacterial infection in mouse mammary epithelium, normal murine mammary gland (NMuMG) epithelial cells were stimulated with lipopolysaccharide (LPS) and lipoteichoic acid (LTA). LPS and LTA significantly enhanced mRNA expression level of the Saa3 gene, whereas no significant change was observed in the Saa1 mRNA level. Furthermore, LPS induced SAA3 protein expression more strongly than LTA, whereas neither LPS nor LTA significantly affected SAA1 protein expression. These data indicate that the expression of SAA3 in mouse mammary epithelial cells was increased by the stimulation with bacterial antigens. SAA3 has been reported to stimulate neutrophils in the intestinal epithelium and increase interleukin-22 expression, which induces activation of the innate immune system and production of antibacterial proteins, such as antimicrobial peptides. Therefore, collectively, these data suggest that SAA3 is involved in the defense against bacterial infection in mouse mammary epithelium.
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Affiliation(s)
- Sato Kamiya
- Laboratory of Food and Environmental Hygiene, Cooperative Department of Veterinary Medicine, Faculty of Applied Biological Sciences, Gifu University, Gifu 501-1193, Japan; (S.K.); (K.S.); (A.O.)
| | - Kaori Shimizu
- Laboratory of Food and Environmental Hygiene, Cooperative Department of Veterinary Medicine, Faculty of Applied Biological Sciences, Gifu University, Gifu 501-1193, Japan; (S.K.); (K.S.); (A.O.)
| | - Ayaka Okada
- Laboratory of Food and Environmental Hygiene, Cooperative Department of Veterinary Medicine, Faculty of Applied Biological Sciences, Gifu University, Gifu 501-1193, Japan; (S.K.); (K.S.); (A.O.)
- Education and Research Center for Food Animal Health, Gifu University (GeFAH), Gifu 501-1193, Japan
| | - Yasuo Inoshima
- Laboratory of Food and Environmental Hygiene, Cooperative Department of Veterinary Medicine, Faculty of Applied Biological Sciences, Gifu University, Gifu 501-1193, Japan; (S.K.); (K.S.); (A.O.)
- Education and Research Center for Food Animal Health, Gifu University (GeFAH), Gifu 501-1193, Japan
- Joint Graduate School of Veterinary Sciences, Gifu University, Gifu 501-1193, Japan
- The United Graduate School of Veterinary Sciences, Gifu University, Gifu 501-1193, Japan
- Correspondence: ; Tel.: +81-58-293-2863
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7
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Methods to study the structure of misfolded protein states in systemic amyloidosis. Biochem Soc Trans 2021; 49:977-985. [PMID: 33929491 DOI: 10.1042/bst20201022] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 04/08/2021] [Accepted: 04/12/2021] [Indexed: 12/19/2022]
Abstract
Systemic amyloidosis is defined as a protein misfolding disease in which the amyloid is not necessarily deposited within the same organ that produces the fibril precursor protein. There are different types of systemic amyloidosis, depending on the protein constructing the fibrils. This review will focus on recent advances made in the understanding of the structural basis of three major forms of systemic amyloidosis: systemic AA, AL and ATTR amyloidosis. The three diseases arise from the misfolding of serum amyloid A protein, immunoglobulin light chains or transthyretin. The presented advances in understanding were enabled by recent progress in the methodology available to study amyloid structures and protein misfolding, in particular concerning cryo-electron microscopy (cryo-EM) and nuclear magnetic resonance (NMR) spectroscopy. An important observation made with these techniques is that the structures of previously described in vitro formed amyloid fibrils did not correlate with the structures of amyloid fibrils extracted from diseased tissue, and that in vitro fibrils were typically more protease sensitive. It is thus possible that ex vivo fibrils were selected in vivo by their proteolytic stability.
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Zhang J, Shi C, Zhang L, Zhang Y, Lu Q, Wang R. Fluorescent quenching probes based SAA 1 genotyping with a fully automated system. Heliyon 2021; 7:e06858. [PMID: 33997392 PMCID: PMC8100075 DOI: 10.1016/j.heliyon.2021.e06858] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 03/31/2021] [Accepted: 04/16/2021] [Indexed: 10/25/2022] Open
Abstract
Objective The aim of the present study is to develop and validate a reliable and simple application for genotyping serum amyloid A1 (SAA1). Methods The specific nested PCR was performed to amplify a product of SAA1 gene. Two quenching probes (QPs) were designed for detecting two single nucleotide polymorphism (SNP) sites, rs1136743(C/T) and rs1136747(C/T) respectively for SAA1 genotypes. The specific nested PCR and QPs of SAA1 genotying was introduced into a fully automated genotyping system (I-densy, ARKRAY, Inc.), which enables the genotyping of SAA1 from whole blood. Results Six genotypes of SAA1 (α+/+, β+/+, γ+/+, αβ, αγ and βγ) could be determined by monitoring the fluorescence intensity of two QPs with melting temperature (TM) analysis. Total 121 clinical samples were SAA1 genotyped in the fluorescent quenching probes based method with a fully automated I-densy system and were further sequence confirmed with a PCR direct sequencing approach. Conclusion This fully automated system is a rapid and reliable strategy for the SAA1 genotyping and for its future clinical application.
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Affiliation(s)
- Jie Zhang
- Department of Biochemical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin, 300072, China.,Shanghai R&D Center, DiaSys Diagnostic Systems (Shanghai) Co., Ltd., Shanghai, 201318, China
| | - Changgen Shi
- NHC Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Fudan University, Shanghai, 200032, China
| | - Lei Zhang
- Department of Biochemical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin, 300072, China
| | - Yan Zhang
- Shanghai R&D Center, DiaSys Diagnostic Systems (Shanghai) Co., Ltd., Shanghai, 201318, China
| | - Qing Lu
- Shanghai Testing & Inspection Institute for Medical Devices (CMTC), Shanghai, 201318, China
| | - Rongfang Wang
- Shanghai R&D Center, DiaSys Diagnostic Systems (Shanghai) Co., Ltd., Shanghai, 201318, China
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9
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Gromova MA, Tsurko VV. Gout and AA-Amyloidosis: A Case-Based Review. Mediterr J Rheumatol 2021; 32:74-80. [PMID: 34386704 PMCID: PMC8314881 DOI: 10.31138/mjr.32.1.74] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 07/07/2020] [Accepted: 07/20/2020] [Indexed: 11/07/2022] Open
Abstract
Background: AA-amyloidosis complicates many chronic infections and inflammatory diseases, including rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis, but its relationship to gout is extremely rare. As it is unknown definitely what the pathophysiological connections between gout and amyloidosis are, treatment issues of the diseases are open for discussion. Aim: To establish a link between gout and AA-amyloidosis, and to improve the quality of treatment in patients suffering from gout and AA-amyloidosis. Methods: We reviewed the English-language literature sources, searching not only for rare cases of the combination of gout and AA amyloidosis, but also detailed descriptions of the medical treatments for the two pathologies. Results: By July 2020, we had identified 14 cases describing AA amyloidosis in patients with gout. Most of those patients had been suffering tophaceous gout for at least 10 years, and were prescribed various methods of treatment; however, not all patients took colchicine regularly. In some cases, therapy with allopurinol and colchicine was effective against attacks of gouty arthritis, although amyloidogenic inflammation was not controlled sufficiently. However, there were no cases that described in detail the successful treatment of both diseases. Besides those 14 patients described in literature, we examined one more patient with amyloidosis that is secondary to gout, in whom the protein of amyloid A (AA) had affected the kidneys, intestines, and adrenal glands. The patient has been successfully treated with the combination of canakinumab, prednisone, colchicine and allopurinol. Conclusion: Clinicians should be aware that patients may have atypical combinations of diseases like gout and amyloidosis. The obtained results help to explain some pathogenic processes associated with AA-amyloidosis. Further research is necessary to confirm the effectiveness of different treatment options such as lifestyle biologic agents or other medicines with anti-inflammatory properties.
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Affiliation(s)
| | - Vladimir Viktorovich Tsurko
- Pirogov Russian National Research Medical University (RNRMU), Moscow, Russian Federation.,I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation
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10
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Abstract
In systemic amyloidosis, serum amyloid A (SAA) fibril deposits cause widespread damages to tissues and organs that eventually may lead to death. A therapeutically intervention therefore has either to dissolve these fibrils or inhibit their formation. However, only recently has the human SAA fibril structure been resolved at a resolution that is sufficient for development of drug candidates. Here, we use molecular dynamic simulations to probe the factors that modulate the stability of this fibril model. Our simulations suggest that fibril formation starts with the stacking of two misfolded monomers into metastable dimers, with the stacking depending on the N-terminal amyloidogenic regions of different chains forming anchors. The resulting dimers pack in a second step into a 2-fold two-layer tetramer that is stable enough to nucleate fibril formation. The stability of the initial dimers is enhanced under acidic conditions by a strong salt bridge and side-chain hydrogen bond network in the C-terminal cavity (residues 23-51) but is not affected by the presence of the disordered C-terminal tail.
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Affiliation(s)
- Wenhua Wang
- Department of Chemistry & Biochemistry, University of Oklahoma, Norman, Oklahoma 73019, United States
| | - Ulrich H E Hansmann
- Department of Chemistry & Biochemistry, University of Oklahoma, Norman, Oklahoma 73019, United States
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11
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Kawasaki H, Murakami T, Badr Y, Kamiya S, Shimizu K, Okada A, Inoshima Y. In vitro and ex vivo expression of serum amyloid A3 in mouse lung epithelia. Exp Lung Res 2020; 46:352-361. [PMID: 32842790 DOI: 10.1080/01902148.2020.1809750] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
BACKGROUND AND PURPOSE Serum amyloid A (SAA), an acute-phase protein whose level tracks infection and inflammation, is the precursor protein of amyloid A (AA) fibrils that is thought to cause AA amyloidosis in human and animals. SAA protein has several isoforms based on the difference of amino acid sequence, such as SAA1 to SAA4 in mice. AA fibrils are associated with chronic inflammation and are mainly originated from SAA1 produced in the liver. SAA3 reportedly contributes to the innate immune response in epithelia; however, little is known about its role at the lung epithelia. Therefore, we investigated SAA3 expression in the lung epithelium activated by bacterial antigens. MATERIALS AND METHODS The expressions of SAA3 and SAA1 mRNA were investigated using quantitative real-time PCR, in vitro using mouse Clara (Club) cells and ex vivo using surgically removed mouse lungs, after their stimulation by using either lipopolysaccharide (LPS), the major outer membranous antigen of gram-negative bacteria, or lipoteichoic acid (LTA), the major outer membranous antigen of gram-positive bacteria. In addition, SAA3 and SAA1/2 proteins in treated lung samples were detected by immunohistochemistry (IHC). RESULTS SAA3 mRNA expression increased in cells and lungs treated with either LPS or LTA. SAA3 mRNA was more sensitively expressed in LPS than LTA treatment. In contrast, SAA1 mRNA expression did not increase by either LPS or LTA treatment. Furthermore, SAA3 mRNA expression increased in a dose-dependent manner in cells treated with tumor necrosis factor-alpha. By IHC, SAA3 protein was highly expressed in the luminal side of the bronchial epithelium, while SAA1/2 was not expressed. CONCLUSION These results obtained from in vitro and ex vivo experiments suggest that SAA3 plays an important role in the innate immune response to bacterial infection in the lung epithelia.
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Affiliation(s)
- Haruka Kawasaki
- Laboratory of Food and Environmental Hygiene, Faculty of Applied Biological Sciences, Cooperative Department of Veterinary Medicine, Gifu University, Gifu, Japan
| | - Tomoaki Murakami
- Laboratory of Veterinary Toxicology, Cooperative Department of Veterinary Medicine, Tokyo University of Agriculture and Technology, Tokyo, Japan
| | - Yassien Badr
- Laboratory of Food and Environmental Hygiene, Faculty of Applied Biological Sciences, Cooperative Department of Veterinary Medicine, Gifu University, Gifu, Japan.,Faculty of Veterinary Medicine, Department of Animal Medicine (Infectious Diseases), Damanhour University, El-Beheira, Egypt
| | - Sato Kamiya
- Laboratory of Food and Environmental Hygiene, Faculty of Applied Biological Sciences, Cooperative Department of Veterinary Medicine, Gifu University, Gifu, Japan
| | - Kaori Shimizu
- Laboratory of Food and Environmental Hygiene, Faculty of Applied Biological Sciences, Cooperative Department of Veterinary Medicine, Gifu University, Gifu, Japan
| | - Ayaka Okada
- Laboratory of Food and Environmental Hygiene, Faculty of Applied Biological Sciences, Cooperative Department of Veterinary Medicine, Gifu University, Gifu, Japan.,Education and Research Center for Food Animal Health, Gifu University (GeFAH), Gifu, Japan
| | - Yasuo Inoshima
- Laboratory of Food and Environmental Hygiene, Faculty of Applied Biological Sciences, Cooperative Department of Veterinary Medicine, Gifu University, Gifu, Japan.,Education and Research Center for Food Animal Health, Gifu University (GeFAH), Gifu, Japan.,Joint Graduate School of Veterinary Sciences, Gifu University, Gifu, Japan.,The United Graduate School of Veterinary Sciences, Gifu University, Gifu, Japan
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12
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Abstract
PURPOSE Amyloidosis represents an increasingly recognized but still frequently missed cause of heart failure. In the light of many effective therapies for light chain (AL) amyloidosis and promising new treatment options for transthyretin (ATTR) amyloidosis, awareness among caregivers needs to be raised to screen for amyloidosis as an important and potentially treatable differential diagnosis. This review outlines the diversity of cardiac amyloidosis, its relation to heart failure, the diagnostic algorithm, and therapeutic considerations that should be applied depending on the underlying type of amyloidosis. RECENT FINDINGS Non-biopsy diagnosis is feasible in ATTR amyloidosis in the absence of a monoclonal component resulting in higher detection rates of cardiac ATTR amyloidosis. Biomarker-guided staging systems have been updated to facilitate risk stratification according to currently available biomarkers independent of regional differences, but have not yet prospectively been tested. Novel therapies for hereditary and wild-type ATTR amyloidosis are increasingly available. The complex treatment options for AL amyloidosis are improving continuously, resulting in better survival and quality of life. Mortality in advanced cardiac amyloidosis remains high, underlining the importance of early diagnosis and treatment initiation. Cardiac amyloidosis is characterized by etiologic and clinical heterogeneity resulting in a frequently delayed diagnosis and an inappropriately high mortality risk. New treatment options for this hitherto partially untreatable condition have become and will become available, but raise challenges regarding their implementation. Referral to specialized centers providing access to extensive and targeted diagnostic investigations and treatment initiation may help to face these challenges.
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Droghetti M, Ercolino A, Piazza P, Bianchi L, Fabbrizio B, Giunchi F, Mineo Bianchi F, Barbaresi U, Casablanca C, Tonin E, Mottaran A, Fiorentino M, Schiavina R, Brunocilla E. Secondary bladder amyloidosis due to Crohn's disease: a case report and literature review. CEN Case Rep 2020; 9:413-417. [PMID: 32572782 DOI: 10.1007/s13730-020-00497-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 06/11/2020] [Indexed: 11/25/2022] Open
Abstract
The presence of amyloid deposits in bladder walls is a rare histological finding. It can be linked to primary (limited to bladder) or secondary (systemic, associated with chronic inflammatory disorders) amyloidosis. Secondary bladder involvement is very uncommon; it usually presents with gross hematuria, which is challenging to manage, due to frail bladder mucosa and/or necrosis. We present a case of 54-year old man with secondary bladder amyloidosis due to Crohn's disease, that caused gross hematuria and severe anemia, which was managed conservatively by endoscopic transurethral resection, diatermocoagulation, clot evacuation and urinary drainage by bilateral percutaneous nephrostomy, with spontaneous resolution. Secondary bladder amyloidosis is a rare condition that presents with severe hematuria, difficult to control with standard management. Owing to chronic nature of the disease, treatment should be aimed to a conservative approach whenever possible. In case of failure, invasive procedures should be considered as salvage therapies.
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Affiliation(s)
- Matteo Droghetti
- Department of Urology, S. Orsola-Malpighi University Hospital, Via P. Palagi 9, 40138, Bologna, Italy.
| | - Amelio Ercolino
- Department of Urology, S. Orsola-Malpighi University Hospital, Via P. Palagi 9, 40138, Bologna, Italy
| | - Pietro Piazza
- Department of Urology, S. Orsola-Malpighi University Hospital, Via P. Palagi 9, 40138, Bologna, Italy
| | - Lorenzo Bianchi
- Department of Urology, S. Orsola-Malpighi University Hospital, Via P. Palagi 9, 40138, Bologna, Italy
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Cardio-Nephro-Thoracic Sciences Doctorate, University of Bologna, Via Massarenti 9, 40138, Bologna, Italy
| | - Benedetta Fabbrizio
- Pathology Unit, S. Orsola-Malpighi University Hospital, Via Massarenti 9, 40138, Bologna, Italy
| | - Francesca Giunchi
- Pathology Unit, S. Orsola-Malpighi University Hospital, Via Massarenti 9, 40138, Bologna, Italy
| | - Federico Mineo Bianchi
- Department of Urology, S. Orsola-Malpighi University Hospital, Via P. Palagi 9, 40138, Bologna, Italy
| | - Umberto Barbaresi
- Department of Urology, S. Orsola-Malpighi University Hospital, Via P. Palagi 9, 40138, Bologna, Italy
| | - Carlo Casablanca
- Department of Urology, S. Orsola-Malpighi University Hospital, Via P. Palagi 9, 40138, Bologna, Italy
| | - Elena Tonin
- Department of Urology, S. Orsola-Malpighi University Hospital, Via P. Palagi 9, 40138, Bologna, Italy
| | - Angelo Mottaran
- Department of Urology, S. Orsola-Malpighi University Hospital, Via P. Palagi 9, 40138, Bologna, Italy
| | - Michelangelo Fiorentino
- Pathology Unit, S. Orsola-Malpighi University Hospital, Via Massarenti 9, 40138, Bologna, Italy
| | - Riccardo Schiavina
- Department of Urology, S. Orsola-Malpighi University Hospital, Via P. Palagi 9, 40138, Bologna, Italy
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Cardio-Nephro-Thoracic Sciences Doctorate, University of Bologna, Via Massarenti 9, 40138, Bologna, Italy
| | - Eugenio Brunocilla
- Department of Urology, S. Orsola-Malpighi University Hospital, Via P. Palagi 9, 40138, Bologna, Italy
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Cardio-Nephro-Thoracic Sciences Doctorate, University of Bologna, Via Massarenti 9, 40138, Bologna, Italy
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14
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Theodorakakou F, Fotiou D, Dimopoulos MA, Kastritis E. Solid Organ Transplantation in Amyloidosis. Acta Haematol 2020; 143:352-364. [PMID: 32535598 DOI: 10.1159/000508262] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Accepted: 04/28/2020] [Indexed: 12/25/2022]
Abstract
Amyloidosis comprises a diverse group of diseases characterized by misfolding of precursor proteins which eventually form amyloid aggregates and preceding intermediaries, which are deposited in target tissues causing progressive organ damage. In all forms of amyloidosis, vital organs may fail; depending on the specific amyloidosis type, this may occur rapidly or progress slowly. Beyond therapies to reduce the precursor protein (chemotherapy for light chain [AL] amyloidosis, anti-inflammatory therapy in serum A amyloid-osis [AA], and antisense RNA therapy in transthyretin amyloidosis [ATTR]), organ transplantation may also be a means to reduce amyloidogenic protein, e.g., in types of amyloid-osis in which the variant precursor is produced by the liver. Heart transplantation is a life-saving approach to the treatment of patients with advanced cardiac amyloidosis; however, amyloidosis may still be considered a contraindication to the procedure despite data supporting improved outcomes, similar to patients with other indications. Kidney transplantation is associated with particularly favorable outcomes in patients with amyloidosis, especially if the precursor protein has been eliminated. Overall, outcomes of solid organ transplantation are improving, but more data are needed to refine the selection criteria and the timing for organ transplantation, which should be performed in highly experienced centers involving multidisciplinary teams with close patient follow-up to detect amyloid recurrence.
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Affiliation(s)
- Foteini Theodorakakou
- Plasma Cell Dyscrasia Unit, Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Athens, Greece
| | - Despina Fotiou
- Plasma Cell Dyscrasia Unit, Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Athens, Greece
| | - Meletios A Dimopoulos
- Plasma Cell Dyscrasia Unit, Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Athens, Greece
| | - Efstathios Kastritis
- Plasma Cell Dyscrasia Unit, Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Athens, Greece,
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15
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Murata E, Kozaki S, Murakami T, Shimizu K, Okada A, Ishiguro N, Inoshima Y. Differential expression of serum amyloid A1 and A3 in bovine epithelia. J Vet Med Sci 2020; 82:764-770. [PMID: 32378645 PMCID: PMC7324830 DOI: 10.1292/jvms.19-0473] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Serum amyloid A (SAA) is both an amyloidogenic protein of amyloid A amyloidosis and an acute phase protein in most animal species. Although SAA isoforms, such as SAA1, 2, 3, and 4, have been identified in cattle, their biological functions are not completely understood. Previous studies using mice indicated that SAA3 mRNA expression increased by stimulation with Escherichia coli and lipopolysaccharide (LPS) in colonic epithelial cells, and subsequently the SAA3 protein enhanced the expression of mucin2 (MUC2) mRNA, which is the major component of the colonic mucus layer. These results suggest that SAA3 plays a role in host innate immunity against bacterial infection in the intestine. In this study, a novel anti-bovine SAA3 monoclonal antibody was produced and SAA3 expression levels in bovine epithelia were examined in vitro and in vivo using real-time PCR and immunohistochemistry (IHC). SAA3 mRNA expression, but not that of SAA1, was enhanced by LPS stimulus in bovine small intestinal and mammary glandular epithelial cells in vitro. Moreover, in bovine epithelia (small intestine, mammary gland, lung, and uterus) obtained from four Holstein dairy cows from a slaughterhouse, SAA3 mRNA expression was higher than that of SAA1. Furthermore, using IHC, SAA3 protein expression was observed in bovine epithelia, whereas SAA1 protein was not. These results suggest that in cattle, SAA3 plays an immunological role against bacterial infection in epithelial tissues, including the small intestine, mammary gland, lung, and uterus.
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Affiliation(s)
- Eriko Murata
- Laboratory of Food and Environmental Hygiene, Cooperative Department of Veterinary Medicine, Faculty of Applied Biological Sciences, Gifu University, Gifu 501-1193, Japan
| | - Satoi Kozaki
- Laboratory of Food and Environmental Hygiene, Cooperative Department of Veterinary Medicine, Faculty of Applied Biological Sciences, Gifu University, Gifu 501-1193, Japan
| | - Tomoaki Murakami
- Laboratory of Veterinary Toxicology, Cooperative Department of Veterinary Medicine, Tokyo University of Agriculture and Technology, Tokyo 183-8509, Japan
| | - Kaori Shimizu
- Laboratory of Food and Environmental Hygiene, Cooperative Department of Veterinary Medicine, Faculty of Applied Biological Sciences, Gifu University, Gifu 501-1193, Japan
| | - Ayaka Okada
- Laboratory of Food and Environmental Hygiene, Cooperative Department of Veterinary Medicine, Faculty of Applied Biological Sciences, Gifu University, Gifu 501-1193, Japan.,Education and Research Center for Food Animal Health, Gifu University (GeFAH), Gifu 501-1193, Japan
| | - Naotaka Ishiguro
- Laboratory of Food and Environmental Hygiene, Cooperative Department of Veterinary Medicine, Faculty of Applied Biological Sciences, Gifu University, Gifu 501-1193, Japan.,The United Graduate School of Veterinary Sciences, Gifu University, Gifu 501-1193, Japan
| | - Yasuo Inoshima
- Laboratory of Food and Environmental Hygiene, Cooperative Department of Veterinary Medicine, Faculty of Applied Biological Sciences, Gifu University, Gifu 501-1193, Japan.,Education and Research Center for Food Animal Health, Gifu University (GeFAH), Gifu 501-1193, Japan.,The United Graduate School of Veterinary Sciences, Gifu University, Gifu 501-1193, Japan.,Joint Graduate School of Veterinary Sciences, Gifu University, Gifu 501-1193, Japan
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16
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Shientag LJ, Cabrera OA, Pazour GJ. Allelic Diversity in the Serum Amyloid A2 Gene and Amyloid A Amyloidosis in a Breeding Colony of Zebra Finches ( Taeniopygia guttata). Comp Med 2019; 69:425-431. [PMID: 31462347 DOI: 10.30802/aalas-cm-18-000139] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
A high incidence of amyloid A (AA) amyloidosis was observed in the research breeding colony of zebra finches at our institution. Some birds with hepatic AA amyloidosis were asymptomatic for comorbid conditions frequently associated with the development of AA amyloidosis, whereas other birds with comorbid conditions failed to develop AA amyloidosis, suggesting a potential genetic component to the disease. Sequencing the SAA2 gene from 20 birds yielded 18 distinct sequences that coded for 5 isoforms of the protein. Most of the amino acid substitutions are unlikely to affect the protein's structure or function, but 2 changes-R52L and V84M-were predicted to be disruptive. In particular, R52 is highly conserved across vertebrates, with only arginine or lysine found at this position in reported sequences to date. The atypical R52L substitution occurred in 2 otherwise healthy birds with hepatic AA amyloidosis, supporting the idea that this change is pathogenic.
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Affiliation(s)
- Lisa J Shientag
- Departments of Animal Medicine and Pathology, University of Massachusetts Medical School, Worcester, Massachusetts;,
| | - Oscar A Cabrera
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts
| | - Gregory J Pazour
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts
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17
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Iwata A, Shimizu K, Kawasaki H, Okada A, Inoshima Y. Lipopolysaccharide and lipoteichoic acid enhance serum amyloid A3 mRNA expression in murine alveolar epithelial cells. J Vet Med Sci 2019; 81:1409-1412. [PMID: 31391358 PMCID: PMC6863727 DOI: 10.1292/jvms.19-0154] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Serum amyloid A (SAA) is an acute-phase protein indicative of inflammation. In murine
colonic epithelial cells, lipopolysaccharide (LPS), a gram-negative bacterial antigen,
strongly enhanced mRNA expression of SAA3, but not SAA1 or SAA2, suggesting that SAA3
might respond to bacterial infection in other epithelia. We examined SAA1/2 and SAA3 mRNA
expression in murine alveolar epithelial cells exposed to LPS or the gram-positive
bacterial antigen, lipoteichoic acid (LTA), using real-time PCR. LPS enhanced SAA3 mRNA
expression at lower concentrations than did LTA, whereas SAA1/2 mRNA expression was not
enhanced by either LPS or LTA. These results suggest that SAA3 expression is enhanced in
lung epithelium upon bacterial infection as part of innate immunity, with higher
sensitivity to LPS than to LTA.
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Affiliation(s)
- Ami Iwata
- Laboratory of Food and Environmental Hygiene, Cooperative Department of Veterinary Medicine, Gifu University, Gifu 501-1193, Japan
| | - Kaori Shimizu
- Laboratory of Food and Environmental Hygiene, Cooperative Department of Veterinary Medicine, Gifu University, Gifu 501-1193, Japan
| | - Haruka Kawasaki
- Laboratory of Food and Environmental Hygiene, Cooperative Department of Veterinary Medicine, Gifu University, Gifu 501-1193, Japan
| | - Ayaka Okada
- Laboratory of Food and Environmental Hygiene, Cooperative Department of Veterinary Medicine, Gifu University, Gifu 501-1193, Japan.,Education and Research Center for Food Animal Health, Gifu University (GeFAH), Gifu 501-1193, Japan
| | - Yasuo Inoshima
- Laboratory of Food and Environmental Hygiene, Cooperative Department of Veterinary Medicine, Gifu University, Gifu 501-1193, Japan.,Education and Research Center for Food Animal Health, Gifu University (GeFAH), Gifu 501-1193, Japan.,The United Graduate School of Veterinary Sciences, Gifu University, Gifu 501-1193, Japan.,Joint Graduate School of Veterinary Sciences, Gifu University, Gifu 501-1193, Japan
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18
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19
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Cryo-EM fibril structures from systemic AA amyloidosis reveal the species complementarity of pathological amyloids. Nat Commun 2019; 10:1104. [PMID: 30846696 PMCID: PMC6405766 DOI: 10.1038/s41467-019-09033-z] [Citation(s) in RCA: 98] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Accepted: 02/13/2019] [Indexed: 02/02/2023] Open
Abstract
Systemic AA amyloidosis is a worldwide occurring protein misfolding disease of humans and animals. It arises from the formation of amyloid fibrils from the acute phase protein serum amyloid A. Here, we report the purification and electron cryo-microscopy analysis of amyloid fibrils from a mouse and a human patient with systemic AA amyloidosis. The obtained resolutions are 3.0 Å and 2.7 Å for the murine and human fibril, respectively. The two fibrils differ in fundamental properties, such as presence of right-hand or left-hand twisted cross-β sheets and overall fold of the fibril proteins. Yet, both proteins adopt highly similar β-arch conformations within the N-terminal ~21 residues. Our data demonstrate the importance of the fibril protein N-terminus for the stability of the analyzed amyloid fibril morphologies and suggest strategies of combating this disease by interfering with specific fibril polymorphs. Systemic AA amyloidosis is caused by misfolding of the acute phase protein serum amyloid A1. Here the authors present the cryo-EM structures of murine and human AA amyloid fibrils that were isolated from tissue samples and describe how the fibrils differ in their fundamental structural properties.
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20
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Bifunctional amyloid-reactive peptide promotes binding of antibody 11-1F4 to diverse amyloid types and enhances therapeutic efficacy. Proc Natl Acad Sci U S A 2018; 115:E10839-E10848. [PMID: 30377267 DOI: 10.1073/pnas.1805515115] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Amyloidosis is a malignant pathology associated with the formation of proteinaceous amyloid fibrils that deposit in organs and tissues, leading to dysfunction and severe morbidity. More than 25 proteins have been identified as components of amyloid, but the most common form of systemic amyloidosis is associated with the deposition of amyloid composed of Ig light chains (AL). Clinical management of amyloidosis focuses on reducing synthesis of the amyloid precursor protein. However, recently, passive immunotherapy using amyloid fibril-reactive antibodies, such as 11-1F4, to remove amyloid from organs has been shown to be effective at restoring organ function in patients with AL amyloidosis. However, 11-1F4 does not bind amyloid in all AL patients, as evidenced by PET/CT imaging, nor does it efficiently bind the many other forms of amyloid. To enhance the reactivity and expand the utility of the 11-1F4 mAb as an amyloid immunotherapeutic, we have developed a pretargeting "peptope" comprising a multiamyloid-reactive peptide, p5+14, fused to a high-affinity peptide epitope recognized by 11-1F4. The peptope, known as p66, bound the 11-1F4 mAb in vitro with subnanomolar efficiency, exhibited multiamyloid reactivity in vitro and, using tissue biodistribution and SPECT imaging, colocalized with amyloid deposits in a mouse model of systemic serum amyloid A amyloidosis. Pretreatment with the peptope induced 11-1F4 mAb accumulation in serum amyloid A deposits in vivo and enhanced 11-1F4-mediated dissolution of a human AL amyloid extract implanted in mice.
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21
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Harata D, Tsuchiya Y, Miyoshi T, Yanai T, Suzuki K, Murakami T. Inhibitory effect of propolis on the development of AA amyloidosis. J Toxicol Pathol 2018; 31:89-93. [PMID: 29749997 PMCID: PMC5938209 DOI: 10.1293/tox.2017-0044] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Accepted: 12/05/2017] [Indexed: 11/19/2022] Open
Abstract
In the several types of amyloidoses, participation of oxidative stresses in the pathogenesis and the effect of antioxidants on amyloidosis have been reported. Meanwhile, the relationship between oxidative stresses and pathogenesis of amyloid A (AA) amyloidosis is still unclear. In this study, we used an antioxidant, Brazilian propolis, to investigate the inhibitory effects on AA amyloidosis. The results showed that AA deposition was inhibited by administration of propolis. Increased expression of antioxidant markers was detected in molecular biological examinations of mice treated with propolis. Although serum amyloid A (SAA) levels were strongly correlated with the immunoreactive area of AA deposits in the control group, the correlation was weaker in the propolis-treated groups. In addition, there were no changes in SAA levels between the control group and the propolis-treated groups. The results indicate that propolis, an antioxidant, may induce inhibitory effects against AA amyloidosis.
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Affiliation(s)
- Daichi Harata
- Laboratory of Veterinary Toxicology, Cooperative Department of Veterinary Medicine, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan
| | - Yuya Tsuchiya
- Nagaragawa Research Center, API Co., Ltd., 692-3 Nagara, Gifu-shi, Gifu 502-0071, Japan.,Laboratory of Veterinary Pathology, Department of Veterinary Medicine, Gifu University, 1-1 Yanagido, Gifu-shi, Gifu 501-1193, Japan
| | - Tomoyuki Miyoshi
- Laboratory of Veterinary Toxicology, Cooperative Department of Veterinary Medicine, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan
| | - Tokuma Yanai
- Laboratory of Veterinary Pathology, Department of Veterinary Medicine, Gifu University, 1-1 Yanagido, Gifu-shi, Gifu 501-1193, Japan
| | - Kazuhiko Suzuki
- Laboratory of Veterinary Toxicology, Cooperative Department of Veterinary Medicine, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan
| | - Tomoaki Murakami
- Laboratory of Veterinary Toxicology, Cooperative Department of Veterinary Medicine, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan
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22
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Milani P, Merlini G, Palladini G. Novel Therapies in Light Chain Amyloidosis. Kidney Int Rep 2018; 3:530-541. [PMID: 29854961 PMCID: PMC5976806 DOI: 10.1016/j.ekir.2017.11.017] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2017] [Revised: 10/28/2017] [Accepted: 11/21/2017] [Indexed: 12/11/2022] Open
Abstract
Light chain (AL) amyloidosis is the most common form of amyloidosis involving the kidney. It is characterized by albuminuria, progressing to overt nephrotic syndrome and eventually end-stage renal failure if diagnosed late or ineffectively treated, and in most cases by concomitant heart involvement. Cardiac amyloidosis is the main determinant of survival, whereas the risk of dialysis is predicted by baseline proteinuria and glomerular filtration rate, and by response to therapy. The backbone of treatment is chemotherapy targeting the underlying plasma cell clone, that needs to be risk-adapted due to the frailty of patients with AL amyloidosis who have cardiac and/or multiorgan involvement. Low-risk patients (∼20%) can be considered for autologous stem cell transplantation that can be preceded by induction and/or followed by consolidation with bortezomib-based regimens. Bortezomib combined with alkylators, such as melphalan, preferred in patients harboring t(11;14), or cyclophosphamide, is used in most intermediate-risk patients, and with cautious dose escalation in high-risk subjects. Novel, powerful anti-plasma cell agents, such as pomalidomide, ixazomib, and daratumumab, prove effective in the relapsed/refractory setting, and are being moved to upfront therapy in clinical trials. Novel approaches based on small molecules interfering with the amyloidogenic process and on antibodies targeting the amyloid deposits gave promising results in preliminary uncontrolled studies, are being tested in controlled trials, and will likely prove powerful complements to chemotherapy. Finally, improvements in the understanding of the molecular mechanisms of organ damage are unveiling novel potential treatment targets, moving toward a cure for this dreadful disease.
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Affiliation(s)
- Paolo Milani
- Amyloidosis Research and Treatment Center, Foundation “Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo,” and Department of Molecular Medicine, University of Pavia, Pavia, Italy
| | - Giampaolo Merlini
- Amyloidosis Research and Treatment Center, Foundation “Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo,” and Department of Molecular Medicine, University of Pavia, Pavia, Italy
| | - Giovanni Palladini
- Amyloidosis Research and Treatment Center, Foundation “Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo,” and Department of Molecular Medicine, University of Pavia, Pavia, Italy
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23
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Kennel SJ, Stuckey A, McWilliams-Koeppen HP, Richey T, Wall JS. Tc-99m Radiolabeled Peptide p5 + 14 is an Effective Probe for SPECT Imaging of Systemic Amyloidosis. Mol Imaging Biol 2017; 18:483-9. [PMID: 26573301 DOI: 10.1007/s11307-015-0914-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
PURPOSE Systemic peripheral amyloidosis is a rare disease in which misfolded proteins deposit in various organs. We have previously developed I-124 labeled peptide p5 + 14 as a tracer for positron emission tomography imaging of amyloid in patients. In this report, we now document the labeling efficiency, bioactivity, and stability of Tc-99m labeled p5 + 14 for single-photon emission computed tomography (SPECT) imaging of amyloidosis, validated in a mouse model of systemic amyloidosis. PROCEDURES Radiochemical yield, purity, and biological activity of [(99m)Tc]p5 + 14 were documented by instant thin-layer chromatography (ITLC), SDS-PAGE and a quantitative amyloid fibril pulldown assay. The efficacy and stability were documented in serum amyloid protein A (AA) amyloid-bearing or wild-type (WT) control mice imaged with SPECT/X-ray computed tomography (CT) at two time points. The uptake and retention of [(99m)Tc]p5 + 14 in hepatosplenic amyloid was evaluated using region of interest (ROI) and tissue counting measurements. RESULTS Tc-99m p5 + 14 was produced with a radiochemical yield of 75 % with greater than 90 % purity and biological activity comparable to that of radioiodinated peptide. AA amyloid was visualized by SPECT/CT imaging with specific uptake seen in amyloid-laden organs at levels ∼5 folds higher than in healthy mice. ROI analyses of decay-corrected SPECT/CT images showed <20 % loss of radiolabel from the 1 to 4 h imaging time points. Biodistribution data confirmed the specificity of the probe accumulation by amyloid-laden organs as compared to non-diseased tissues. CONCLUSION [(99m)Tc]p5 + 14 is a specific and stable radiotracer for systemic amyloid in mice and may provide a convenient and inexpensive alternative to imaging of peripheral amyloidosis in patients.
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Affiliation(s)
- Stephen J Kennel
- Department of Medicine, University of Tennessee, Graduate School of Medicine, Knoxville, TN, USA. .,Department of Radiology, University of Tennessee, Graduate School of Medicine, Knoxville, TN, USA. .,University of Tennessee Medical Center, 1924 Alcoa Highway, Knoxville, TN, 37920, USA.
| | - Alan Stuckey
- Department of Radiology, University of Tennessee, Graduate School of Medicine, Knoxville, TN, USA
| | | | - Tina Richey
- Department of Medicine, University of Tennessee, Graduate School of Medicine, Knoxville, TN, USA
| | - Jonathan S Wall
- Department of Medicine, University of Tennessee, Graduate School of Medicine, Knoxville, TN, USA.,Department of Radiology, University of Tennessee, Graduate School of Medicine, Knoxville, TN, USA
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24
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Serum amyloid A forms stable oligomers that disrupt vesicles at lysosomal pH and contribute to the pathogenesis of reactive amyloidosis. Proc Natl Acad Sci U S A 2017; 114:E6507-E6515. [PMID: 28743750 DOI: 10.1073/pnas.1707120114] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Serum amyloid A (SAA) is an acute-phase plasma protein that functions in innate immunity and lipid homeostasis. SAA is a protein precursor of reactive AA amyloidosis, the major complication of chronic inflammation and one of the most common human systemic amyloid diseases worldwide. Most circulating SAA is protected from proteolysis and misfolding by binding to plasma high-density lipoproteins. However, unbound soluble SAA is intrinsically disordered and is either rapidly degraded or forms amyloid in a lysosome-initiated process. Although acidic pH promotes amyloid fibril formation by this and many other proteins, the molecular underpinnings are unclear. We used an array of spectroscopic, biochemical, and structural methods to uncover that at pH 3.5-4.5, murine SAA1 forms stable soluble oligomers that are maximally folded at pH 4.3 with ∼35% α-helix and are unusually resistant to proteolysis. In solution, these oligomers neither readily convert into mature fibrils nor bind lipid surfaces via their amphipathic α-helices in a manner typical of apolipoproteins. Rather, these oligomers undergo an α-helix to β-sheet conversion catalyzed by lipid vesicles and disrupt these vesicles, suggesting a membranolytic potential. Our results provide an explanation for the lysosomal origin of AA amyloidosis. They suggest that high structural stability and resistance to proteolysis of SAA oligomers at pH 3.5-4.5 help them escape lysosomal degradation, promote SAA accumulation in lysosomes, and ultimately damage cellular membranes and liberate intracellular amyloid. We posit that these soluble prefibrillar oligomers provide a missing link in our understanding of the development of AA amyloidosis.
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25
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Tashiro M, Iwata A, Yamauchi M, Shimizu K, Okada A, Ishiguro N, Inoshima Y. The N-terminal region of serum amyloid A3 protein activates NF-κB and up-regulates MUC2 mucin mRNA expression in mouse colonic epithelial cells. PLoS One 2017; 12:e0181796. [PMID: 28738073 PMCID: PMC5524290 DOI: 10.1371/journal.pone.0181796] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2017] [Accepted: 07/09/2017] [Indexed: 01/01/2023] Open
Abstract
Serum amyloid A (SAA) is the major acute-phase protein and a precursor of amyloid A (AA) in AA amyloidosis in humans and animals. SAA isoforms have been identified in a wide variety of animals, such as SAA1, SAA2, SAA3, and SAA4 in mouse. Although the biological functions of SAA isoforms are not completely understood, recent studies have suggested that SAA3 plays a role in host defense. Expression of SAA3 is increased on the mouse colon surface in the presence of microbiota in vivo, and it increases mRNA expression of mucin 2 (MUC2) in murine colonic epithelial cells in vitro, which constitutes a protective mucus barrier in the intestinal tract. In this study, to identify responsible regions in SAA3 for MUC2 expression, recombinant murine SAA1 (rSAA1), rSAA3, and rSAA1/3, a chimera protein constructed with mature SAA1 (amino acids 1–36) and SAA3 (amino acids 37–103), and vice versa for rSAA3/1, were added to murine colonic epithelial CMT-93 cells, and the mRNA expressions of MUC2 and cytokines were measured. Inhibition assays with NF-κB inhibitor or TLR4/MD2 inhibitor were also performed. Up-regulation of MUC2 mRNA expression was strongly stimulated by rSAA3 and rSAA3/1, but not by rSAA1 or rSAA1/3. Moreover, NF-κB and TLR4/MD2 inhibitors suppressed the increase of MUC2 mRNA expression. These results suggest that the major responsible region for MUC2 expression exists in amino acids 1–36 of SAA3, and that up-regulations of MUC2 expression by SAA3 and SAA3/1 are involved with activation of NF-κB via the TLR4/MD2 complex.
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Affiliation(s)
- Manami Tashiro
- Laboratory of Food and Environmental Hygiene, Cooperative Department of Veterinary Medicine, Faculty of Applied Biological Sciences, Gifu University, Gifu, Japan
| | - Ami Iwata
- Laboratory of Food and Environmental Hygiene, Cooperative Department of Veterinary Medicine, Faculty of Applied Biological Sciences, Gifu University, Gifu, Japan
| | - Marika Yamauchi
- Laboratory of Food and Environmental Hygiene, Cooperative Department of Veterinary Medicine, Faculty of Applied Biological Sciences, Gifu University, Gifu, Japan
| | - Kaori Shimizu
- Laboratory of Food and Environmental Hygiene, Cooperative Department of Veterinary Medicine, Faculty of Applied Biological Sciences, Gifu University, Gifu, Japan
| | - Ayaka Okada
- Laboratory of Food and Environmental Hygiene, Cooperative Department of Veterinary Medicine, Faculty of Applied Biological Sciences, Gifu University, Gifu, Japan
| | - Naotaka Ishiguro
- Laboratory of Food and Environmental Hygiene, Cooperative Department of Veterinary Medicine, Faculty of Applied Biological Sciences, Gifu University, Gifu, Japan
- The United Graduate School of Veterinary Sciences, Gifu University, Gifu, Japan
| | - Yasuo Inoshima
- Laboratory of Food and Environmental Hygiene, Cooperative Department of Veterinary Medicine, Faculty of Applied Biological Sciences, Gifu University, Gifu, Japan
- The United Graduate School of Veterinary Sciences, Gifu University, Gifu, Japan
- Education and Research Center for Food Animal Health, Gifu University (GeFAH), Yanagido, Gifu, Gifu, Japan
- * E-mail:
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Hepatic expression of serum amyloid A1 is induced by traumatic brain injury and modulated by telmisartan. THE AMERICAN JOURNAL OF PATHOLOGY 2016; 185:2641-52. [PMID: 26435412 DOI: 10.1016/j.ajpath.2015.06.016] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/12/2014] [Revised: 04/16/2015] [Accepted: 06/01/2015] [Indexed: 12/27/2022]
Abstract
Traumatic brain injury affects the whole body in addition to the direct impact on the brain. The systemic response to trauma is associated with the hepatic acute-phase response. To further characterize this response, we performed controlled cortical impact injury on male mice and determined the expression of serum amyloid A1 (SAA1), an apolipoprotein, induced at the early stages of the acute-phase response in liver and plasma. After cortical impact injury, induction of SAA1 was detectable in plasma at 6 hours post-injury and in liver at 1 day post-injury, followed by gradual diminution over time. In the liver, cortical impact injury increased neutrophil and macrophage infiltration, apoptosis, and expression of mRNA encoding the chemokines CXCL1 and CXCL10. An increase in angiotensin II AT1 receptor mRNA at 3 days post-injury was also observed. Administration of the AT1 receptor antagonist telmisartan 1 hour post-injury significantly decreased liver SAA1 levels and CXCL10 mRNA expression, but did not affect CXCL1 expression or the number of apoptotic cells or infiltrating leukocytes. To our knowledge, this is the first study to demonstrate that SAA1 is induced in the liver after traumatic brain injury and that telmisartan prevents this response. Elucidating the molecular pathogenesis of the liver after brain injury will assist in understanding the efficacy of therapeutic approaches to brain injury.
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27
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Electron tomography reveals the fibril structure and lipid interactions in amyloid deposits. Proc Natl Acad Sci U S A 2016; 113:5604-9. [PMID: 27140609 DOI: 10.1073/pnas.1523496113] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Electron tomography is an increasingly powerful method to study the detailed architecture of macromolecular complexes or cellular structures. Applied to amyloid deposits formed in a cell culture model of systemic amyloid A amyloidosis, we could determine the structural morphology of the fibrils directly in the deposit. The deposited fibrils are arranged in different networks, and depending on the relative fibril orientation, we can distinguish between fibril meshworks, fibril bundles, and amyloid stars. These networks are frequently infiltrated by vesicular lipid inclusions that may originate from the death of the amyloid-forming cells. Our data support the role of nonfibril components for constructing fibril deposits and provide structural views of different types of lipid-fibril interactions.
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Scarpioni R, Ricardi M, Albertazzi V. Secondary amyloidosis in autoinflammatory diseases and the role of inflammation in renal damage. World J Nephrol 2016; 5:66-75. [PMID: 26788465 PMCID: PMC4707170 DOI: 10.5527/wjn.v5.i1.66] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2015] [Revised: 11/24/2015] [Accepted: 12/09/2015] [Indexed: 02/06/2023] Open
Abstract
The release of proinflammatory cytokines during inflammation represents an attempt to respond to injury, but it may produce detrimental effects. The inflammasome is a large, multiprotein complex that drives proinflammatory cytokine production in response to infection and tissue injury; the best-characterized inflammasome is the nod-like receptor protein-3 (NLRP3). Once activated, inflammasome leads to the active form of caspase-1, the enzyme required for the maturation of interleukin-1beta. Additional mechanisms bringing to renal inflammatory, systemic diseases and fibrotic processes were recently reported, via the activation of the inflammasome that consists of NLRP3, apoptosis associated speck-like protein and caspase-1. Several manuscripts seem to identify NLRP3 inflammasome as a possible therapeutic target in the treatment of progressive chronic kidney disease. Serum amyloid A (SAA), as acute-phase protein with also proinflammatory properties, has been shown to induce the secretion of cathepsin B and inflammasome components from human macrophages. SAA is a well recognised potent activator of the NLRP3. Here we will address our description on the involvement of the kidney in autoinflammatory diseases driven mainly by secondary, or reactive, AA amyloidosis with a particular attention on novel therapeutic approach which has to be addressed in suppressing underlying inflammatory disease and reducing the SAA concentration.
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29
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Gaffney PM, Witte C, Clifford DL, Imai DM, O'Brien TD, Trejo M, Liberta F, Annamalai K, Fändrich M, Masliah E, Munson L, Sigurdson CJ. Systemic Amyloid A Amyloidosis in Island Foxes (Urocyon littoralis): Severity and Risk Factors. Vet Pathol 2015; 53:637-47. [PMID: 26419399 DOI: 10.1177/0300985815604725] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Systemic amyloid A (AA) amyloidosis is highly prevalent (34%) in endangered island foxes (Urocyon littoralis) and poses a risk to species recovery. Although elevated serum AA (SAA) from prolonged or recurrent inflammation predisposes to AA amyloidosis, additional risk factors are poorly understood. Here we define the severity of glomerular and medullary renal amyloid and identify risk factors for AA amyloidosis in 321 island foxes necropsied from 1987 through 2010. In affected kidneys, amyloid more commonly accumulated in the medullary interstitium than in the glomeruli (98% [n= 78 of 80] vs 56% [n= 45], respectively;P< .0001), and medullary deposition was more commonly severe (19% [n= 20 of 105]) as compared with glomeruli (7% [n= 7];P= .01). Univariate odds ratios (ORs) of severe renal AA amyloidosis were greater for short- and long-term captive foxes as compared with free-ranging foxes (ORs = 3.2, 3.7, respectively; overall P= .05) and for females as compared with males (OR = 2.9;P= .05). Multivariable logistic regression revealed that independent risk factors for amyloid development were increasing age class (OR = 3.8;P< .0001), San Clemente Island subspecies versus San Nicolas Island subspecies (OR = 5.3;P= .0003), captivity (OR = 5.1;P= .0001), and nephritis (OR = 2.3;P= .01). The increased risk associated with the San Clemente subspecies or captivity suggests roles for genetic as well as exogenous risk factors in the development of AA amyloidosis.
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Affiliation(s)
- P M Gaffney
- Departments of Pathology and Medicine, University of California-San Diego, La Jolla, CA, USA Department of Pathology, Immunology, and Microbiology, University of California-Davis, Davis, CA, USA
| | - C Witte
- Wildlife Disease Laboratories, Institute for Conservation Research, San Diego Zoo Global, Escondido, CA, USA
| | - D L Clifford
- Wildlife Investigations Laboratory, California Department of Fish and Wildlife, Rancho Cordova, CA, USA Department of Veterinary Medicine and Epidemiology, University of California-Davis, Davis, CA, USA
| | - D M Imai
- Department of Pathology, Immunology, and Microbiology, University of California-Davis, Davis, CA, USA
| | - T D O'Brien
- Veterinary Population Medicine Department, Veterinary Diagnostic Laboratory, University of Minnesota, St Paul, MN, USA
| | - M Trejo
- Departments of Pathology and Neuroscience, University of California-San Diego, La Jolla, CA, USA
| | - F Liberta
- Institute for Pharmaceutical Biotechnology, Ulm University, Helmholtzstrasse, Ulm, Germany
| | - K Annamalai
- Institute for Pharmaceutical Biotechnology, Ulm University, Helmholtzstrasse, Ulm, Germany
| | - M Fändrich
- Institute for Pharmaceutical Biotechnology, Ulm University, Helmholtzstrasse, Ulm, Germany
| | - E Masliah
- Departments of Pathology and Neuroscience, University of California-San Diego, La Jolla, CA, USA
| | - L Munson
- Department of Pathology, Immunology, and Microbiology, University of California-Davis, Davis, CA, USA Deceased Supplemental material for this article is available on the Veterinary Pathology website at http://vet.sagepub.com/supplemental
| | - C J Sigurdson
- Departments of Pathology and Medicine, University of California-San Diego, La Jolla, CA, USA Department of Pathology, Immunology, and Microbiology, University of California-Davis, Davis, CA, USA
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Intestinal Amyloidosis in Common Variable Immunodeficiency and Rheumatoid Arthritis. Case Rep Gastrointest Med 2015; 2015:405695. [PMID: 26351592 PMCID: PMC4553190 DOI: 10.1155/2015/405695] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2015] [Revised: 07/23/2015] [Accepted: 07/26/2015] [Indexed: 11/18/2022] Open
Abstract
We present a case of reactive amyloidosis that developed secondary to common variable immunodeficiency and rheumatoid arthritis. A 66-year-old woman, with prior history of common variable immunodeficiency and rheumatoid arthritis, was referred to our clinic for chronic diarrhea investigation. The patient was submitted to colonoscopy with ileoscopy, which did not show relevant endoscopic alterations. However, undertaken biopsies revealed amyloid deposition. Since amyloidosis with GI involvement is a rare cause of chronic diarrhea, this pathology should be considered in etiologic investigation, especially when associated with chronic inflammatory diseases.
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31
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Gaffney PM, Barr B, Rowe JD, Bett C, Drygiannakis I, Giannitti F, Trejo M, Ghassemian M, Martin P, Masliah E, Sigurdson CJ. Protein profiling of isolated uterine AA amyloidosis causing fetal death in goats. FASEB J 2014; 29:911-9. [PMID: 25422367 DOI: 10.1096/fj.14-256081] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Pathologic amyloid accumulates in the CNS or in peripheral organs, yet the mechanism underlying the targeting of systemic amyloid deposits is unclear. Serum amyloid A (SAA) 1 and 2 are produced predominantly by the liver and form amyloid most commonly in the spleen, liver, and kidney. In contrast, SAA3 is produced primarily extrahepatically and has no causal link to amyloid formation. Here, we identified 8 amyloidosis cases with amyloid composed of SAA3 expanding the uterine wall of goats with near-term fetuses. Uterine amyloid accumulated in the endometrium, only at the site of placental attachment, compromising maternal-fetal gas and nutrient exchange and leading to fetal ischemia and death. No other organ contained amyloid. SAA3 mRNA levels in the uterine endometrium were as high as SAA2 in the liver, yet mass spectrometry of the insoluble uterine peptides identified SAA3 as the predominant protein, and not SAA1 or SAA2. These findings suggest that high local SAA3 production led to deposition at this unusual site. Although amyloid A (AA) amyloid deposits typically consist of an N-terminal fragment of SAA1 or SAA2, here, abundant C-terminal peptides indicated that the uterine amyloid was largely composed of full-length SAA3. The exclusive deposition of SAA3 amyloid in the uterus, together with elevated uterine SAA3 transcripts, suggests that the uterine amyloid deposits were due to locally produced SAA3. This is the first report of SAA3 as a cause of amyloidosis and of AA amyloid deposited exclusively in the uterus.
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Affiliation(s)
- Patricia M Gaffney
- Departments of *Pathology, Neuroscience, and Chemistry and Biochemistry, University of California, San Diego, La Jolla, California, USA; Departments of Pathology, Immunology and Microbiology and Population Health & Reproduction, and California Animal Health and Food Safety Laboratory System, University of California, Davis, Davis, California, USA; and INRA, UMR1313 Unité Génétique Animale et Biologie Intégrative, Jouy-en-Josas, France
| | - Bradd Barr
- Departments of *Pathology, Neuroscience, and Chemistry and Biochemistry, University of California, San Diego, La Jolla, California, USA; Departments of Pathology, Immunology and Microbiology and Population Health & Reproduction, and California Animal Health and Food Safety Laboratory System, University of California, Davis, Davis, California, USA; and INRA, UMR1313 Unité Génétique Animale et Biologie Intégrative, Jouy-en-Josas, France
| | - Joan D Rowe
- Departments of *Pathology, Neuroscience, and Chemistry and Biochemistry, University of California, San Diego, La Jolla, California, USA; Departments of Pathology, Immunology and Microbiology and Population Health & Reproduction, and California Animal Health and Food Safety Laboratory System, University of California, Davis, Davis, California, USA; and INRA, UMR1313 Unité Génétique Animale et Biologie Intégrative, Jouy-en-Josas, France
| | - Cyrus Bett
- Departments of *Pathology, Neuroscience, and Chemistry and Biochemistry, University of California, San Diego, La Jolla, California, USA; Departments of Pathology, Immunology and Microbiology and Population Health & Reproduction, and California Animal Health and Food Safety Laboratory System, University of California, Davis, Davis, California, USA; and INRA, UMR1313 Unité Génétique Animale et Biologie Intégrative, Jouy-en-Josas, France
| | - Ioannis Drygiannakis
- Departments of *Pathology, Neuroscience, and Chemistry and Biochemistry, University of California, San Diego, La Jolla, California, USA; Departments of Pathology, Immunology and Microbiology and Population Health & Reproduction, and California Animal Health and Food Safety Laboratory System, University of California, Davis, Davis, California, USA; and INRA, UMR1313 Unité Génétique Animale et Biologie Intégrative, Jouy-en-Josas, France
| | - Federico Giannitti
- Departments of *Pathology, Neuroscience, and Chemistry and Biochemistry, University of California, San Diego, La Jolla, California, USA; Departments of Pathology, Immunology and Microbiology and Population Health & Reproduction, and California Animal Health and Food Safety Laboratory System, University of California, Davis, Davis, California, USA; and INRA, UMR1313 Unité Génétique Animale et Biologie Intégrative, Jouy-en-Josas, France
| | - Margarita Trejo
- Departments of *Pathology, Neuroscience, and Chemistry and Biochemistry, University of California, San Diego, La Jolla, California, USA; Departments of Pathology, Immunology and Microbiology and Population Health & Reproduction, and California Animal Health and Food Safety Laboratory System, University of California, Davis, Davis, California, USA; and INRA, UMR1313 Unité Génétique Animale et Biologie Intégrative, Jouy-en-Josas, France
| | - Majid Ghassemian
- Departments of *Pathology, Neuroscience, and Chemistry and Biochemistry, University of California, San Diego, La Jolla, California, USA; Departments of Pathology, Immunology and Microbiology and Population Health & Reproduction, and California Animal Health and Food Safety Laboratory System, University of California, Davis, Davis, California, USA; and INRA, UMR1313 Unité Génétique Animale et Biologie Intégrative, Jouy-en-Josas, France
| | - Patrice Martin
- Departments of *Pathology, Neuroscience, and Chemistry and Biochemistry, University of California, San Diego, La Jolla, California, USA; Departments of Pathology, Immunology and Microbiology and Population Health & Reproduction, and California Animal Health and Food Safety Laboratory System, University of California, Davis, Davis, California, USA; and INRA, UMR1313 Unité Génétique Animale et Biologie Intégrative, Jouy-en-Josas, France
| | - Eliezer Masliah
- Departments of *Pathology, Neuroscience, and Chemistry and Biochemistry, University of California, San Diego, La Jolla, California, USA; Departments of Pathology, Immunology and Microbiology and Population Health & Reproduction, and California Animal Health and Food Safety Laboratory System, University of California, Davis, Davis, California, USA; and INRA, UMR1313 Unité Génétique Animale et Biologie Intégrative, Jouy-en-Josas, France
| | - Christina J Sigurdson
- Departments of *Pathology, Neuroscience, and Chemistry and Biochemistry, University of California, San Diego, La Jolla, California, USA; Departments of Pathology, Immunology and Microbiology and Population Health & Reproduction, and California Animal Health and Food Safety Laboratory System, University of California, Davis, Davis, California, USA; and INRA, UMR1313 Unité Génétique Animale et Biologie Intégrative, Jouy-en-Josas, France
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Chronic renal failure due to amyloid nephropathy caused by chronic infection after total hip replacement. CEN Case Rep 2014; 3:217-222. [PMID: 28509203 DOI: 10.1007/s13730-014-0121-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2013] [Accepted: 03/26/2014] [Indexed: 10/25/2022] Open
Abstract
A 75-year-old woman was admitted to our hospital because of proteinuria, pitting edema on the foot, and renal impairment. She had undergone total hip replacement (THR) for femoral neck fracture at the age of 66. Nine years later, she met with an accident during farming and was treated at an emergency hospital for severe general trauma. On the basis of systemic symptoms, she was diagnosed with nephrotic syndrome. Renal biopsy by Congo-red staining and electron microscopy revealed amyloid deposition on glomeruli, interstitium, and interlobar arteries. The amyloid was immunohistochemically identified as AA amyloidosis. The patient eventually required maintenance hemodialysis because of impaired renal function. AA amyloidosis is an unusual complication of intractable inflammation. Chronic infection with abscess occurred around the artificial hip joint following THR and possibly induced secondary amyloidosis. THR is a common and necessary procedure adopted for femoral neck fracture. Orthopedic surgeons should, however, carefully monitor the occurrence of chronic infection after THR because such an infection could lead to renal dysfunction and/or failure via AA amyloidosis in rare cases.
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33
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Tanaka T, Hishitani Y, Ogata A. Monoclonal antibodies in rheumatoid arthritis: comparative effectiveness of tocilizumab with tumor necrosis factor inhibitors. Biologics 2014; 8:141-53. [PMID: 24741293 PMCID: PMC3984066 DOI: 10.2147/btt.s37509] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by persistent joint inflammation, systemic inflammation, and immunological abnormalities. Because cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-6 play a major role in the development of RA, their targeting could constitute a reasonable novel therapeutic strategy for treating RA. Indeed, worldwide clinical trials of TNF inhibiting biologic disease modifying antirheumatic drugs (bDMARDs) including infliximab, adalimumab, golimumab, certolizumab pegol, and etanercept as well as the humanized anti-human IL-6 receptor antibody, tocilizumab, have demonstrated outstanding clinical efficacy and tolerable safety profiles, resulting in worldwide approval for using these bDMARDs to treat moderate to severe active RA in patients with an inadequate response to synthetic disease modifying antirheumatic drugs (sDMARDs). Although bDMARDs have elicited to a paradigm shift in the treatment of RA due to the prominent efficacy that had not been previously achieved by sDMARDs, a substantial percentage of patients failed primary or secondary responses to bDMARD therapy. Because RA is a heterogeneous disease in which TNF-α and IL-6 play overlapping but distinct pathological roles, further studies are required to determine the best use of TNF inhibitors and tocilizumab in individual RA patients.
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Affiliation(s)
- Toshio Tanaka
- Department of Clinical Application of Biologics, Osaka University Graduate School of Medicine, Osaka University, Osaka, Japan
- Department of Immunopathology, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan
| | - Yoshihiro Hishitani
- Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Osaka University Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Atsushi Ogata
- Department of Immunopathology, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan
- Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Osaka University Graduate School of Medicine, Osaka University, Osaka, Japan
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Shigemura H, Ishiguro N, Inoshima Y. Up-regulation of MUC2 mucin expression by serum amyloid A3 protein in mouse colonic epithelial cells. J Vet Med Sci 2014; 76:985-91. [PMID: 24694941 PMCID: PMC4143660 DOI: 10.1292/jvms.14-0007] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Serum amyloid A (SAA) proteins
are acute-phase proteins and are classified into multiple isoforms; however, the
biological functions of each SAA isoform are not fully understood. In this study, to
clarify the roles of SAA3 in the intestine, we characterized mRNA expression in mouse
colonic epithelial CMT-93 cells treated with rotavirus, Toxoplasma,
Staphylococcus aureus, and Escherichia coli, as well
as lipopolysaccharide (LPS) and recombinant murine SAAs (rSAAs). E. coli
together with LPS, but not the other pathogens, enhanced SAA3 mRNA expression. The mRNA
expression of SAA3 by dead E. coli was higher than that by living
E. coli, and the mRNA expression by E. coli and LPS
increased in a dose-dependent manner. In contrast, mRNA expressions of SAA1 and/or SAA2
were not stimulated by any of the treatments. In comparisons of cell treatments with rSAA1
or rSAA3, rSAA3 significantly up-regulated the mRNA expression of mucin 2 (MUC2), a major
component of the mucus layer of the intestines that acts as an epithelial cell barrier
against pathogens, while MUC2 mRNA expression was not significantly increased by
E. coli and LPS. Furthermore, treatment with rSAAs intensively induced
tumor necrosis factor-α mRNA expression. These results suggest that SAA3 plays a role in
host innate immunity in the colon by up-regulating MUC2 mucin production, which builds a
physiological barrier of colonic epithelia against bacterial invasion.
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Affiliation(s)
- Hiroaki Shigemura
- Laboratory of Food and Environmental Hygiene, Cooperative Department of Veterinary Medicine, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan
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Serum amyloid A induces mitogenic signals in regulatory T cells via monocyte activation. Mol Immunol 2014; 59:172-9. [PMID: 24632292 DOI: 10.1016/j.molimm.2014.02.011] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2014] [Revised: 02/12/2014] [Accepted: 02/14/2014] [Indexed: 12/23/2022]
Abstract
Serum amyloid A (SAA) has recently been identified by our group as a mitogen for regulatory T cells (Treg). However, the molecular mechanism by which SAA induces Treg proliferation is unknown. Here we provide evidence that IL-1β and IL-6 are directly involved in the SAA-mediated proliferation of Treg. By engaging its several cognate receptors, SAA induces IL-1β and IL-6 secretion by monocytes and drives them toward an HLA-DR(hi) HVEM(lo) phenotype resembling immature dendritic cells, which have been implicated in tolerance generation. This monocyte-derived cytokine milieu is required for Treg expansion, as inhibition of IL-1β and IL-6 abrogate the ability of SAA to induce Treg proliferation. Furthermore, both IL-1β and IL-6 are required for ERK1/2 and AKT signaling in proliferating Treg. Collectively, these results point to a novel mechanism, by which SAA initiates a monocyte-dependent process that drives mitogenic signals in Treg.
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36
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Kapoor S. Assessing disease severity and activity in patients with familial Mediterranean fever. Inflammation 2014; 37:833-4. [PMID: 24390269 DOI: 10.1007/s10753-013-9803-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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37
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Cooper C, Bilbao JE, Said S, Alkhateeb H, Bizet J, Elfar A, Davalos O, Meza AT, Hernandez GT. Serum amyloid A renal amyloidosis in a chronic subcutaneous ("skin popping") heroin user. J Nephropathol 2013; 2:196-200. [PMID: 24475449 DOI: 10.12860/jnp.2013.31] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2012] [Revised: 12/20/2012] [Accepted: 01/29/2013] [Indexed: 11/20/2022] Open
Abstract
BACKGROUND Systemic AA amyloidosis is a long-term complication of several chronic inflammatory disorders. Organ damage results from the extracellular deposition of proteolytic fragments of the acute-phase reactant serum amyloid A (SAA) as amyloid fibrils. Drug users that inject drug by a subcutaneous route ("skin popping") have a higher chance of developing secondary amyloidosis. The kidneys, liver, and spleen are the main target organs of AA amyloid deposits. More than 90% of patients with renal amyloidosis will present with proteinuria, nephrotic syndrome, or renal function. CASE PRESENTATION A 37 year-old female presented to the hospital with a one-week history of pain and redness in her right axilla. Her relevant medical history included multiple skin abscesses secondary to "skin popping", heroin abuse for 18 years, and hepatitis C. The physical examination revealed "skin popping" lesions, bilateral costovertebral angle tenderness, and bilateral knee swelling. The laboratory workup was significant for renal insufficiency with a serum creatinine of 5 mg/dL and 14.8 grams of urine protein per 1 gram of urine creatinine. The renal biopsy findings were consistent with a diagnosis of renal amyloidosis due to serum amyloid A deposition and acute tubulointerstitial nephritis. CONCLUSIONS AA renal amyloidosis among heroin addicts seems to be associated with chronic suppurative skin infection secondary to "skin popping". It is postulated that the chronic immunologic stimulation by one or more exogenous antigens or multiple acute inflammatory episodes is an important factor in the pathogenesis of amyloidosis in these patients. Therefore, AA renal amyloidosis should always be considered in chronic heroin users presenting with proteinuria and renal impairment.
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Affiliation(s)
- Chad Cooper
- Division of Nephrology & Hypertension, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, Texas, USA
| | | | - Sarmad Said
- Division of Nephrology & Hypertension, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, Texas, USA
| | - Haider Alkhateeb
- Division of Nephrology & Hypertension, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, Texas, USA
| | - Jorge Bizet
- Division of Nephrology & Hypertension, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, Texas, USA
| | - Ahmed Elfar
- Division of Nephrology & Hypertension, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, Texas, USA
| | | | - Ana T Meza
- The University of Texas at El Paso, El Paso, Texas, USA
| | - German T Hernandez
- Division of Nephrology & Hypertension, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, Texas, USA
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