|
1
|
Eric Chen Z. Leukocyte Cell-Derived Chemotaxin 2 (LECT2) Amyloidosis in the Liver. Mayo Clin Proc 2025:S0025-6196(24)00598-6. [PMID: 39903146 DOI: 10.1016/j.mayocp.2024.11.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Accepted: 11/08/2024] [Indexed: 02/06/2025]
Affiliation(s)
- Zongming Eric Chen
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.
| |
Collapse
|
|
2
|
Bijzet J, Nienhuis HLA, Kroesen BJ, Diepstra A, Hazenberg BPC. ELISA-4-amyloid: diagnostic accuracy of an ELISA panel for typing the four main types of systemic amyloidosis in subcutaneous abdominal fat tissue samples. Amyloid 2024; 31:275-284. [PMID: 39105560 DOI: 10.1080/13506129.2024.2385977] [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: 04/14/2024] [Revised: 07/17/2024] [Accepted: 07/23/2024] [Indexed: 08/07/2024]
Abstract
BACKGROUND Reliable typing of amyloid is essential. Amyloid extraction from tissue enables immunochemical typing of the precursor protein using an enzyme-linked immunosorbent assay (ELISA). OBJECTIVE To assess the diagnostic accuracy of a panel of ELISAs for typing the four main types (AA, ATTR, AL-kappa and AL-lambda amyloid). METHODS From 1996 to 2023 subcutaneous abdominal fat tissue aspirates were obtained from 1339 amyloidosis patients and 868 controls. Amyloid was visually graded 0-4+ in Congo red-stained smears. Amyloid extracted from tissue by Guanidine was typed using a panel comprising four ELISAs. RESULTS All amyloid protein concentrations in extracts correlated with amyloid grade in smears. Typing sensitivity was low (23.3%) in samples with grade 1+/2+ amyloid. Overall typing sensitivity of the panel was 81.6% for all easily visible amyloid (grade 3+/4+): high for AA (98.8%) and ATTR (96.8%) and fair for AL-kappa (66.7%) and AL-lambda (75.9). Overall typing specificity was 98.0% and the overall positive predictive value was 98.0%. CONCLUSIONS We describe a highly specific ELISA panel for routine typing of the main amyloid types in fat tissue. Until more sensitive typing techniques will become generally available, typing easily visible amyloid in fat tissue using this ELISA panel is reliable, affordable and straightforward.
Collapse
Affiliation(s)
- Johan Bijzet
- Department of Laboratory Medicine, Groningen Amyloidosis Center of Expertise (GrACE), University Medical Center Groningen, Groningen, The Netherlands
| | - Hans L A Nienhuis
- Department of Internal Medicine, Groningen Amyloidosis Center of Expertise (GrACE), University Medical Center Groningen, Groningen, The Netherlands
| | - Bart-Jan Kroesen
- Department of Laboratory Medicine, Groningen Amyloidosis Center of Expertise (GrACE), University Medical Center Groningen, Groningen, The Netherlands
| | - Arjan Diepstra
- Department of Pathology and Medical Biology, Groningen Amyloidosis Center of Expertise (GrACE), University Medical Center Groningen, Groningen, The Netherlands
| | - Bouke P C Hazenberg
- Department of Rheumatology & Clinical Immunology, Groningen Amyloidosis Center of Expertise (GrACE), University Medical Center Groningen, Groningen, The Netherlands
| |
Collapse
|
|
3
|
Yasir S, Chen ZE, Hartley C, Zhang L, Torbenson M. Morphological findings in different subtypes of hepatic amyloid. Hum Pathol 2024; 146:35-42. [PMID: 38460799 DOI: 10.1016/j.humpath.2024.03.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Revised: 02/28/2024] [Accepted: 03/06/2024] [Indexed: 03/11/2024]
Abstract
The classic findings have been well described for light-chain amyloid involving the liver. In addition to light chain, however, many additional proteins are now known to be amyloidogenic and can involve the liver. A total of 58 surgical pathology specimens with amyloid deposits were analyzed for patterns of amyloid deposition, including amyloid from light chain lambda (N = 17), light chain kappa (N = 15), transthyretin (N = 15), serum amyloid A (N = 4), apolipoprotein A1 (N = 4), fibrinogen alpha (N = 2), LECT2 (N = 1). Amyloid deposits predominately targeted the liver vasculature, including the walls of the hepatic arteries, portal veins, and sinusoids. While there was overlap, light chain amyloid predominately involved the sinusoids, while transthyretin amyloid predominately targeted the hepatic arteries, especially the larger ones in the hilum and larger portal tracts. Serum amyloid A formed nodular deposits that started in the portal vasculature but then extended into the portal tract stroma, leading to large, bulbous, portal-based amyloid deposits. Apolipoprotein A amyloid also formed large portal-based nodules. Fibrinogen was mild and subtle on H&E and predominately affected portal veins. Amyloid deposits in hilar nerves were prominent with amyloid light chain, transthyretin, and apolipoprotein A1. In conclusion, the histology of hepatic amyloid is diverse and shows several distinct clusters of findings that can aide in recognition in surgical pathology specimens.
Collapse
Affiliation(s)
- Saba Yasir
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Zongming Eric Chen
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Chris Hartley
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Lizhi Zhang
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Michael Torbenson
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
| |
Collapse
|
|
4
|
Bellamy CO, Burt AD. Liver in Systemic Disease. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:1039-1095. [DOI: 10.1016/b978-0-7020-8228-3.00015-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
|
|
5
|
Anand SK, Sanchorawala V, Verma A. Systemic Amyloidosis and Kidney Transplantation: An Update. Semin Nephrol 2024; 44:151496. [PMID: 38490903 DOI: 10.1016/j.semnephrol.2024.151496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/17/2024]
Abstract
Amyloidosis is a heterogeneous disorder characterized by abnormal protein aggregate deposition that often leads to kidney involvement and end-stage kidney disease. With advancements in diagnostic techniques and treatment options, the prevalence of patients with amyloidosis requiring chronic dialysis has increased. Kidney transplantation is a promising avenue for extending survival and enhancing quality of life in these patients. However, the complex and heterogeneous nature of amyloidosis presents challenges in determining optimal referral timing for transplantation and managing post-transplantation course. This review focuses on recent developments and outcomes of kidney transplantation for amyloidosis-related end-stage kidney disease. This review also aims to guide clinical decision-making and improve management of patients with amyloidosis-associated kidney disease, offering insights into optimizing patient selection and post-transplant care for favorable outcomes.
Collapse
Affiliation(s)
- Shankara K Anand
- Boston University Chobanian & Avedisian School of Medicine and Boston Medical Center, Boston, MA
| | - Vaishali Sanchorawala
- Amyloidosis Center, Boston University Chobanian and Avedisian School of Medicine, Boston, MA; Section of Hematology and Oncology, Department of Medicine, Boston University Chobanian and Avedisian School of Medicine, Boston, MA
| | - Ashish Verma
- Renal Section, Department of Medicine, Boston University Chobanian and Avedisian School of Medicine, Boston, MA; Amyloidosis Center, Boston University Chobanian and Avedisian School of Medicine, Boston, MA; Boston University Chobanian & Avedisian School of Medicine and Boston Medical Center, Boston, MA.
| |
Collapse
|
|
6
|
Proteomic Identification and Clinicopathologic Characterization of Splenic Amyloidosis. Am J Surg Pathol 2023; 47:74-80. [PMID: 35968972 PMCID: PMC9760463 DOI: 10.1097/pas.0000000000001948] [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] [Indexed: 02/05/2023]
Abstract
The spleen is a commonly encountered specimen in surgical pathology. However, little is known about the incidence, morphologic pattern, and clinical features of spleens involved by amyloidosis. We retrospectively identified 69 spleen amyloid cases typed using a proteomics-based method between 2008 and 2020. The frequency of amyloid types, clinicopathologic features, and distribution of amyloid deposits were assessed. Four amyloid types were detected: immunoglobulin light chain (AL) (N=30; 43.5%); leukocyte chemotactic factor 2 amyloidosis (ALECT2) (N=30; 43.5%); amyloid A (AA) (N=8; 11.6%); and fibrinogen alpha (AFib) (N=1; 1.4%). The splenic amyloid showed 5 distinct distribution patterns: (1) diffuse pattern, exhibited by most AL cases; (2) red pulp pattern, exhibited by most ALECT2 cases; (3) multinodular pattern, seen in subsets of AA and AL-kappa cases; (4) mass-forming pattern, seen in the AFib case; and (5) vascular only, seen in a subset of AA cases. Atraumatic splenic rupture was the most common reason for splenectomy in AL cases, while most ALECT2 spleens were removed incidentally during an unrelated abdominal surgery. Splenomegaly was significantly more common in AA spleens than in AL or ALECT2 spleens and was often the reason for splenectomy in this group. In conclusion, splenic amyloid may be underrecognized as it is often an incidental finding. Although, as expected, many of the spleens were involved by AL amyloidosis, ALECT2 emerged as another common spleen amyloid type. Although the spleen amyloid types exhibited characteristic distribution patterns, proteomics-based typing is warranted as some morphologic overlap still exists. Awareness of ALECT2 as a major spleen amyloid type is important for appropriate diagnostic workup and patient management.
Collapse
|
|
7
|
Current Understanding of Systemic Amyloidosis and Underlying Disease Mechanisms. Am J Cardiol 2022; 185 Suppl 1:S2-S10. [PMID: 36549788 DOI: 10.1016/j.amjcard.2022.10.057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Revised: 10/17/2022] [Accepted: 10/27/2022] [Indexed: 12/24/2022]
Abstract
Amyloidosis is a group of diverse disorders caused by misfolded proteins that aggregate into insoluble fibrils and ultimately cause organ damage. In medical practice, amyloidosis classification is based on the amyloid precursor protein type, of which amyloid immunoglobulin light chain, amyloid transthyretin, amyloid leukocyte chemotactic factor 2, and amyloid derived from serum amyloid A protein are the most common. Distinct mechanisms appear to be predominantly operational in the pathogenesis of particular types of amyloidosis, including increased protein precursor synthesis, somatic or germ line mutations, and inherent instability in the precursor protein in its wild form. An increased supply of misfolded proteins and/or a decreased capacity of the protein quality control systems can result in an imbalance that leads to increased circulation of misfolded proteins. Although the detection of mature fibrils is the basis for diagnosis of amyloidosis, a growing body of evidence has implicated the prefibrillar species as proteotoxic and key contributors to the development of the disease.
Collapse
|
|
8
|
Chu TH, Ko CY, Tai PH, Chang YC, Huang CC, Wu TY, Chan HH, Wu PH, Weng CH, Lin YW, Kung ML, Fang CC, Wu JC, Wen ZH, Lee YK, Hu TH, Tai MH. Leukocyte cell-derived chemotaxin 2 regulates epithelial-mesenchymal transition and cancer stemness in hepatocellular carcinoma. J Biol Chem 2022; 298:102442. [PMID: 36055405 PMCID: PMC9530851 DOI: 10.1016/j.jbc.2022.102442] [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: 02/25/2022] [Revised: 08/07/2022] [Accepted: 08/08/2022] [Indexed: 11/27/2022] Open
Abstract
Leukocyte cell-derived chemotaxin 2 (LECT2) acts as a tumor suppressor in hepatocellular carcinoma (HCC). However, the antineoplastic mechanism of LECT2, especially its influence on hepatic cancer stem cells (CSCs), remains largely unknown. In The Cancer Genome Atlas cohort, LECT2 mRNA expression was shown to be associated with stage, grade, recurrence, and overall survival in human HCC patients, and LECT2 expression was downregulated in hepatoma tissues compared with the adjacent nontumoral liver. Here, we show by immunofluorescence and immunoblot analyses that LECT2 was expressed at lower levels in tumors and in poorly differentiated HCC cell lines. Using functional assays, we also found LECT2 was capable of suppressing oncogenic behaviors such as cell proliferation, anchorage-independent growth, migration, invasiveness, and epithelial-mesenchymal transition in hepatoma cells. Moreover, we show exogenous LECT2 treatment inhibited CSC functions such as tumor sphere formation and drug efflux. Simultaneously, hepatic CSC marker expression was also downregulated, including expression of CD133 and CD44. This was supported by infection with adenovirus encoding LECT2 (Ad-LECT2) in HCC cells. Furthermore, in animal experiments, Ad-LECT2 gene therapy showed potent efficacy in treating HCC. We demonstrate LECT2 overexpression significantly promoted cell apoptosis and reduced neovascularization/CSC expansion in rat hepatoma tissues. Mechanistically, we showed using immunoblot and immunofluorescence analyses that LECT2 inhibited β-catenin signaling via the suppression of the hepatocyte growth factor/c-MET axis to diminish CSC properties in HCC cells. In summary, we reveal novel functions of LECT2 in the suppression of hepatic CSCs, suggesting a potential alternative strategy for HCC therapy.
Collapse
Affiliation(s)
- Tian-Huei Chu
- Medical Laboratory, Medical Education and Research Center, Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan
| | - Chou-Yuan Ko
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan; Institute of Medical Science and Technology, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Po-Han Tai
- Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Yi-Chen Chang
- Doctoral Degree Program in Marine Biotechnology, National Sun Yat-sen University and Academia Sinica, Kaohsiung, Taiwan
| | - Chao-Cheng Huang
- Department of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Tung-Yang Wu
- Department of Chest Medicine, Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan
| | - Hoi-Hung Chan
- Division of Gastroenterology, Department of Medicine, Conde S. Januário Hospital, Macau, China
| | - Ping-Hsuan Wu
- Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Chien-Hui Weng
- Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Yu-Wei Lin
- Department of Radiation Oncology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Mei-Lang Kung
- Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Cheng-Chieh Fang
- Center for Neuroscience, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Jian-Ching Wu
- Doctoral Degree Program in Marine Biotechnology, National Sun Yat-sen University and Academia Sinica, Kaohsiung, Taiwan; LabTurbo Biotech Corporation, Taipei, Taiwan
| | - Zhi-Hong Wen
- Department of Marine Biotechnology and Resources, Asia-Pacific Ocean Research Center, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Yung-Kuo Lee
- Medical Laboratory, Medical Education and Research Center, Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan
| | - Tsung-Hui Hu
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
| | - Ming-Hong Tai
- Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan; Doctoral Degree Program in Marine Biotechnology, National Sun Yat-sen University and Academia Sinica, Kaohsiung, Taiwan; Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan; Center for Neuroscience, National Sun Yat-sen University, Kaohsiung, Taiwan.
| |
Collapse
|
|
9
|
Wang S, Yu XJ, Li DY, Xu J, Wang SX. Concurrence of leukocyte chemotactic factor 2-associated amyloidosis and autoimmune diseases: A case report. Front Immunol 2022; 13:966591. [PMID: 36059556 PMCID: PMC9437290 DOI: 10.3389/fimmu.2022.966591] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2022] [Accepted: 07/19/2022] [Indexed: 11/13/2022] Open
Abstract
Leukocyte chemotactic factor 2-associated (ALECT2) amyloidosis is one of the recently reported types of amyloidosis, which is caused by the extracellular deposition of leukocyte chemotactic factor 2 (LECT2). There have not been any reports involving the concurrence of ALECT2 amyloidosis with Sjögren’s syndrome (SS) or systemic lupus erythematosus (SLE)s. Herein, we report a case of a 68-year-old Chinese woman presenting with long duration of sicca symptoms. The clinical evaluation and laboratory findings showed that she had SS overlapped with SLE. Kidney biopsy revealed a membranoproliferative glomerulonephritis (MPGN) with glomerular deposition of dominant IgG3-kappa by immunofluorescene, which was related to SS/SLE. Furthermore, patchy congophilic amyloid deposits in the tubulointerstitium were detected, which were positive for LECT2 protein by immunohistochemical staining and immunoelectron microscopy. This is the first case of ALECT2 amyloidosis that coexisted with SS/SLE, and the causal relationship between ALECT2 amyloidosis and autoimmune diseases remain unclear.
Collapse
Affiliation(s)
- Shuang Wang
- Laboratory of Electron Microscopy, Pathological Center, Peking University First Hospital, Beijing, China
- Renal Division, Department of Medicine, Peking University First Hospital; Renal Pathological Center, Institute of Nephrology, Peking University; Key Laboratory of Chronic Kidney Disease (CKD) Prevention and Treatment, Ministry of Education of China; Key Laboratory of Renal Diseases, Ministry of Health of China, Beijing, China
| | - Xiao-juan Yu
- Renal Division, Department of Medicine, Peking University First Hospital; Renal Pathological Center, Institute of Nephrology, Peking University; Key Laboratory of Chronic Kidney Disease (CKD) Prevention and Treatment, Ministry of Education of China; Key Laboratory of Renal Diseases, Ministry of Health of China, Beijing, China
| | - Dan-yang Li
- Laboratory of Electron Microscopy, Pathological Center, Peking University First Hospital, Beijing, China
- Renal Division, Department of Medicine, Peking University First Hospital; Renal Pathological Center, Institute of Nephrology, Peking University; Key Laboratory of Chronic Kidney Disease (CKD) Prevention and Treatment, Ministry of Education of China; Key Laboratory of Renal Diseases, Ministry of Health of China, Beijing, China
| | - Jin Xu
- Laboratory of Electron Microscopy, Pathological Center, Peking University First Hospital, Beijing, China
| | - Su-xia Wang
- Laboratory of Electron Microscopy, Pathological Center, Peking University First Hospital, Beijing, China
- Renal Division, Department of Medicine, Peking University First Hospital; Renal Pathological Center, Institute of Nephrology, Peking University; Key Laboratory of Chronic Kidney Disease (CKD) Prevention and Treatment, Ministry of Education of China; Key Laboratory of Renal Diseases, Ministry of Health of China, Beijing, China
- *Correspondence: Su-xia Wang,
| |
Collapse
|
|
10
|
Xie Y, Fan K, Guan S, Hu Y, Gao Y, Zhou W. LECT2: A pleiotropic and promising hepatokine, from bench to bedside. J Cell Mol Med 2022; 26:3598-3607. [PMID: 35656863 PMCID: PMC9258709 DOI: 10.1111/jcmm.17407] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Revised: 03/12/2022] [Accepted: 05/02/2022] [Indexed: 11/28/2022] Open
Abstract
LECT2 (leucocyte cell-derived chemotaxin 2) is a 16-kDa protein mainly produced by hepatocytes. It was first isolated in PHA-activated human T-cell leukaemia SKW-3 cells and originally identified as a novel neutrophil chemotactic factor. However, many lines of studies suggested that LECT2 was a pleiotropic protein, it not only functioned as a cytokine to exhibit chemotactic property, but also played multifunctional roles in some physiological conditions and pathological abnormalities, involving liver regeneration, neuronal development, HSC(haematopoietic stem cells) homeostasis, liver injury, liver fibrosis, hepatocellular carcinoma, metabolic disorders, inflammatory arthritides, systemic sepsis and systemic amyloidosis. Among the above studies, it was discovered that LECT2 could be a promising molecular biomarker and therapeutic target. This review summarizes LECT2-related receptors and pathways, basic and clinical researches, primarily in mice and human, for a better comprehension and management of these diseases in the future.
Collapse
Affiliation(s)
- Yuan Xie
- General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative MedicineZhujiang Hospital, Southern Medical UniversityGuangzhouChina
- Department of General Surgery IIThe First People's Hospital of ZhaoqingZhaoqingChina
| | - Kai‐Wei Fan
- Department of Cerebrovascular DiseaseThe First People's Hospital of ZhaoqingZhaoqingChina
| | - Shi‐Xing Guan
- Department of Pathology, School of Basic Medical SciencesSouthern Medical UniversityGuangzhouChina
| | - Yang Hu
- Department of Pathology, School of Basic Medical SciencesSouthern Medical UniversityGuangzhouChina
| | - Yi Gao
- General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative MedicineZhujiang Hospital, Southern Medical UniversityGuangzhouChina
| | - Wei‐Jie Zhou
- General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative MedicineZhujiang Hospital, Southern Medical UniversityGuangzhouChina
- Department of Pathology, School of Basic Medical SciencesSouthern Medical UniversityGuangzhouChina
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, First Clinical Medical CollegeSouthern Medical UniversityGuangzhouChina
| |
Collapse
|
|
11
|
Ke M, Li X, Wang L, Yue S, Zhao B. A stepwise data interpretation process for renal amyloidosis typing by LMD-MS. BMC Nephrol 2022; 23:144. [PMID: 35418036 PMCID: PMC9008935 DOI: 10.1186/s12882-022-02785-9] [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: 09/18/2021] [Accepted: 04/07/2022] [Indexed: 11/25/2022] Open
Abstract
Backgrounds Systemic amyloidosis is classified according to the deposited amyloid fibril protein (AFP), which determines its best therapeutic scheme. The most common type of AFP found are immunoglobulin light chains. The laser microdissection combined with mass spectrometry (LMD-MS) technique is a promising approach for precise typing of amyloidosis, however, the major difficulty in interpreting the MS data is how to accurately identify the precipitated AFP from background. Objectives The objective of the present study is to establish a complete data interpretation procedure for LMD-MS based amyloidosis typing. Methods Formalin-fixed paraffin-embedded specimens from patients with renal amyloidosis and non-amyloid nephropathies (including diabetic nephropathy, fibrillary glomerulonephritis, IgA nephropathy, lupus nephritis, membranous nephropathy, and normal tissue adjacent to tumors) were analyzed by LMD-MS. Forty-two specimens were used to train the data interpretation procedure, which was validated by another 50 validation specimens. Area under receiver operating curve (AUROC) analysis of amyloid accompanying proteins (AAPs, including apolipoprotein A-IV, apolipoprotein E and serum amyloid P-component) for discriminating amyloidosis from non-amyloid nephropathies was performed. Results A stepwise data interpretation procedure that includes or excludes the types of amyloidosis group by group was established. The involvement of AFPs other than immunoglobulin was determined by P-score, as well as immunoglobulin light chain by variable of λ-κ, and immunoglobulin heavy chain by H-score. This achieved a total of 88% accuracy in 50 validation specimens. The AAPs showed significantly different expression levels between amyloidosis specimens and non-amyloid nephropathies. Each of the single AAP had a AUROC value more than 0.9 for diagnosis of amyloidosis from non-amyloid control, and the averaged level of the three AAPs showed the highest AUROC (0.966), which might be an alternative indicator for amyloidosis diagnosis. Conclusions The proteomic data interpretation procedure for LMD-MS based amyloidosis typing was established successfully that has a high practicability in clinical application. Supplementary Information The online version contains supplementary material available at 10.1186/s12882-022-02785-9.
Collapse
Affiliation(s)
- Ming Ke
- Guangzhou KingMed Center for Clinical Laboratory Co.,Ltd, Guangzhou, 510005, China
| | - Xin Li
- Guangzhou KingMed Center for Clinical Laboratory Co.,Ltd, Guangzhou, 510005, China
| | - Lin Wang
- Guangzhou KingMed Center for Clinical Laboratory Co.,Ltd, Guangzhou, 510005, China
| | - Shuling Yue
- Guangzhou KingMed Center for Clinical Laboratory Co.,Ltd, Guangzhou, 510005, China
| | - Beibei Zhao
- Guangzhou KingMed Center for Clinical Laboratory Co.,Ltd, Guangzhou, 510005, China.
| |
Collapse
|
|
12
|
Sak JJ, Prystupa A, Kiciński P, Luchowska-Kocot D, Kurys-Denis E, Bis-Wencel H. Leukocyte cell-derived chemotaxin-2 and fibroblast growth factor 21 in alcohol-induced liver cirrhosis. World J Hepatol 2021; 13:2071-2080. [PMID: 35070009 PMCID: PMC8727211 DOI: 10.4254/wjh.v13.i12.2071] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 07/22/2021] [Accepted: 11/25/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The importance of early diagnosis of alcoholic liver disease underscores the need to seek better and especially non-invasive diagnostic procedures. Leukocyte cell-derived chemotaxin-2 (LECT2) has been widely studied to determine its usefulness in monitoring the course of non-alcoholic fatty liver disease but not for alcoholic liver cirrhosis (ALC).
AIM To determine the concentration of LECT2 in the blood serum of patients in relation to progressive stages of ALC, its relation to fibroblast growth factor 1 (FGF-1) and FGF-21, and to examine the possible wider use of LECT2 in diagnosing ALC.
METHODS A retrospective case-control study was conducted with 69 ALC cases and 17 controls with no ALC. Subjects were recruited from the region of Lublin (eastern Poland). Liver cirrhosis was diagnosed based on clinical features, history of heavy alcohol consumption, laboratory tests, and abdominal ultrasonography. The degree of ALC was evaluated according to Pugh-Child criteria (the Pugh-Child score). Blood was drawn and, after centrifugation, serum was collected for analysis. LECT2, FGF-1, and FGF-21 were determined using enzyme-linked immunosorbent assay kits.
RESULTS The LECT2 Levels in the control group were 18.99 ± 5.36 ng/mL. In the study groups, they declined with the progression of cirrhosis to 11.06 ± 6.47 ng/mL in one group and to 8.06 ± 5.74 ng/mL in the other (P < 0.0001). Multiple comparison tests confirmed the statistically significant differences in LECT2 Levels between the control group and both test groups (P = 0.006 and P < 0.0001). FGF-21 Levels were 44.27 ± 64.19 pg/mL in the first test group, 45.4 ± 51.69 pg/mL in the second (P = 0.008), and 13.52 ± 7.51 pg/mL in the control group. The difference between the control group and the second test group was statistically significant (P = 0.007).
CONCLUSION We suggest that LECT2 may be a non-invasive diagnostic factor for alcohol-induced liver cirrhosis. The usefulness of LECT2 for non-invasive monitoring of alcohol-induced liver cirrhosis was indirectly confirmed by the multiple regression model developed on the basis of our statistical analysis.
Collapse
Affiliation(s)
- Jarosław Jerzy Sak
- Chair and Department of Humanities and Social Medicine, Medical University of Lublin, Lublin 20-093, Poland
| | - Andrzej Prystupa
- Department of Internal Medicine, Medical University of Lublin, Lublin 20-081, Poland
| | - Paweł Kiciński
- Department of Experimental Hematooncology, Medical University of Lublin, Lublin 20-080, Poland
| | | | - Ewa Kurys-Denis
- The Second Department of Radiology, Medical University of Lublin, Lublin 20-081, Poland
| | - Hanna Bis-Wencel
- Department of Microbiology and Reproductive Biology, University of Life Sciences in Lublin, Lublin 20-950, Poland
| |
Collapse
|
|
13
|
Almasri H, Razok A, Badi A, Almohannadi M, Lutf A, Petkar M, Elzouki A. Leukocyte chemotactic factor 2-related amyloidosis presenting with severe jaundice and hepatic encephalopathy. Clin Case Rep 2021; 9:e05185. [PMID: 34917382 PMCID: PMC8645169 DOI: 10.1002/ccr3.5185] [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: 09/14/2021] [Revised: 11/20/2021] [Accepted: 11/23/2021] [Indexed: 11/12/2022] Open
Abstract
Amyloidosis is a well-known disease with various types and subtypes. One of the most recently identified types is leukocyte chemotactic factor 2 amyloidosis (LECT 2), which was found to be common in certain ethnic backgrounds. It is suggested that the diagnosis of this type is vital to prevent any therapy-related complications when it is erroneously diagnosed as AL amyloidosis. The clinical presentation is usually slowly progressive kidney disease and mild hepatic impairment. We report a case of LECT2 amyloidosis, which presented with severe painless cholestasis and hepatic encephalopathy alongside progressive kidney disease.
Collapse
Affiliation(s)
- Hussam Almasri
- Department of MedicineHamad Medical CorporationDohaQatar
| | | | - Ahmed Badi
- Department of gastroenterology and hepatologyHamad Medical CorporationDohaQatar
| | - Muneera Almohannadi
- Department of gastroenterology and hepatologyHamad Medical CorporationDohaQatar
| | - Abdo Lutf
- Department of MedicineHamad Medical CorporationDohaQatar
| | - Mahir Petkar
- Department of PathologyHamad Medical CorporationDohaQatar
| | | |
Collapse
|
|
14
|
Mann BK, Bhandohal JS, Cobos E, Chitturi C, Eppanapally S. LECT-2 amyloidosis: what do we know? J Investig Med 2021; 70:348-353. [PMID: 34848562 DOI: 10.1136/jim-2021-002149] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/20/2021] [Indexed: 01/20/2023]
Abstract
Amyloidosis is a rare group of diseases characterized by abnormal folding of proteins and extracellular deposition of insoluble fibrils. It can be localized to one organ system or can have systemic involvement. The kidney is the most common organ to be involved in systemic amyloidosis often leading to renal failure and the nephrotic syndrome. The two most common types of renal amyloidosis are immunoglobulin light chain-derived amyloidosis (AL) and reactive amyloidosis (AA). A novel form of amyloidosis (ALECT2) derived from leukocyte chemotactic factor 2 (LECT-2) and primarily involving the kidneys was first described by Benson et al in 2008. The liver was subsequently identified as the second most common organ involved in ALECT2 amyloidosis. LECT-2 is a unique protein that can form amyloid deposits even in its unmutated form. Patients with ALECT2 present with minimal proteinuria in contrast to other forms of amyloidosis especially AL and AA. They may present with slightly elevated serum creatinine. Nephrotic syndrome and hematuria are rare. ALECT2 can be found in association with other types of amyloidosis as well as malignancies or autoimmune diseases. ALECT2 may be confused with amyloidosis associated with light and heavy chain monoclonal gammopathy if the immunofluorescence is positive with anti-light chain and anti-AA sera. The other organs involved are the duodenum, adrenal gland, spleen, prostate, gall bladder, pancreas, small bowel, parathyroid gland, heart, and pulmonary alveolar septa, but consistently uninvolved organs included brain and fibroadipose tissue. A renal biopsy along with characteristic features found on immunohistochemistry and mass spectrometry is diagnostic of ALECT2. ALECT2 should be suspected when all markers for AL and AA are negative. Proper diagnosis of ALECT2 can determine need for supportive care versus more aggressive interventions.
Collapse
Affiliation(s)
- Baldeep Kaur Mann
- Internal Medicine, Kern Medical Center, Bakersfield, California, USA
| | | | | | | | | |
Collapse
|
|
15
|
Eletta O, Ali M, Grieff A, Puri S, Matsuda K, Bongu A, Fyfe B. Clinically occult amyloidosis derived from leukocyte chemotactic factor 2 (ALECT 2) with cardiac involvement complicating renal transplantation: case report and literature review. Cardiovasc Pathol 2021; 55:107375. [PMID: 34371188 DOI: 10.1016/j.carpath.2021.107375] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 07/24/2021] [Accepted: 07/30/2021] [Indexed: 12/12/2022] Open
Abstract
INTRODUCTION Amyloidosis derived from leukocyte chemotactic factor 2 (ALECT2) may be associated with slowly progressive renal failure that is clinically unsuspected at the time of transplantation. While this is typically clinically insignificant, we report a case with extensive systemic ALECT2 amyloidosis that also involved the myocardium, contributing to perioperative death post renal transplantation. CASE DESCRIPTION A 72-year-old Hispanic woman presented for renal transplantation due to end-stage renal disease secondary to hypertension. She was bradycardic on admission. Cardiac workup prior to transplantation had not identified an infiltrative process. Post-transplant hypotensive bradycardic arrests lead to multiorgan failure, anoxic brain injury, and death. Autopsy revealed massive amyloid deposition in the native kidneys, adrenals, spleen, and less extensive infiltration of liver and myocardium. Cardiac intramural vasculature from venules to capillaries, arterioles, and arteries showed amyloid deposition. Mass spectrometry revealed ALECT2 as the amyloidogenic protein. DISCUSSION ALECT2 is a systemic amyloidosis that typically involves kidneys, adrenals, spleen, and liver. It may be clinically unsuspected at the time of renal transplantation and should be considered in older patients, especially from higher ALECT2 amyloid prevalence populations. Complications related to systemic disease may add to morbidity or mortality post-transplantation. Cardiac involvement in ALECT2 amyloidosis has not been previously identified as a significant clinical or autopsy finding, but our case demonstrates that the cardiovascular system may indeed rarely be involved by ALECT2 amyloidosis in cases with extensive systemic disease, and it may be associated with significant clinical sequelae.
Collapse
Affiliation(s)
- Olanrewaju Eletta
- Department of Surgery, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA
| | - Mahmoud Ali
- Department of Pathology and Laboratory Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA
| | - Anthony Grieff
- Department of Surgery, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA
| | - Sonika Puri
- Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA
| | - Kant Matsuda
- Department of Pathology and Laboratory Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA
| | - Advaith Bongu
- Department of Surgery, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA
| | - Billie Fyfe
- Department of Pathology and Laboratory Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
| |
Collapse
|
|
16
|
Li Q, Zhang Z, Fan W, Huang Y, Niu J, Luo G, Liu X, Huang Y, Jian J. LECT2 Protects Nile Tilapia ( Oreochromis niloticus) Against Streptococcus agalatiae Infection. Front Immunol 2021; 12:667781. [PMID: 34093564 PMCID: PMC8174566 DOI: 10.3389/fimmu.2021.667781] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2021] [Accepted: 04/30/2021] [Indexed: 01/09/2023] Open
Abstract
Leukocyte cell-derived chemotaxin 2 (LECT2) is a multifunctional cytokine that especially plays an important role in innate immune. However, the roles of LECT2 in the immune response of the economically important fish Nile tilapia (Oreochromis niloticus) against bacterial infection remains unclear. In this study, a lect2 gene from Nile tilapia (On-lect2) was identified, and its roles in the fish’s immune response against bacterial infection were determined and characterised. On-lect2 contains an open reading frame of 456 bp that encodes a peptide of 151 amino acids, as well as the conservative peptidase M23 domain. On-LECT2 is 62%–84% identical to other fish species and about 50% identical to mammals. The highest transcriptional level of On-lect2 was detected in the liver, whereas the lowest levels were detected in the other tissues. Moreover, the On-LECT2 protein is located mainly in the brain and head kidney. The transcriptional levels of On-lect2 substantially increased in the head kidney, brain, liver and spleen after Streptococcus agalactiae infection. Knockdown On-lect2 led to higher mortality due to liver necrosis or haemorrhage and splenomegaly. In vitro analysis indicated that the recombinant protein of On-LECT2 improved phagocytic activity of head kidney-derived macrophages. In vivo challenge experiments revealed several functions of On-LECT2 in the immune response of Nile tilapia against bacterial infection, including promotion of inflammation, reduction of tissue damages and improvement of survival rate.
Collapse
Affiliation(s)
- Qi Li
- College of Fishery, Guangdong Ocean University, Guangdong Provincial Key Laboratory of Pathogenic Biology and Epidemiology for Aquatic Economic Animal, Key Laboratory of Control for Disease of Aquatic Animals of Guangdong Higher Education Institutes, Southern Marine Science and Engineering Guangdong Laboratory, Zhanjiang, China
| | - Zhiqiang Zhang
- College of Fishery, Guangdong Ocean University, Guangdong Provincial Key Laboratory of Pathogenic Biology and Epidemiology for Aquatic Economic Animal, Key Laboratory of Control for Disease of Aquatic Animals of Guangdong Higher Education Institutes, Southern Marine Science and Engineering Guangdong Laboratory, Zhanjiang, China
| | - Weiqi Fan
- College of Fishery, Guangdong Ocean University, Guangdong Provincial Key Laboratory of Pathogenic Biology and Epidemiology for Aquatic Economic Animal, Key Laboratory of Control for Disease of Aquatic Animals of Guangdong Higher Education Institutes, Southern Marine Science and Engineering Guangdong Laboratory, Zhanjiang, China
| | - Yongxiong Huang
- College of Fishery, Guangdong Ocean University, Guangdong Provincial Key Laboratory of Pathogenic Biology and Epidemiology for Aquatic Economic Animal, Key Laboratory of Control for Disease of Aquatic Animals of Guangdong Higher Education Institutes, Southern Marine Science and Engineering Guangdong Laboratory, Zhanjiang, China
| | - Jinzhong Niu
- College of Fishery, Guangdong Ocean University, Guangdong Provincial Key Laboratory of Pathogenic Biology and Epidemiology for Aquatic Economic Animal, Key Laboratory of Control for Disease of Aquatic Animals of Guangdong Higher Education Institutes, Southern Marine Science and Engineering Guangdong Laboratory, Zhanjiang, China
| | - Guoling Luo
- College of Fishery, Guangdong Ocean University, Guangdong Provincial Key Laboratory of Pathogenic Biology and Epidemiology for Aquatic Economic Animal, Key Laboratory of Control for Disease of Aquatic Animals of Guangdong Higher Education Institutes, Southern Marine Science and Engineering Guangdong Laboratory, Zhanjiang, China
| | - Xinchao Liu
- College of Fishery, Guangdong Ocean University, Guangdong Provincial Key Laboratory of Pathogenic Biology and Epidemiology for Aquatic Economic Animal, Key Laboratory of Control for Disease of Aquatic Animals of Guangdong Higher Education Institutes, Southern Marine Science and Engineering Guangdong Laboratory, Zhanjiang, China
| | - Yu Huang
- College of Fishery, Guangdong Ocean University, Guangdong Provincial Key Laboratory of Pathogenic Biology and Epidemiology for Aquatic Economic Animal, Key Laboratory of Control for Disease of Aquatic Animals of Guangdong Higher Education Institutes, Southern Marine Science and Engineering Guangdong Laboratory, Zhanjiang, China.,Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China.,Guangdong Provincial Engineering Research Center for Aquatic Animal Health Assessment, Shenzhen, China
| | - Jichang Jian
- College of Fishery, Guangdong Ocean University, Guangdong Provincial Key Laboratory of Pathogenic Biology and Epidemiology for Aquatic Economic Animal, Key Laboratory of Control for Disease of Aquatic Animals of Guangdong Higher Education Institutes, Southern Marine Science and Engineering Guangdong Laboratory, Zhanjiang, China.,Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China.,Guangdong Provincial Engineering Research Center for Aquatic Animal Health Assessment, Shenzhen, China
| |
Collapse
|
|
17
|
Hill MM, Dasari S, Mollee P, Merlini G, Costello CE, Hazenberg BPC, Grogan M, Dispenzieri A, Gertz MA, Kourelis T, McPhail ED. The Clinical Impact of Proteomics in Amyloid Typing. Mayo Clin Proc 2021; 96:1122-1127. [PMID: 33840526 PMCID: PMC8934443 DOI: 10.1016/j.mayocp.2020.12.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2020] [Revised: 12/03/2020] [Accepted: 12/11/2020] [Indexed: 12/14/2022]
Affiliation(s)
- Michelle M Hill
- Department of Cell and Molecular Biology, QIMR Berghofer Medical Research Institute, Brisbane, Australia; Faculty of Medicine, The University of Queensland, Brisbane, Australia.
| | - Surendra Dasari
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN
| | - Peter Mollee
- Faculty of Medicine, The University of Queensland, Brisbane, Australia; Department of Haematology, Princess Alexandra Hospital, Brisbane, Australia
| | - Giampaolo Merlini
- Foundation IRRCS Policlinico San Matteo, Department of Molecular Medicine, University of Pavia, Italy
| | - Catherine E Costello
- Center for Biomedical Mass Spectrometry, Boston University School of Medicine, Boston, MA
| | - Bouke P C Hazenberg
- Amyloidosis Center of Expertise, University Medical Center Groningen, University of Groningen, Groningen
| | - Martha Grogan
- Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN
| | | | | | | | - Ellen D McPhail
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.
| |
Collapse
|
|
18
|
Abstract
The diagnosis of myeloma and other plasma cell disorders has traditionally been done with the aid of electrophoretic methods, whereas amyloidosis has been characterized by immunohistochemistry. Mass spectrometry has recently been established as an alternative to these traditional methods and has been proved to bring added benefit for patient care. These newer mass spectrometry-based methods highlight some of the key advantages of modern proteomic methods and how they can be applied to the routine care of patients.
Collapse
Affiliation(s)
- David L Murray
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
| | - Surendra Dasari
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
| |
Collapse
|
|
19
|
Shye M, Sisk A, Schulze C, Barsoum M, Mikhail M, Arman F, Rastogi A, Hanna RM. A case of renal and splenic LECT 2 amyloidosis: A recently recognized cause of renal and systemic amyloidosis. SAUDI JOURNAL OF KIDNEY DISEASES AND TRANSPLANTATION 2021; 31:508-514. [PMID: 32394925 DOI: 10.4103/1319-2442.284027] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Amyloidosis has traditionally been of a few defined varieties, most commonly including light-chain amyloidosis (AL amyloidosis) and secondary amyloidosis due to chronic inflammation (AA amyloidosis). Apolipoprotein A-I/A-II cystatin C, gelsolin, lysozyme, fibrinogen alpha chain, beta 2 microglobulin, and transthyretin familial amyloidosis represent rarer but reported varieties. Ten years ago, the first reports linked leukocyte chemotactic factor 2 (LECT2) amyloidosis as a pathological agent identified as a novel class of amyloid-generating protein. Epidemiology suggested that this was a new cause of amyloidosis that is especially common in Hispanic patients and somewhat common among patients from the Middle East-North Africa (MENA) region. We report a case of splenic and renal LECT 2 amyloidosis in a 62-year- old Hispanic male with diabetes mellitus. After an unremarkable serological workup, LECT 2 amyloidosis was diagnosed on renal biopsy. The case presentation is reviewed as a typical presentation, and the literature is reviewed regarding this newly reported entity, resulting in infiltrative renal amyloidosis and chronic renal disease.
Collapse
Affiliation(s)
- Michael Shye
- Department of Medicine, Division of Nephrology, UCLA David Geffen School of Medicine, Los Angeles, CA, USA
| | - Anthony Sisk
- Department of Pathology, Division of Renal Pathology, UCLA David Geffen School of Medicine, Los Angeles, CA, USA
| | - Carl Schulze
- Department of Medicine, Division of Nephrology, UCLA David Geffen School of Medicine, Los Angeles, CA, USA
| | - Marina Barsoum
- Department of Medicine, Division of Nephrology, UCLA David Geffen School of Medicine, Los Angeles, CA, USA
| | - Mira Mikhail
- Department of Medicine, Division of Nephrology, UCLA David Geffen School of Medicine, Los Angeles, CA, USA
| | - Farid Arman
- Department of Medicine, Division of Nephrology, UCLA David Geffen School of Medicine, Los Angeles, CA, USA
| | - Anjay Rastogi
- Department of Medicine, Division of Nephrology, UCLA David Geffen School of Medicine, Los Angeles, CA, USA
| | - Ramy M Hanna
- Department of Medicine, Division of Nephrology, UCLA David Geffen School of Medicine, Los Angeles; Department of Medicine, Division of Nephrology, University of California, Irvine School of Medicine, Irvine, CA, USA
| |
Collapse
|
|
20
|
Muchtar E, Dispenzieri A, Magen H, Grogan M, Mauermann M, McPhail ED, Kurtin PJ, Leung N, Buadi FK, Dingli D, Kumar SK, Gertz MA. Systemic amyloidosis from A (AA) to T (ATTR): a review. J Intern Med 2021; 289:268-292. [PMID: 32929754 DOI: 10.1111/joim.13169] [Citation(s) in RCA: 168] [Impact Index Per Article: 42.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Accepted: 07/15/2020] [Indexed: 01/09/2023]
Abstract
Systemic amyloidosis is a rare protein misfolding and deposition disorder leading to progressive organ failure. There are over 15 types of systemic amyloidosis, each caused by a different precursor protein which promotes amyloid formation and tissue deposition. Amyloidosis can be acquired or hereditary and can affect various organs, including the heart, kidneys, liver, nerves, gastrointestinal tract, lungs, muscles, skin and soft tissues. Symptoms are usually insidious and nonspecific resulting in diagnostic delay. The field of amyloidosis has seen significant improvements over the past decade in diagnostic accuracy, prognosis prediction and management. The advent of mass spectrometry-based shotgun proteomics has revolutionized amyloid typing and has led to the discovery of new amyloid types. Accurate typing of the precursor protein is of paramount importance as the type dictates a specific management approach. In this article, we review each type of systemic amyloidosis to provide the practitioner with practical tools to improve diagnosis and management of these rare disorders.
Collapse
Affiliation(s)
- E Muchtar
- From the, Division of Hematology, Mayo Clinic, Rochester, MN, USA
| | - A Dispenzieri
- From the, Division of Hematology, Mayo Clinic, Rochester, MN, USA
| | - H Magen
- Hematology Institute, Chaim Sheba Medical Center, Tel Hashomer, Israel
| | - M Grogan
- Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA
| | - M Mauermann
- Department of Neurology, Mayo Clinic, Rochester, MN, USA
| | - E D McPhail
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - P J Kurtin
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - N Leung
- From the, Division of Hematology, Mayo Clinic, Rochester, MN, USA.,Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
| | - F K Buadi
- From the, Division of Hematology, Mayo Clinic, Rochester, MN, USA
| | - D Dingli
- From the, Division of Hematology, Mayo Clinic, Rochester, MN, USA
| | - S K Kumar
- From the, Division of Hematology, Mayo Clinic, Rochester, MN, USA
| | - M A Gertz
- From the, Division of Hematology, Mayo Clinic, Rochester, MN, USA
| |
Collapse
|
|
21
|
Donor-Derived ALECT2 Amyloidosis and Recurrent Fibrillary Glomerulonephritis in a Transplant Allograft. Kidney Med 2021; 3:433-437. [PMID: 34136788 PMCID: PMC8178471 DOI: 10.1016/j.xkme.2020.11.019] [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] [Indexed: 11/23/2022] Open
Abstract
The occurrence of renal amyloidosis and fibrillary glomerulonephritis in the same biopsy specimen is exceptional and poses a diagnostic challenge. We describe the case of a non-Hispanic White patient with end-stage kidney disease due to fibrillary glomerulonephritis who received a second living donor kidney from a Hispanic individual. A 40-month–posttransplantation biopsy performed for an elevated serum creatinine level revealed interstitial congophilic deposits and glomerular noncongophilic fibrillary deposits, in addition to rejection. Separate laser microdissections of the glomerular and interstitial deposits followed by liquid chromatography–tandem mass spectrometry (LC MS/MS) revealed DNAJB9 peptide spectra in glomeruli and a peptide profile consistent with leukocyte chemotactic factor 2 (ALECT2) amyloidosis in the interstitium. Based on these findings, a 2-week–posttransplantation biopsy was re-reviewed and analyzed using LC MS/MS, which revealed a peptide profile consistent with ALECT2 amyloidosis in the interstitium, without peptide spectra for ALECT2 or DNAJB9 in glomeruli. The findings were consistent with donor-derived ALECT2 amyloidosis and recurrent fibrillary glomerulonephritis. At 49 months posttransplantation, allograft function was stable with minimal proteinuria. Thus, LC MS/MS was crucial to establish the accurate diagnosis of these 2 nephropathies characterized by fibrillary deposits. The indolent posttransplantation course suggests that donated kidneys with focal interstitial ALECT2 deposits may be suitable for transplantation but the deposits persist for many years.
Collapse
|
|
22
|
Takata N, Ishii KA, Takayama H, Nagashimada M, Kamoshita K, Tanaka T, Kikuchi A, Takeshita Y, Matsumoto Y, Ota T, Yamamoto Y, Yamagoe S, Seki A, Sakai Y, Kaneko S, Takamura T. LECT2 as a hepatokine links liver steatosis to inflammation via activating tissue macrophages in NASH. Sci Rep 2021; 11:555. [PMID: 33436955 PMCID: PMC7804418 DOI: 10.1038/s41598-020-80689-0] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Accepted: 12/10/2020] [Indexed: 12/31/2022] Open
Abstract
It remains unclear how hepatic steatosis links to inflammation. Leukocyte cell-derived chemotaxin 2 (LECT2) is a hepatokine that senses fat in the liver and is upregulated prior to weight gain. The aim of this study was to investigate the significance of LECT2 in the development of nonalcoholic steatohepatitis (NASH). In human liver biopsy samples, elevated LECT2 mRNA levels were positively correlated with body mass index (BMI) and increased in patients who have steatosis and inflammation in the liver. LECT2 mRNA levels were also positively correlated with the mRNA levels of the inflammatory genes CCR2 and TLR4. In C57BL/6J mice fed with a high-fat diet, mRNA levels of the inflammatory cytokines Tnfa and Nos2 were significantly lower in Lect2 KO mice. In flow cytometry analyses, the number of M1-like macrophages and M1/M2 ratio were significantly lower in Lect2 KO mice than in WT mice. In KUP5, mouse kupffer cell line, LECT2 selectively enhanced the LPS-induced phosphorylation of JNK, but not that of ERK and p38. Consistently, LECT2 enhanced the LPS-induced phosphorylation of MKK4 and TAB2, upstream activators of JNK. Hepatic expression of LECT2 is upregulated in association with the inflammatory signature in human liver tissues. The elevation of LECT2 shifts liver residual macrophage to the M1-like phenotype, and contributes to the development of liver inflammation. These findings shed light on the hepatokine LECT2 as a potential therapeutic target that can dissociate liver steatosis from inflammation.
Collapse
Affiliation(s)
- Noboru Takata
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, 920-8640, Japan
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, 920-8640, Japan
| | - Kiyo-Aki Ishii
- Department of Integrative Medicine for Longevity, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, 920-8640, Japan
| | - Hiroaki Takayama
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, 920-8640, Japan
- Life Sciences Division, Engineering and Technology Department, Kanazawa University, Kanazawa, Ishikawa, 920-8640, Japan
| | - Mayumi Nagashimada
- Technology Department of Clinical Laboratory Science, Kanazawa University Graduate School of Medical Science and Technology, Kanazawa, Ishikawa, 920-0942, Japan
| | - Kyoko Kamoshita
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, 920-8640, Japan
| | - Takeo Tanaka
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, 920-8640, Japan
| | - Akihiro Kikuchi
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, 920-8640, Japan
| | - Yumie Takeshita
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, 920-8640, Japan
| | - Yukako Matsumoto
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, 920-8640, Japan
| | - Tsuguhito Ota
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, 920-8640, Japan
| | - Yasuhiko Yamamoto
- Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa, 920-8640, Japan
| | - Satoshi Yamagoe
- Department of Chemotherapy and Mycoses, National Institute of Infectious Diseases, Shinjuku-ku, Tokyo, 162-8640, Japan
| | - Akihiro Seki
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, 920-8640, Japan
| | - Yoshio Sakai
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, 920-8640, Japan
| | - Shuichi Kaneko
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, 920-8640, Japan
| | - Toshinari Takamura
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, 920-8640, Japan.
| |
Collapse
|
|
23
|
Ha JH, Tu HC, Wilkens S, Loh SN. Loss of bound zinc facilitates amyloid fibril formation of leukocyte-cell-derived chemotaxin 2 (LECT2). J Biol Chem 2021; 296:100446. [PMID: 33617884 PMCID: PMC8039541 DOI: 10.1016/j.jbc.2021.100446] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 02/05/2021] [Accepted: 02/18/2021] [Indexed: 02/06/2023] Open
Abstract
Aggregation of the circulating protein leukocyte-cell-derived chemotaxin 2 (LECT2) causes amyloidosis of LECT2 (ALECT2), one of the most prevalent forms of systemic amyloidosis affecting the kidney and liver. The I40V mutation is thought to be necessary but not sufficient for ALECT2, with a second, as-yet undetermined condition being required for the disease. EM, X-ray diffraction, NMR, and fluorescence experiments demonstrate that LECT2 forms amyloid fibrils in vitro in the absence of other proteins. Removal of LECT2's single bound Zn2+ appears to be obligatory for fibril formation. Zinc-binding affinity is strongly dependent on pH: 9-13 % of LECT2 is calculated to exist in the zinc-free state over the normal pH range of blood, with this fraction rising to 80 % at pH 6.5. The I40V mutation does not alter zinc-binding affinity or kinetics but destabilizes the zinc-free conformation. These results suggest a mechanism in which loss of zinc together with the I40V mutation leads to ALECT2.
Collapse
Affiliation(s)
- Jeung-Hoi Ha
- Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, New York, USA
| | - Ho-Chou Tu
- Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA
| | - Stephan Wilkens
- Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, New York, USA
| | - Stewart N Loh
- Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, New York, USA.
| |
Collapse
|
|
24
|
Singh K, Sethi J, Duggal R, Joshi K, Bains AS. Rare, Yet Emerging Cause of Graft Dysfunction-ALECT 2 Amyloidosis. Indian J Nephrol 2020; 30:204-206. [PMID: 33013073 PMCID: PMC7470195 DOI: 10.4103/ijn.ijn_258_19] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Revised: 09/04/2019] [Accepted: 10/18/2019] [Indexed: 11/04/2022] Open
Abstract
Amyloidosis is characterized by pathological deposition of abnormal protein aggregates in various tissues, AL protein being the commonest. Amyloidosis derived from leukocyte cell-derived chemotaxin 2 (LECT2) is a recently recognized form of amyloidosis in the United States with predominant involvement of kidney and liver. We present a case of ALECT2 renal amyloid in a transplant recipient who presented with gradual worsening of graft function and subnephrotic proteinuria. To our knowledge, this is first case of LECT2 amyloidosis from Northern India in a transplant recipient. There is no effective therapy for amyloidosis derived from leukocyte cell-derived chemotaxin 2.
Collapse
Affiliation(s)
- Kulwant Singh
- Division of Nephrology, Grecian Hospital, Mohali, Punjab, India
| | - Jasmine Sethi
- Division of Nephrology, Grecian Hospital, Mohali, Punjab, India
| | - Rajan Duggal
- Department of Histopathology, Core Diagnostics, Gurgaon, Haryana, India
| | - Kusum Joshi
- Department of Histopathology, Medicos Centre, Chandigarh, India
| | - Arjinder S Bains
- Department of Transplant Surgery, Surya Kidney Hospital, Mohali, Punjab, India
| |
Collapse
|
|
25
|
Dasari S, Theis JD, Vrana JA, Rech KL, Dao LN, Howard MT, Dispenzieri A, Gertz MA, Hasadsri L, Highsmith WE, Kurtin PJ, McPhail ED. Amyloid Typing by Mass Spectrometry in Clinical Practice: a Comprehensive Review of 16,175 Samples. Mayo Clin Proc 2020; 95:1852-1864. [PMID: 32861330 DOI: 10.1016/j.mayocp.2020.06.029] [Citation(s) in RCA: 128] [Impact Index Per Article: 25.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Revised: 05/11/2020] [Accepted: 06/03/2020] [Indexed: 12/29/2022]
Abstract
OBJECTIVE To map the occurrence of amyloid types in a large clinical cohort using mass spectrometry-based shotgun proteomics, an unbiased method that unambiguously identifies all amyloid types in a single assay. METHODS A mass spectrometry-based shotgun proteomics assay was implemented in a central reference laboratory. We documented our experience of typing 16,175 amyloidosis specimens over an 11-year period from January 1, 2008, to December 31, 2018. RESULTS We identified 21 established amyloid types, including AL (n=9542; 59.0%), ATTR (n=4600; 28.4%), ALECT2 (n=511; 3.2%), AA (n=463; 2.9%), AH (n=367; 2.3%), AIns (n=182; 1.2%), KRT5-14 (n=94; <1%), AFib (n=71; <1%), AApoAIV (n=57; <1%), AApoA1 (n=56; <1%), AANF (n=47; <1%), Aβ2M (n=38; <1%), ASem1 (n=34; <1%), AGel (n=29; <1%), TGFB1 (n=29; <1%), ALys (n=15; <1%), AIAPP (n=13; <1%), AApoCII (n=11; <1%), APro (n=8; <1%), AEnf (n=6; <1%), and ACal (n=2; <1%). We developed the first comprehensive organ-by-type map showing the relative frequency of 21 amyloid types in 31 different organs, and the first type-by-organ map showing organ tropism of 18 rare types. Using a modified bioinformatics pipeline, we detected amino acid substitutions in cases of hereditary amyloidosis with 100% specificity. CONCLUSION Amyloid typing by proteomics, which effectively recognizes all amyloid types in a single assay, optimally supports the diagnosis and treatment of amyloidosis patients in routine clinical practice.
Collapse
Affiliation(s)
- Surendra Dasari
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN
| | - Jason D Theis
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - Julie A Vrana
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - Karen L Rech
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - Linda N Dao
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - Matthew T Howard
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - Angela Dispenzieri
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN; Department of Medicine, Mayo Clinic, Rochester, MN
| | | | - Linda Hasadsri
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - W Edward Highsmith
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - Paul J Kurtin
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - Ellen D McPhail
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.
| |
Collapse
|
|
26
|
Li DY, Liu D, Wang SX, Yu XJ, Cui Z, Zhou FD, Zhao MH. Renal leukocyte chemotactic factor 2 (ALECT2)-associated amyloidosis in Chinese patients. Amyloid 2020; 27:134-141. [PMID: 32024381 DOI: 10.1080/13506129.2020.1722097] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Background: Leukocyte chemotactic factor 2 (ALECT2) amyloidosis is one of the recently described types of amyloidosis. In this study, we reported the first large case series of renal ALECT2 amyloidosis in Chinese patients.Methods: We studied the prevalence, clinical characteristics, renal pathology, outcome and genetic features among seven patients diagnosed with renal ALECT2 amyloidosis at Peking University First Hospital of China from 2000 to 2018.Results: Seven patients were diagnosed with ALECT2 amyloidosis, representing 1.9% of the renal biopsy-proven amyloidosis cases. The mean age at diagnosis was 68 years without gender preference. The patients mainly manifested with varying impaired kidney function with a mean estimated glomerular filtration rate of 42.7 mL/min/1.73 m2 (range 8.0-80.5) and proteinuria at 3.9 g/24 h (range 0.4-11.3). There were four ALECT2 amyloidosis patients with concurrent membranous nephropathy (MN), who presented a higher proteinuria (6.4 ± 4.0 g/24 h vs. 2.0 ± 1.8 g/24 h) and higher frequency of nephrotic syndrome (50% vs. 0) than patients with isolated ALECT2 amyloidosis. Renal biopsy showed strongly congophilic amyloid deposits distributed mainly in the renal cortical interstitium, as well as the glomerular mesangium, the inner layer of glomerular basement membrane (GBM), and vascular walls. Two patients with concurrent ALECT2 amyloidosis and MN showed mild amyloid deposits, which have not been identified as ALECT2 amyloidosis by IHC and LMD/MS methods. All patients were corroborated by immunoelectron microscopy to exhibit the specific location of LECT2 in the amyloid fibrils. Genetic analysis revealed no mutations but homozygosity for the G allele encoding valine at position 40 in the mature protein in all patients. Except for one patient who died 8 years later after he was diagnosed with ALECT2 amyloidosis, the others presented with relatively stable renal function during the mean follow-up period of 12.5 months.Conclusions: ALECT2 amyloidosis was the third most common type of renal amyloidosis in Chinese patients from a single centre. The majority of ALECT2 amyloidosis patients were of Han ethnicity, with a high rate of concurrent MN. The recognition and accurate diagnosis of renal ALECT2 amyloidosis should be considered in Chinese patients.
Collapse
Affiliation(s)
- Dan-Yang Li
- Laboratory of Electron Microscopy, Pathological Center, Peking University First Hospital, Beijing, PR China.,Department of Medicine, Renal Division, Peking University First Hospital; Renal Pathological Center, Institute of Nephrology, Peking University; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, PR China
| | - Dan Liu
- Proteomics Laboratory, Medical and Healthy Analytical Center, Peking University Health Science Center, Beijing, PR China
| | - Su-Xia Wang
- Laboratory of Electron Microscopy, Pathological Center, Peking University First Hospital, Beijing, PR China.,Department of Medicine, Renal Division, Peking University First Hospital; Renal Pathological Center, Institute of Nephrology, Peking University; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, PR China
| | - Xiao-Juan Yu
- Department of Medicine, Renal Division, Peking University First Hospital; Renal Pathological Center, Institute of Nephrology, Peking University; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, PR China
| | - Zhao Cui
- Department of Medicine, Renal Division, Peking University First Hospital; Renal Pathological Center, Institute of Nephrology, Peking University; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, PR China
| | - Fu-de Zhou
- Department of Medicine, Renal Division, Peking University First Hospital; Renal Pathological Center, Institute of Nephrology, Peking University; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, PR China
| | - Ming-Hui Zhao
- Department of Medicine, Renal Division, Peking University First Hospital; Renal Pathological Center, Institute of Nephrology, Peking University; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, PR China
| |
Collapse
|
|
27
|
Gibier JB, Gilbertson JA, Perbet R, Leriche W, Truant S, Leteurtre E, Gillmore JD, Gnemmi V. [Incidental finding of leukocyte cell-derived chemotaxin 2 - Associated amyloidosis in a liver]. Ann Pathol 2020; 40:472-477. [PMID: 32446730 DOI: 10.1016/j.annpat.2020.04.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Revised: 03/09/2020] [Accepted: 04/15/2020] [Indexed: 11/30/2022]
Abstract
Leukocyte cell-derived chemotaxin 2-associated amyloidosis (ALECT2) is a recently described of amyloidosis described in the United States in 2007. It is a systemic disease that is predominantly associated with some ethnics groups. ALECT2 is usually diagnosed on a kidney biopsy performed in the context of slowly progressive chronic renal disease but can also be found incidentally on a liver sample. We report the case of a Syrian patient who benefited from a partial hepatectomy for the treatment of multiple metastasis of a colorectal adenocarcinoma. Microscopic analysis of the surgical specimen revealed numerous amyloid deposits that did not match any of the usual forms of liver amyloidosis after immunohistochemistry typing. Some morphologic features of the deposits were highly suggestive of ALECT2. Complementary immunohistochemical study and mass spectrometry confirmed the diagnosis.
Collapse
Affiliation(s)
- Jean-Baptiste Gibier
- Inserm UMR-S 1172, institut de pathologie, centre de biologie pathologie, University Lille, CHU de Lille, 59000 Lille, France.
| | - Janet A Gilbertson
- National Amyloidosis Centre, Royal Free Hospital, University College London, London, Royaume-Uni
| | - Romain Perbet
- Inserm UMR-S 1172, institut de pathologie, centre de biologie pathologie, University Lille, CHU de Lille, 59000 Lille, France
| | - William Leriche
- Inserm UMR-S 1172, institut de pathologie, centre de biologie pathologie, University Lille, CHU de Lille, 59000 Lille, France
| | - Stéphanie Truant
- Service de chirurgie digestive et transplantation, University Lille, CHU de Lille, 59000 Lille, France
| | - Emmanuelle Leteurtre
- Inserm UMR-S 1172, institut de pathologie, centre de biologie pathologie, University Lille, CHU de Lille, 59000 Lille, France
| | - Julian D Gillmore
- National Amyloidosis Centre, Royal Free Hospital, University College London, London, Royaume-Uni
| | - Viviane Gnemmi
- Inserm UMR-S 1172, institut de pathologie, centre de biologie pathologie, University Lille, CHU de Lille, 59000 Lille, France
| |
Collapse
|
|
28
|
Abildgaard N, Rojek AM, Møller HE, Palstrøm NB, Nyvold CG, Rasmussen LM, Hansen CT, Beck HC, Marcussen N. Immunoelectron microscopy and mass spectrometry for classification of amyloid deposits. Amyloid 2020; 27:59-66. [PMID: 31752543 DOI: 10.1080/13506129.2019.1688289] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Amyloidosis is a shared name for several rare, complex and serious diseases caused by extra-cellular deposits of different misfolded proteins. Accurate characterization of the amyloid protein is essential for patient care. Immunoelectron microscopy (IEM) and laser microdissection followed by tandem mass spectrometry (LMD-MS) are new gold standards for molecular subtyping. Both methods perform superiorly to immunohistochemistry, but their complementarities, strengths and weaknesses across amyloid subtypes and organ biopsy origin remain undefined. Therefore, we performed a retrospective study of 106 Congo Red positive biopsies from different involved organs; heart, kidney, lung, gut mucosa, skin and bone marrow. IEM, performed with gold-labelled antibodies against kappa light chains, lambda light chains, transthyretin and amyloid A, identified specific staining of amyloid fibrils in 91.6%; in six biopsies amyloid fibrils were not identified, and in two, the fibril subtype could not be established. LMD-MS identified amyloid protein signature in 98.1%, but in nine the amyloid protein could not be clearly identified. MS identified protein subtype in 89.6%. Corresponding specificities ranged at organ level from 94-100%. Concordance was 89.6-100% for different amyloid subtypes. Importantly, combined use of both methods increased the diagnostic classification to 100%. Some variety in performances at organ level was observed.
Collapse
Affiliation(s)
- Niels Abildgaard
- Odense Amyloidosis Centre, Odense, Denmark.,Department of Haematology, Odense University Hospital, Odense, Denmark.,Department of Clinical Research, University of Southern Denmark, Odense, Denmark.,Odense Patient Explorative Network (OPEN), Odense, Denmark
| | - Aleksandra M Rojek
- Odense Amyloidosis Centre, Odense, Denmark.,Department of Pathology, Odense University Hospital, Odense, Denmark
| | - Hanne Eh Møller
- Odense Amyloidosis Centre, Odense, Denmark.,Department of Pathology, Odense University Hospital, Odense, Denmark
| | - Nicolai Bjødstrup Palstrøm
- Odense Amyloidosis Centre, Odense, Denmark.,Department of Clinical Biochemistry and Pharmacology, Centre for Clinical Proteomics, Odense, Denmark
| | - Charlotte Guldborg Nyvold
- Odense Amyloidosis Centre, Odense, Denmark.,Department of Clinical Research, University of Southern Denmark, Odense, Denmark.,Haematology Pathology Research Laboratory, Department of Haematology, Odense University Hospital, Odense, Denmark
| | - Lars Melholt Rasmussen
- Odense Amyloidosis Centre, Odense, Denmark.,Department of Clinical Biochemistry and Pharmacology, Centre for Clinical Proteomics, Odense, Denmark
| | - Charlotte Toftmann Hansen
- Odense Amyloidosis Centre, Odense, Denmark.,Department of Haematology, Odense University Hospital, Odense, Denmark
| | - Hans Christian Beck
- Odense Amyloidosis Centre, Odense, Denmark.,Department of Clinical Biochemistry and Pharmacology, Centre for Clinical Proteomics, Odense, Denmark
| | - Niels Marcussen
- Odense Amyloidosis Centre, Odense, Denmark.,Department of Pathology, Odense University Hospital, Odense, Denmark
| |
Collapse
|
|
29
|
Giannini G, Nast CC. An Organ System-Based Approach to Differential Diagnosis of Amyloid Type in Surgical Pathology. Arch Pathol Lab Med 2019; 144:379-387. [PMID: 31697170 DOI: 10.5858/arpa.2018-0509-ra] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
CONTEXT.— Amyloidosis is an uncommon but important entity. A protein-based classification of amyloidosis defines the underlying disease process, directing clinical management and providing prognostic information. However, in routine surgical pathology there often is no attempt to classify amyloid other than staining to determine light chain-associated amyloidosis. Systemic and localized amyloidosis vary with respect to frequency of organ involvement by different amyloid types, and most amyloid proteins have commercial antibodies available for identification. OBJECTIVE.— To provide a guide for the likelihood of amyloid type by organ system. DATA SOURCES.— Literature review based on PubMed searches containing the word amyloid, specifically addressing the prevalence and significance of amyloid proteins in each organ system other than the brain, and the authors' practice experience. CONCLUSIONS.— In patients with amyloidosis, determination of the responsible protein is critical for appropriate patient care. In large subspecialty practices and reference laboratories with experience in using and analyzing relevant immunohistochemistry, most amyloid proteins can be identified with an organ-specific algorithm. Referring to an organ-based algorithm may be helpful in providing clinicians with a more specific differential diagnosis regarding amyloid type to help guide clinical evaluation and treatment. When the protein cannot be characterized, mass spectrometry can be performed to definitively classify the amyloid type.
Collapse
Affiliation(s)
- Gabriel Giannini
- From the Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, California
| | - Cynthia C Nast
- From the Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, California
| |
Collapse
|
|
30
|
Delving into the amyloidogenic core of human leukocyte chemotactic factor 2. J Struct Biol 2019; 207:260-269. [PMID: 31170474 DOI: 10.1016/j.jsb.2019.06.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Revised: 05/31/2019] [Accepted: 06/02/2019] [Indexed: 11/22/2022]
Abstract
ALECT2 (leukocyte chemotactic factor 2) amyloidosis is one of the most recently identified amyloid-related diseases, with LECT2 amyloids commonly found in different types of tissues. Under physiological conditions, LECT2 is a 16 kDa multifunctional protein produced by the hepatocytes and secreted into circulation. The pathological mechanisms causing LECT2 transition into the amyloid state are still largely unknown. In the case of ALECT2 patients, there is no disease-causing mutation, yet almost all patients carry a common polymorphism that appears to be necessary but not sufficient to directly trigger amyloidogenesis. In this work, we followed a reductionist methodology in order to detect critical amyloidogenic "hot-spots" during the fibrillation of LECT2. By associating experimental and computational assays, this approach reveals the explicit amyloidogenic core of human LECT2 and pinpoints regions with distinct amyloidogenic properties. The fibrillar architecture of LECT2 polymers, based on our results, provides a wealth of detailed information about the amyloidogenic "hot-spot" interactions and represents a starting point for future peptide-driven intervention in ALECT2 amyloidosis.
Collapse
|
|
31
|
Xu M, Xu HH, Lin Y, Sun X, Wang LJ, Fang ZP, Su XH, Liang XJ, Hu Y, Liu ZM, Cheng Y, Wei Y, Li J, Li L, Liu HJ, Cheng Z, Tang N, Peng C, Li T, Liu T, Qiao L, Wu D, Ding YQ, Zhou WJ. LECT2, a Ligand for Tie1, Plays a Crucial Role in Liver Fibrogenesis. Cell 2019; 178:1478-1492.e20. [PMID: 31474362 DOI: 10.1016/j.cell.2019.07.021] [Citation(s) in RCA: 153] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2018] [Revised: 04/23/2019] [Accepted: 07/12/2019] [Indexed: 12/12/2022]
Abstract
Liver fibrosis is a very common condition seen in millions of patients with various liver diseases, and yet no effective treatments are available owing to poorly characterized molecular pathogenesis. Here, we show that leukocyte cell-derived chemotaxin 2 (LECT2) is a functional ligand of Tie1, a poorly characterized endothelial cell (EC)-specific orphan receptor. Upon binding to Tie1, LECT2 interrupts Tie1/Tie2 heterodimerization, facilitates Tie2/Tie2 homodimerization, activates PPAR signaling, and inhibits the migration and tube formations of EC. In vivo studies showed that LECT2 overexpression inhibits portal angiogenesis, promotes sinusoid capillarization, and worsens fibrosis, whereas these changes were reversed in Lect2-KO mice. Adeno-associated viral vector serotype 9 (AAV9)-LECT2 small hairpin RNA (shRNA) treatment significantly attenuates fibrosis. Upregulation of LECT2 is associated with advanced human liver fibrosis staging. We concluded that targeting LECT2/Tie1 signaling may represent a potential therapeutic target for liver fibrosis, and serum LECT2 level may be a potential biomarker for the screening and diagnosis of liver fibrosis.
Collapse
Affiliation(s)
- Meng Xu
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong 510515, China
| | - Hong-Hai Xu
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong 510515, China; The First Affiliated Hospital of Anhui Medical University, Anhui, Hefei 230022, China
| | - Yuan Lin
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong 510515, China; Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde Foshan), Shunde, Guangdong 528333, China
| | - Xiangnan Sun
- Helmholtz International Lab, State Key Laboratory of Microbial Technology, Shandong University, Qingdao, Shandong 266237, China
| | - Li-Jing Wang
- Vascular Biology Research Institute, School of Life Sciences and Biopharmaceuticals, Guangdong Pharmaceutical University, Guangzhou, Guangdong 510006, China
| | - Zhe-Ping Fang
- Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang 317000, China
| | - Xue-Han Su
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong 510515, China
| | - Xiang-Jing Liang
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong 510515, China
| | - Yang Hu
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong 510515, China
| | - Zhi-Min Liu
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong 510515, China
| | - Yuanxiong Cheng
- Department of Respiratory and Critical Care Medicine, The Third Affiliated Hospital, Southern Medical University, Guangzhou, Guangdong 510630, China
| | - Yuanyuan Wei
- The First Affiliated Hospital of Anhui Medical University, Anhui, Hefei 230022, China
| | - Jiabin Li
- The First Affiliated Hospital of Anhui Medical University, Anhui, Hefei 230022, China
| | - Li Li
- Vascular Biology Research Institute, School of Life Sciences and Biopharmaceuticals, Guangdong Pharmaceutical University, Guangzhou, Guangdong 510006, China
| | - Hong-Juan Liu
- Department of Bioinformation, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Zhiqiang Cheng
- Department of Pathology, Shenzhen People's Hospital, Shenzhen, Guangdong 515020, China
| | - Na Tang
- Department of Pathology, Shenzhen People's Hospital, Shenzhen, Guangdong 515020, China
| | - Chao Peng
- National Facility for Protein Science in Shanghai, Zhangjiang Lab, Shanghai 201210, China
| | - Tingting Li
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong 510515, China
| | - Tengfei Liu
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong 510515, China
| | - Liang Qiao
- Storr Liver Centre, Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital and Western Clinical School, Westmead, NSW 2145, Australia
| | - Dalei Wu
- Helmholtz International Lab, State Key Laboratory of Microbial Technology, Shandong University, Qingdao, Shandong 266237, China
| | - Yan-Qing Ding
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong 510515, China.
| | - Wei-Jie Zhou
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong 510515, China; Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde Foshan), Shunde, Guangdong 528333, China; Microbiome Medicine Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China; Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, Guangdong 510005, China.
| |
Collapse
|
|
32
|
Rezk T, Gilbertson JA, Rowczenio D, Bass P, Lachmann HJ, Wechalekar AD, Fontana M, Mahmood S, Sachchithanantham S, Whelan CJ, Wong J, Rendell N, Taylor GW, Hawkins PN, Gillmore JD. Diagnosis, pathogenesis and outcome in leucocyte chemotactic factor 2 (ALECT2) amyloidosis. Nephrol Dial Transplant 2019; 33:241-247. [PMID: 29401357 DOI: 10.1093/ndt/gfw375] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2016] [Accepted: 09/17/2016] [Indexed: 11/14/2022] Open
Abstract
Introduction Renal biopsy series from North America suggest that leucocyte chemotactic factor 2 (ALECT2) amyloid is the third most common type of renal amyloid. We report the first case series from a European Centre of prevalence, clinical presentation and diagnostic findings in ALECT2 amyloidosis and report long-term patient and renal outcomes for the first time. Methods We studied the clinical features, diagnostic investigations and the outcome of all patients with ALECT2 amyloidosis followed systematically at the UK National Amyloidosis Centre (NAC) between 1994 and 2015. Results Twenty-four patients, all non-Caucasian, were diagnosed with ALECT2 amyloidosis representing 1.3% of all patients referred to the NAC with biopsy-proved renal amyloid. Diagnosis was made at median age of 62 years, usually from renal histology; immunohistochemical staining was definitive for ALECT2 fibril type. Median estimated glomerular filtration rate (GFR) at diagnosis was 33 mL/min/1.73 m2 and median proteinuria was 0.5 g/24 h. Hepatic amyloid was evident on serum amyloid P component (SAP) scintigraphy in 11/24 cases but was not associated with significant derangement of liver function. No patient had evidence of cardiac amyloidosis or amyloid neuropathy. Median follow-up was 4.8 (range 0.5-15.2) years, during which four patients died and four progressed to end-stage renal disease. The mean rate of GFR loss was 4.2 (range 0.5-9.6) mL/min/year and median estimated renal survival from diagnosis was 8.2 years. Serial SAP scans revealed little or no change in total body amyloid burden. Conclusions ALECT2 amyloidosis is a relatively benign type of renal amyloid, associated with a slow GFR decline, which is reliably diagnosed on renal histology. Neither the molecular basis nor the factors underlying the apparent restriction of ALECT2 amyloidosis to non-Caucasian populations have been determined.
Collapse
Affiliation(s)
- Tamer Rezk
- National Amyloidosis Centre, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, Royal Free Campus, University College London, London, UK.,UCL Centre for Nephrology, UCL Medical School, Royal Free Hospital, London, UK
| | - Janet A Gilbertson
- National Amyloidosis Centre, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, Royal Free Campus, University College London, London, UK
| | - Dorota Rowczenio
- National Amyloidosis Centre, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, Royal Free Campus, University College London, London, UK
| | - Paul Bass
- UCL Centre for Nephrology, UCL Medical School, Royal Free Hospital, London, UK
| | - Helen J Lachmann
- National Amyloidosis Centre, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, Royal Free Campus, University College London, London, UK
| | - Ashutosh D Wechalekar
- National Amyloidosis Centre, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, Royal Free Campus, University College London, London, UK
| | - Marianna Fontana
- National Amyloidosis Centre, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, Royal Free Campus, University College London, London, UK
| | - Shameem Mahmood
- National Amyloidosis Centre, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, Royal Free Campus, University College London, London, UK
| | - Sajitha Sachchithanantham
- National Amyloidosis Centre, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, Royal Free Campus, University College London, London, UK
| | - Carol J Whelan
- National Amyloidosis Centre, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, Royal Free Campus, University College London, London, UK
| | - Jonathan Wong
- National Amyloidosis Centre, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, Royal Free Campus, University College London, London, UK
| | - Nigel Rendell
- National Amyloidosis Centre, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, Royal Free Campus, University College London, London, UK
| | - Graham W Taylor
- National Amyloidosis Centre, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, Royal Free Campus, University College London, London, UK
| | - Philip N Hawkins
- National Amyloidosis Centre, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, Royal Free Campus, University College London, London, UK
| | - Julian D Gillmore
- National Amyloidosis Centre, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, Royal Free Campus, University College London, London, UK
| |
Collapse
|
|
33
|
Shamir ER, Lee MM, Walavalkar V. De novo leukocyte chemotactic factor 2 amyloidosis in a pediatric renal allograft, 15 years post-transplant. Pediatr Transplant 2019; 23:e13371. [PMID: 30714275 DOI: 10.1111/petr.13371] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2018] [Revised: 12/19/2018] [Accepted: 01/10/2019] [Indexed: 01/01/2023]
Abstract
Leukocyte chemotactic factor 2 amyloidosis (ALECT2) is a recently described form of systemic amyloidosis, which most commonly affects the kidney and liver. The LECT2 protein is produced during inflammatory processes, but its precise function in renal diseases in unclear. ALECT2, however, is known to be a relatively common form of renal amyloidosis, after amyloid light chain and serum amyloid A types and is most often seen in patients of Hispanic ethnicity. ALECT2 can occur de novo or as recurrent disease in kidney transplants. We present the first case, to our knowledge, of de novo ALECT2 in a pediatric kidney transplant patient, 15 years post-transplant.
Collapse
Affiliation(s)
- Eliah R Shamir
- Department of Pathology, University of California San Francisco, San Francisco, California
| | - Marsha M Lee
- Department of Pediatric Nephrology, University of California San Francisco, San Francisco, California
| | - Vighnesh Walavalkar
- Department of Pathology, University of California San Francisco, San Francisco, California
| |
Collapse
|
|
34
|
Muchtar E, Gertz MA, Kyle RA, Lacy MQ, Dingli D, Leung N, Buadi FK, Hayman SR, Kapoor P, Hwa YL, Fonder A, Hobbs M, Gonsalves W, Kourelis TV, Warsame R, Russell S, Lust JA, Lin Y, Go RS, Zeldenrust S, Rajkumar SV, Kumar SK, Dispenzieri A. A Modern Primer on Light Chain Amyloidosis in 592 Patients With Mass Spectrometry-Verified Typing. Mayo Clin Proc 2019; 94:472-483. [PMID: 30770096 DOI: 10.1016/j.mayocp.2018.08.006] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Revised: 06/30/2018] [Accepted: 08/09/2018] [Indexed: 02/06/2023]
Abstract
OBJECTIVE To describe the clinical and laboratory characteristics of patients with meticulously typed light chain (AL) amyloidosis. PATIENTS AND METHODS Patients (N=592) with biopsy-proven, mass spectrometry-confirmed AL amyloidosis diagnosed from January 1, 2008, through August 31, 2015, were included. RESULTS The median patient age at diagnosis was 63 years. Thirty-four percent of patients (n=204) had isolated organ involvement, mostly heart (19% [n=115]) followed by kidney (9% [n=53]). In contrast, 25% (n=146) had more than 2 involved organs. Patients with isolated cardiac involvement had similar cardiac dysfunction compared with those with nonisolated cardiac amyloidosis. In contrast, isolated renal involvement was associated with increased proteinuria and higher estimated glomerular filtration rate compared with nonisolated renal amyloidosis. Serum and urine immunofixation electrophoresis results were positive in 80% and 88% of patients, respectively, with 94% of patients having at least 1 positive immunofixation electrophoresis result (serum or urine). The serum free light chain ratio was abnormal in 91% of patients. When all monoclonal protein studies were combined, only 1 patient (0.2%) had normal results. The 1- and 5-year survival rates were 65% and 46%, respectively. Survival of patients with cardiac amyloidosis was not influenced by the number of involved organs (1 vs >1 organ), emphasizing the prognostic significance of cardiac involvement. CONCLUSION When mass spectrometry is used to definitively type amyloid, only a fraction of a percent of patients with AL have negative monoclonal protein studies, unlike historical reports. Patient characteristics and outcomes of accurately typed patients are described.
Collapse
Affiliation(s)
- Eli Muchtar
- Division of Hematology, Mayo Clinic, Rochester, MN
| | | | | | | | - David Dingli
- Division of Hematology, Mayo Clinic, Rochester, MN
| | - Nelson Leung
- Division of Hematology, Mayo Clinic, Rochester, MN; Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN
| | | | | | | | - Yi Lisa Hwa
- Division of Hematology, Mayo Clinic, Rochester, MN
| | - Amie Fonder
- Division of Hematology, Mayo Clinic, Rochester, MN
| | - Miriam Hobbs
- Division of Hematology, Mayo Clinic, Rochester, MN
| | | | | | | | | | - John A Lust
- Division of Hematology, Mayo Clinic, Rochester, MN
| | - Yi Lin
- Division of Hematology, Mayo Clinic, Rochester, MN
| | - Ronald S Go
- Division of Hematology, Mayo Clinic, Rochester, MN
| | | | | | | | | |
Collapse
|
|
35
|
Nuvolone M, Milani P, Palladini G, Merlini G. Management of the elderly patient with AL amyloidosis. Eur J Intern Med 2018; 58:48-56. [PMID: 29801808 DOI: 10.1016/j.ejim.2018.05.004] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2018] [Accepted: 05/04/2018] [Indexed: 12/25/2022]
Abstract
Systemic immunoglobulin light chain (AL) amyloidosis is an aging-associated protein misfolding and deposition disease. This condition is caused by a small and otherwise indolent plasma cell (or B cell) clone secreting an unstable circulating light chain, which misfolds and deposits as amyloid fibrils possibly leading to progressive dysfunction of affected organs. AL amyloidosis can occur in the typical setting of other, rarer forms of systemic amyloidosis and can mimic other more prevalent conditions of the elderly. Therefore, its diagnosis requires a high degree of clinical suspicion and reliable diagnostic tools for accurate amyloid typing, available at specialized referral centers. In AL amyloidosis, frailty is dictated by the type and severity of organ involvement, with heart involvement being the main determinant of morbidity and mortality. Still, given a similar disease stage, elderly patients with AL amyloidosis are often an even frailer group, due to significant comorbidities, associated disability and polypharmacotherapy, socioeconomic restrictions, and limited access to clinical trials. Recent improvements in the use of biomarkers for early diagnosis, risk stratification and response monitoring, the flourishing of novel, effective anti-plasma cell therapies developed against multiple myeloma and adapted to treat AL amyloidosis, and possibly the introduction of anti-amyloid therapies are rapidly changing the clinical management of this disease and are reflected by improved outcomes. Of note, hematologic and organ responses in elderly patients with AL amyloidosis do translate in better outcome, advocating the importance of treating these patients and striving for a rapid response to therapy also in this challenging clinical setting.
Collapse
Affiliation(s)
- Mario Nuvolone
- Amyloidosis Research and Treatment Center, Foundation IRCCS Policlinico San Matteo, Department of Molecular Medicine, University of Pavia, Italy
| | - Paolo Milani
- Amyloidosis Research and Treatment Center, Foundation IRCCS Policlinico San Matteo, Department of Molecular Medicine, University of Pavia, Italy
| | - Giovanni Palladini
- Amyloidosis Research and Treatment Center, Foundation IRCCS Policlinico San Matteo, Department of Molecular Medicine, University of Pavia, Italy
| | - Giampaolo Merlini
- Amyloidosis Research and Treatment Center, Foundation IRCCS Policlinico San Matteo, Department of Molecular Medicine, University of Pavia, Italy.
| |
Collapse
|
|
36
|
Kaur G, Bijin B, Saleem K, Sarsah B, Thajudeen B. Leukocyte Cell-Derived Chemotaxin 2-Associated Renal Amyloidosis: A Case Report. Case Rep Nephrol Dial 2018; 7:121-129. [PMID: 29464179 PMCID: PMC5814782 DOI: 10.1159/000479678] [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: 01/23/2017] [Accepted: 07/20/2017] [Indexed: 11/19/2022] Open
Abstract
Amyloidosis is a disorder characterized by the deposition of abnormal protein fibrils in tissues. Leukocyte cell-derived chemotaxin 2-associated amyloidosis is a recently recognized entity and is characterized by a distinctive clinicopathologic type of amyloid deposition manifested in adults by varying degrees of impaired kidney function and proteinuria. There are only a limited number of cases reported in the literature. We present a 64-year-old Hispanic female with a history of hypertension who was referred for chronic kidney disease management. The review of her laboratory tests revealed a serum creatinine of 1.5–1.8 mg/dL and microalbuminuria (in the presence of a bland urine sediment) in the past year. She denied any history of diabetes, rheumatologic disorders or exposure to intravenous contrast, nonsteroidal anti-inflammatory drugs, herbals, and heavy metals. Serological workup was negative. A renal biopsy showed diffuse infiltration of glomerulus with pale eosinophilic material strongly positive for Congo red stain and a similar eosinophilic material in the interstitium, muscular arteries, and arterioles. Electron microscopy showed marked infiltration of the mesangium, capillary loops, and interstitium with haphazardly arranged fibrillary deposits (9.8 nm thick). Liquid chromatography tandem mass spectrometry confirmed leukocyte cell-derived chemotaxin 2 (LECT2) amyloid deposition. LECT2 amyloidosis (ALECT2) should be suspected in renal biopsy specimens exhibiting extensive and strong mesangial as well as interstitial congophilia. Individuals with LECT2 renal amyloidosis have a varying prognosis. Therapeutic options include supportive measures and consideration of a kidney transplant for those with end-stage renal disease.
Collapse
Affiliation(s)
- Gagandeep Kaur
- Department of Nephrology, Banner University of Arizona Medical Center, Tucson, Arizona, USA
| | - Babitha Bijin
- Department of Nephrology, Banner University of Arizona Medical Center, Tucson, Arizona, USA
| | - Kamron Saleem
- Department of Nephrology, Banner University of Arizona Medical Center, Tucson, Arizona, USA
| | - Benjamin Sarsah
- Department of Nephrology, Banner University of Arizona Medical Center, Tucson, Arizona, USA
| | - Bijin Thajudeen
- Department of Nephrology, Banner University of Arizona Medical Center, Tucson, Arizona, USA
| |
Collapse
|
|
37
|
|
|
38
|
Canetti D, Rendell NB, Di Vagno L, Gilbertson JA, Rowczenio D, Rezk T, Gillmore JD, Hawkins PN, Verona G, Mangione PP, Giorgetti S, Mauri P, Motta S, De Palma A, Bellotti V, Taylor GW. Misidentification of transthyretin and immunoglobulin variants by proteomics due to methyl lysine formation in formalin-fixed paraffin-embedded amyloid tissue. Amyloid 2017; 24:233-241. [PMID: 29016222 DOI: 10.1080/13506129.2017.1385452] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Proteomics is becoming the de facto gold standard for identifying amyloid proteins and is now used routinely in a number of centres. The technique is compound class independent and offers the added ability to identify variant and modified proteins. We re-examined proteomics results from a number of formalin-fixed paraffin-embedded amyloid samples, which were positive for transthyretin (TTR) by immunohistochemistry and proteomics, using the UniProt human protein database modified to include TTR variants. The amyloidogenic variant, V122I TTR, was incorrectly identified in 26/27 wild-type and non-V122I variant samples due to its close mass spectral similarity with the methyl lysine-modified WT peptide [126KMe]105-127 (p.[146 KMe]125-147) generated during formalin fixation. Similarly, the methyl lysine peptide, [50KMe]43-59, from immunoglobulin lambda light chain constant region was also misidentified as arising from a rare myeloma-derived lambda variant V49I. These processing-derived modifications are not present in fresh cardiac tissue, non-fixed fat nor serum and do not materially affect the identification of amyloid proteins. They could result in the incorrect assignment of a variant, and this may have consequences for the immediate family who will require genetic counselling and potentially early clinical intervention. As proteomics becomes a routine clinical test for amyloidosis, it becomes important to be aware of potentially confounding issues such as formalin-mediated lysine methylation, and how these may influence diagnosis and possibly treatment.
Collapse
Affiliation(s)
- Diana Canetti
- a Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins , University College London , London , UK.,b National Amyloidosis Centre, Division of Medicine , University College London , London , UK.,c Department of Molecular Medicine , Institute of Biochemistry, University of Pavia , Pavia , Italy.,d CEINGE , University of Naples , Naples , Italy.,e Department of Chemical Sciences , University of Naples , Naples , Italy
| | - Nigel Brian Rendell
- a Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins , University College London , London , UK.,b National Amyloidosis Centre, Division of Medicine , University College London , London , UK
| | - Lucia Di Vagno
- a Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins , University College London , London , UK.,b National Amyloidosis Centre, Division of Medicine , University College London , London , UK
| | - Janet A Gilbertson
- a Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins , University College London , London , UK.,b National Amyloidosis Centre, Division of Medicine , University College London , London , UK
| | - Dorota Rowczenio
- a Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins , University College London , London , UK.,b National Amyloidosis Centre, Division of Medicine , University College London , London , UK
| | - Tamar Rezk
- a Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins , University College London , London , UK.,b National Amyloidosis Centre, Division of Medicine , University College London , London , UK
| | - Julian D Gillmore
- a Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins , University College London , London , UK.,b National Amyloidosis Centre, Division of Medicine , University College London , London , UK
| | - Phillip N Hawkins
- a Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins , University College London , London , UK.,b National Amyloidosis Centre, Division of Medicine , University College London , London , UK
| | - Guglielmo Verona
- a Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins , University College London , London , UK.,b National Amyloidosis Centre, Division of Medicine , University College London , London , UK
| | - Palma Patrizia Mangione
- a Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins , University College London , London , UK.,b National Amyloidosis Centre, Division of Medicine , University College London , London , UK.,c Department of Molecular Medicine , Institute of Biochemistry, University of Pavia , Pavia , Italy
| | - Sofia Giorgetti
- c Department of Molecular Medicine , Institute of Biochemistry, University of Pavia , Pavia , Italy
| | - Pierluigi Mauri
- f Proteomics and Metabolomics Laboratory , CNR-ITB , Segrate , Italy
| | - Sara Motta
- f Proteomics and Metabolomics Laboratory , CNR-ITB , Segrate , Italy
| | | | - Vittorio Bellotti
- a Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins , University College London , London , UK.,b National Amyloidosis Centre, Division of Medicine , University College London , London , UK.,c Department of Molecular Medicine , Institute of Biochemistry, University of Pavia , Pavia , Italy
| | - Graham W Taylor
- a Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins , University College London , London , UK.,b National Amyloidosis Centre, Division of Medicine , University College London , London , UK
| |
Collapse
|
|
39
|
Srinivasan S, Tofteland N. An Unusual Cause of Elevated Liver Enzymes. Gastroenterology 2017; 153:e4-e5. [PMID: 28988918 DOI: 10.1053/j.gastro.2017.03.062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2017] [Accepted: 03/13/2017] [Indexed: 12/02/2022]
Affiliation(s)
- Sachin Srinivasan
- Department of Internal Medicine, Kansas University School of Medicine, Wichita, Kansas
| | - Nathan Tofteland
- Department of Internal Medicine, Kansas University School of Medicine, Wichita, Kansas
| |
Collapse
|
|
40
|
Tariq H, Sharkey FE. Leukocyte Cell-Derived Chemotaxin-2 Amyloidosis (ALECT2) in a Patient With Lung Adenocarcinoma: An Autopsy Report and Literature Review. Int J Surg Pathol 2017; 26:271-275. [PMID: 29017384 DOI: 10.1177/1066896917735893] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Amyloidosis caused by deposition of leukocyte cell-derived chemotaxin-2 amyloidosis (ALECT2) is the most recently described form of systemic amyloidosis and has quickly emerged as a common and possibly underdiagnosed cause of slowly declining renal function, particularly in patients of Hispanic ancestry. We describe the autopsy findings in a 70-year-old Hispanic woman who died of metastatic lung adenocarcinoma and was incidentally found to have extensive amyloid deposition in the kidneys, liver, spleen, adrenal glands, small intestine, gallbladder, lungs, bilateral ovaries, and uterus. The type of amyloid was confirmed to be ALECT2 by mass spectrometry. The pattern of amyloid deposition in the kidneys and the liver was typical for what has been described for ALECT2. In addition, a unique pattern of amyloid deposition was observed in spleen, adrenal glands, small intestine, gallbladder, lungs, ovaries, and uterus. The pattern of amyloid deposition in ALECT2 is distinct from amyloid A and amyloid light-chain and needs to be recognized to avoid misdiagnosis as amyloid light-chain or amyloid A amyloidosis. After recognition, an accurate diagnosis by mass spectrometry and/or immunohistochemical staining is essential to guide treatment and avoid toxic therapies.
Collapse
Affiliation(s)
- Hamza Tariq
- 1 University of Texas Health Science Center at San Antonio, TX, USA
| | | |
Collapse
|
|
41
|
Slowik V, Apte U. Leukocyte Cell-Derived Chemotaxin-2: It's Role in Pathophysiology and Future in Clinical Medicine. Clin Transl Sci 2017; 10:249-259. [PMID: 28466965 PMCID: PMC5504477 DOI: 10.1111/cts.12469] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2016] [Accepted: 04/01/2017] [Indexed: 12/15/2022] Open
Affiliation(s)
- V Slowik
- Department of Gastroenterology, Hepatology, and Nutrition, Children's Mercy Hospitals and Clinic, 2401 Gillham Road, Kansas City, Missouri, 64108, USA
| | - U Apte
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, MS1018, Kansas City, Kansas, 66160, USA
| |
Collapse
|
|
42
|
Hill MM, Mollee PN. Mass spectrometry analysis for amyloidosis typing - is the future bright for its clinical implementation? Expert Rev Proteomics 2017; 14:565-566. [PMID: 28438056 DOI: 10.1080/14789450.2017.1322905] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Affiliation(s)
- Michelle M Hill
- a Principal Research Fellow, The University of Queensland Diamantina Institute, Faculty of Medicine , The University of Queensland, Translational Research Institute , Brisbane , Australia
| | - Peter N Mollee
- b Haematologist , Amyloidosis Centre , Brisbane , Australia.,c School of Medicine , University of Queensland , Brisbane , Australia
| |
Collapse
|
|
43
|
Abstract
Amyloidoses are a spectrum of disorders caused by abnormal folding and extracellular deposition of proteins. The deposits lead to tissue damage and organ dysfunction, particularly in the heart, kidneys, and nerves. There are at least 30 different proteins that can cause amyloidosis. The clinical management depends entirely on the type of protein deposited, and thus on the underlying pathogenesis, and often requires high-risk therapeutic intervention. Application of mass spectrometry-based proteomic technologies for analysis of amyloid plaques has transformed the way amyloidosis is diagnosed and classified. Proteomic assays have been extensively used for clinical management of patients with amyloidosis, providing unprecedented diagnostic and biological information. They have shed light on the pathogenesis of different amyloid types and have led to identification of numerous new amyloid types, including ALECT2 amyloidosis, which is now recognized as one of the most common causes of systemic amyloidosis in North America.
Collapse
Affiliation(s)
- Ahmet Dogan
- Departments of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065;
| |
Collapse
|
|
44
|
Lavatelli F, Merlini G. Advances in proteomic study of cardiac amyloidosis: progress and potential. Expert Rev Proteomics 2016; 13:1017-1027. [PMID: 27678147 DOI: 10.1080/14789450.2016.1242417] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
INTRODUCTION More than ten distinct forms of amyloidoses that can involve the heart have been described, classified according to which protein originates the deposits. Cardiac amyloid infiltration translates into progressive and often life-threatening cardiomyopathy, but disease severity, prognosis and treatment drastically differ according to the amyloidosis type. The notion that protein misfolding and aggregation play a more general role in human cardiomyopathies has further raised attention towards the definition of the proteotoxicity mechanisms. Areas covered: Mass spectrometry-based proteomics plays an important role as a diagnostic tool and for understanding the molecular bases of amyloid cardiomyopathies. The landscape of applications of proteomics to the study of cardiac amyloidoses and amyloid-related cardiotoxicity is summarized, with a critical synthesis of the major achievements. Expert commentary: Current strengths and limitations of proteomics in the clinical setting and in translational research on amyloid cardiomyopathy are discussed, with the foreseen potential future directions in the field.
Collapse
Affiliation(s)
- Francesca Lavatelli
- a Amyloidosis Research and Treatment Center , Fondazione IRCCS Policlinico San Matteo, and University of Pavia , Pavia , Italy
| | - Giampaolo Merlini
- a Amyloidosis Research and Treatment Center , Fondazione IRCCS Policlinico San Matteo, and University of Pavia , Pavia , Italy
| |
Collapse
|
|
45
|
Díaz-Balzac CA, Rahman M, Lázaro-Peña MI, Martin Hernandez LA, Salzberg Y, Aguirre-Chen C, Kaprielian Z, Bülow HE. Muscle- and Skin-Derived Cues Jointly Orchestrate Patterning of Somatosensory Dendrites. Curr Biol 2016; 26:2379-87. [PMID: 27451901 PMCID: PMC5021591 DOI: 10.1016/j.cub.2016.07.008] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2016] [Revised: 06/30/2016] [Accepted: 07/06/2016] [Indexed: 01/22/2023]
Abstract
Sensory dendrite arbors are patterned through cell-autonomously and non-cell-autonomously functioning factors [1-3]. Yet, only a few non-cell-autonomously acting proteins have been identified, including semaphorins [4, 5], brain-derived neurotrophic factors (BDNFs) [6], UNC-6/Netrin [7], and the conserved MNR-1/Menorin-SAX-7/L1CAM cell adhesion complex [8, 9]. This complex acts from the skin to pattern the stereotypic dendritic arbors of PVD and FLP somatosensory neurons in Caenorhabditis elegans through the leucine-rich transmembrane receptor DMA-1/LRR-TM expressed on PVD neurons [8, 9]. Here we describe a role for the diffusible C. elegans protein LECT-2, which is homologous to vertebrate leukocyte cell-derived chemotaxin 2 (LECT2)/Chondromodulin II. LECT2/Chondromodulin II has been implicated in a variety of pathological conditions [10-13], but the developmental functions of LECT2 have remained elusive. We find that LECT-2/Chondromodulin II is required for development of PVD and FLP dendritic arbors and can act as a diffusible cue from a distance to shape dendritic arbors. Expressed in body-wall muscles, LECT-2 decorates neuronal processes and hypodermal cells in a pattern similar to the cell adhesion molecule SAX-7/L1CAM. LECT-2 functions genetically downstream of the MNR-1/Menorin-SAX-7/L1CAM adhesion complex and upstream of the DMA-1 receptor. LECT-2 localization is dependent on SAX-7/L1CAM, but not on MNR-1/Menorin or DMA-1/LRR-TM, suggesting that LECT-2 functions as part of the skin-derived MNR-1/Menorin-SAX-7/L1CAM adhesion complex. Collectively, our findings suggest that LECT-2/Chondromodulin II acts as a muscle-derived, diffusible cofactor together with a skin-derived cell adhesion complex to orchestrate the molecular interactions of three tissues during patterning of somatosensory dendrites.
Collapse
Affiliation(s)
- Carlos A Díaz-Balzac
- Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
| | - Maisha Rahman
- Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
| | - María I Lázaro-Peña
- Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
| | | | - Yehuda Salzberg
- Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
| | - Cristina Aguirre-Chen
- Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
| | - Zaven Kaprielian
- Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
| | - Hannes E Bülow
- Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, 10461, USA; Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
| |
Collapse
|
|
46
|
Zheng H, Miyakawa T, Sawano Y, Asano A, Okumura A, Yamagoe S, Tanokura M. Crystal Structure of Human Leukocyte Cell-derived Chemotaxin 2 (LECT2) Reveals a Mechanistic Basis of Functional Evolution in a Mammalian Protein with an M23 Metalloendopeptidase Fold. J Biol Chem 2016; 291:17133-42. [PMID: 27334921 DOI: 10.1074/jbc.m116.720375] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2016] [Indexed: 01/19/2023] Open
Abstract
Human leukocyte cell-derived chemotaxin 2 (LECT2), which is predominantly expressed in the liver, is a multifunctional protein. LECT2 is becoming a potential therapeutic target for several diseases of worldwide concern such as rheumatoid arthritis, hepatocellular carcinoma, and obesity. Here, we present the crystal structure of LECT2, the first mammalian protein whose structure contains an M23 metalloendopeptidase fold. The LECT2 structure adopts a conserved Zn(II) coordination configuration but lacks a proposed catalytic histidine residue, and its potential substrate-binding groove is blocked in the vicinity of the Zn(II)-binding site by an additional intrachain loop at the N terminus. Consistent with these structural features, LECT2 was found to be catalytically inactive as a metalloendopeptidase against various types of peptide sequences, including pentaglycine. In addition, a surface plasmon resonance analysis demonstrated that LECT2 bound to the c-Met receptor with micromolar affinity. These results indicate that LECT2 likely plays its critical roles by acting as a ligand for the corresponding protein receptors rather than as an enzymatically active peptidase. The intrachain loop together with the pseudo-active site groove in LECT2 structure may be specific for interactions between LECT2 and receptors. Our study reveals a mechanistic basis for the functional evolution of a mammalian protein with an M23 metalloendopeptidase fold and potentially broadens the implications for the biological importance of noncatalytic peptidases in the M23 family.
Collapse
Affiliation(s)
- Hai Zheng
- From the Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan
| | - Takuya Miyakawa
- From the Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan
| | - Yoriko Sawano
- From the Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan, Department of Chemistry, College of Liberal Arts and Sciences, Tokyo Medical and Dental University, 2-8-30 Kounodai, Ichikawa-shi, Chiba 272-0827, Japan
| | - Atsuko Asano
- From the Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan
| | - Akinori Okumura
- Department of Diabetic Complications, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan, and
| | - Satoshi Yamagoe
- Department of Chemotherapy and Mycoses, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan
| | - Masaru Tanokura
- From the Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan,
| |
Collapse
|
|
47
|
Larsen CP, Beggs ML, Wilson JD, Lathrop SL. Prevalence and organ distribution of leukocyte chemotactic factor 2 amyloidosis (ALECT2) among decedents in New Mexico. Amyloid 2016; 23:119-23. [PMID: 26912093 PMCID: PMC4898138 DOI: 10.3109/13506129.2016.1145110] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Leukocyte chemotactic factor 2 (LECT2) amyloidosis is one of the most recently described types of amyloidosis. Since its description, it has been found to be one the most common types of amyloidosis in large series of amyloid cases involving the kidney and liver in the United States, where it primarily affects patients of Hispanic ethnicity. We sought to investigate the prevalence of this disease among Hispanic adult decedents who had an autopsy performed at the New Mexico Office of the Medical Investigator and determine the organ distribution of amyloid deposition. LECT2 amyloid deposits were identified within the kidney in 3.1% of Hispanic decedents. It was consistently deposited in the liver, spleen, adrenals, and lungs but did not involve the myocardium or brain. LECT2 amyloidosis is likely not rare among Hispanics in the Southwest United States and could represent an important but under-recognized etiology of chronic kidney disease in this population.
Collapse
Affiliation(s)
| | | | | | - Sarah L Lathrop
- b UNM Health Sciences Center, Office of the Medical Investigator , Albuquerque , NM , USA
| |
Collapse
|
|
48
|
Lavatelli F, di Fonzo A, Palladini G, Merlini G. Systemic amyloidoses and proteomics: The state of the art. EUPA OPEN PROTEOMICS 2016; 11:4-10. [PMID: 29900105 PMCID: PMC5988550 DOI: 10.1016/j.euprot.2016.02.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/10/2015] [Revised: 02/01/2016] [Accepted: 02/16/2016] [Indexed: 12/11/2022]
Abstract
Proteomics is an established approach for diagnostic amyloid typing. Mass spectrometry-based methods to analyze amyloid precursors have been developed. Proteomic studies are ongoing to identify novel biomarkers and clarify disease mechanisms. Systemic amyloidoses are caused by misfolding-prone proteins that polymerize in tissues, causing organ dysfunction. Since proteins are etiological agents of these diseases, proteomics was soon recognized as a privileged instrument for their investigation. Mass spectrometry-based proteomics has acquired a fundamental role in management of systemic amyloidoses, being now considered a gold standard approach for amyloid typing. In parallel, approaches for analyzing circulating amyloid precursors have been developed. Moreover, differential and functional proteomics hold promise for identifying novel biomarkers and clarifying disease mechanisms. This review discusses recent proteomics achievements in systemic amyloidoses, providing a perspective on its present and future applications.
Collapse
Affiliation(s)
- Francesca Lavatelli
- Amyloidosis Research and Treatment Center and Department of Molecular Medicine, Fondazione IRCCS Policlinico San Matteo and University of Pavia, Pavia, Italy
| | - Andrea di Fonzo
- Amyloidosis Research and Treatment Center and Department of Molecular Medicine, Fondazione IRCCS Policlinico San Matteo and University of Pavia, Pavia, Italy
| | - Giovanni Palladini
- Amyloidosis Research and Treatment Center and Department of Molecular Medicine, Fondazione IRCCS Policlinico San Matteo and University of Pavia, Pavia, Italy
| | - Giampaolo Merlini
- Amyloidosis Research and Treatment Center and Department of Molecular Medicine, Fondazione IRCCS Policlinico San Matteo and University of Pavia, Pavia, Italy.,Clinical Chemistry Laboratory, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| |
Collapse
|
|
49
|
Abstract
Immunoglobulin light chain amyloidosis (AL) is a rare, complex disease caused by misfolded free light chains produced by a usually small, indolent plasma cell clone. Effective treatments exist that can alter the natural history, provided that they are started before irreversible organ damage has occurred. The cornerstones of the management of AL amyloidosis are early diagnosis, accurate typing, appropriate risk-adapted therapy, tight follow-up, and effective supportive treatment. The suppression of the amyloidogenic light chains using the cardiac biomarkers as guide to choose chemotherapy is still the mainstay of therapy. There are exciting possibilities ahead, including the study of oral proteasome inhibitors, antibodies directed at plasma cell clone, and finally antibodies attacking the amyloid deposits are entering the clinic, offering unprecedented opportunities for radically improving the care of this disease.
Collapse
Affiliation(s)
- Angela Dispenzieri
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
- Division of Laboratory Medicine, Mayo Clinic, Rochester, MN, USA
| | - Giampaolo Merlini
- Amyloidosis Research and Treatment Center, Foundation IRCCS Policlinico San Matteo and Department of Molecular Medicine, University of Pavia, Pavia, Italy.
| |
Collapse
|
|
50
|
Angell TE, Swaika A, Sood N, Goldfarb M, Siddiqi I, Ailawadhi S. Localized LECT2 amyloidosis of the adrenal gland with coexisting MGUS: a diagnostic challenge. Ann Hematol 2015; 94:1603-4. [DOI: 10.1007/s00277-015-2419-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2015] [Accepted: 05/30/2015] [Indexed: 11/29/2022]
|