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Ursula Unterberger, Beate Eichelberger, Anja Ulz, Simon Panzer
In immune thrombocytopenia (ITP), antibodies reacting with platelet membrane glycoproteins (GP) mediate premature platelet cleavage, resulting in thrombocytopenia and therefore a risk of bleeding. These antibodies may induce complement activation, thus mediating complement-induced platelet destruction. In this study, we investigated the possibility of an additional complement-related pathogenic mechanism, where antibodies against the complement-regulatory factors CD55 and CD59 may directly interfere with normal complement function...
October 13, 2016: Platelets
Fengming Liu, Rupam Sahoo, Xiaowen Ge, Lin Wu, Pamela Ghosh, Xuebin Qin, Jose A Halperin
AIMS: Clinical and experimental evidence supports a strong link between the complement system, complement regulatory proteins and the pathogenesis of diabetes vascular complications. We previously reported that the complement regulatory protein CD59 is inactivated by glycation in humans with diabetes. Our objective for this study is to assess experimentally how the deficiency of CD59 impacts the development of diabetic atherosclerosis in vivo. METHODS: We crossed mCD59 sufficient and deficient mice into the ApoE(-/-) background to generate mCd59ab(+/+)/ApoE(-/-) and mCd59ab(-/-)/ApoE(-/-) mice, and induced diabetes by multiple low dose injections of streptozotocin...
August 28, 2016: Journal of Diabetes and its Complications
Peter Kraiczy
Overcoming the first line of the innate immune system is a general hallmark of pathogenic microbes to avoid recognition and to enter the human host. In particular, spirochetes belonging to the Borrelia burgdorferi sensu lato complex have developed various means to counter the immune response and to successfully survive in diverse host environments for a prolonged period of time. In regard to complement resistance, Borrelia utilize a plethora of immune evasion strategies involves capturing of host-derived complement regulators, terminating complement activation as well as shedding of cell-destroying complement complexes to manipulate and to expeditiously inhibit human complement...
2016: Frontiers in Immunology
Yoshiko Murakami
Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired GPI deficiency caused by somatic mutation of the PIGA gene in one or several hematopoietic stem cells. Recently, PNH caused by somatic mutation of one allele of the PIGT gene in combination with a germline mutation of the other allele was reported, showing that PIGA is not the only gene responsible for PNH, though other causes are rare. These mutant cells become GPI deficient, expand clonally and differentiate into all of the hematopoietic lineages. When GPI deficient erythrocytes increase in proportion, massive hemolysis occurs due to activated complement attack during infection...
2016: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Simon Edvardson, Yoshiko Murakami, Thi Tuyet Mai Nguyen, Maher Shahrour, Anik St-Denis, Avraham Shaag, Nadira Damseh, Françoise Le Deist, Yenan Bryceson, Bassam Abu-Libdeh, Philippe M Campeau, Taroh Kinoshita, Orly Elpeleg
BACKGROUND: Of our 1400 exome-studied patients, 67% originate from consanguineous families. ∼80% suffer from variable degree of intellectual disability (ID). The search for disease causing genes using homozygosity mapping was progressing slowly until 2010, then markedly accelerated by the introduction of exome analysis. OBJECTIVES: To identify the disease causing mutation(s) in three patients from two unrelated families who suffered from global developmental delay, severe ID and drug-responsive seizure disorder...
September 30, 2016: Journal of Medical Genetics
Daniela Viecceli, Mariana Pires Garcia, Laiana Schneider, Ana Paula Alegretti, Cristiano Kohler Silva, André Lucas Ribeiro, Claiton Viegas Brenol, Ricardo Machado Xavier
OBJECTIVES: To correlate the basal expression of complement regulatory proteins (CRPs) CD55, CD59, CD35, and CD46 in B-lymphocytes from the peripheral blood of a cohort of 10 patients with rheumatoid arthritis (RA) initiating treatment with rituximab (RTX) with depletion and time repopulation of such cells. METHODS: Ten patients with RA received two infusions of 1g of RTX with an interval of 14 days. Immunophenotypic analysis for the detection of CD55, CD59, CD35, and CD46 on B-lymphocytes was carried out immediately before the first infusion...
September 17, 2016: Revista Brasileira de Reumatologia
Zhi-Hai Sui, Mo-Fei Li, Li Sun
CD59 is a complement regulatory protein that inhibits the formation of membrane attack complex of complement. In this study, we examined the expression and activity of tongue sole (Cynoglossus semilaevis) CD59 (CsCD59). CsCD59 possesses the conserved structural features of CD59 and shares 33%-46% sequence identities with other fish CD59. Expression of CsCD59 was high in liver, spleen, and muscle, and was stimulated by infection of bacterial pathogens. Recombinant CsCD59 (rCsCD59) exhibited an apparent inhibition effect on the activation of tongue sole serum complement...
September 26, 2016: Fish & Shellfish Immunology
Lama Al-Faris, Monera Al-Rukhayes, Salah Al-Humood
OBJECTIVES: To investigate the pattern of CD55 and CD59 expression on RBCs of SCD patients, and its association with anemia, biochemical parameters of hemolysis, level of erythropoietin, and pro-inflammatory markers. METHODS: Flow cytometric analysis was performed on RBCs from 71 adult SCD patients and 53 healthy controls, using the commercial REDQUANT kit. RESULTS: CD59 deficiency was significantly higher among SCD patients than among healthy controls...
September 25, 2016: Hematology (Amsterdam, Netherlands)
E Raposio, S Bonomini, F Calderazzi
INTRODUCTION: Adipose tissue represents an abundant and accessible source of adult stem cells that can differentiate into cells and tissues of mesodermal origin, including osteogenic cells. METHODS: This paper describes the procedure to obtain a 5-cm(3) saline sample, containing the adipose-derived stem cells (ASCs) pellet, starting from lipoaspirate obtained from a conventional abdominal liposuction. RESULTS: A mean of 2.5×10(6) cells is isolated for each procedure; 35% (875000) of these are CD34+/CD45- cells, which express a subset of both positive (CD10, CD13, CD44, CD59, CD73, CD90, HLAABC) and negative (CD33, CD39, CD102, CD106, CD146, HLADR) cell-associated surface antigens, characterizing them as ASCs...
September 13, 2016: Orthopaedics & Traumatology, Surgery & Research: OTSR
Katsuyoshi Horibata, Akiko Ukai, Shigeo Ishikawa, Ayako Sugano, Masamitsu Honma
The recently introduced Pig-a in vivo gene mutation assay measures endogeneous mutations of Pig-a (human, PIG-A), an X-linked gene that is conserved across species from rodents to humans. Flow cytometric analysis enables the enumeration of glycosylphosphatidylinositol (GPI) anchor-deficient erythrocytes, resulting from a mutation in Pig-a/PIG-A, in only a few microliters of peripheral blood. Pig-a/PIG-A mutations appear to function in a neutral manner, allowing evaluation of the accumulated genotoxic effects of repeated exposures...
September 15, 2016: Mutation Research. Genetic Toxicology and Environmental Mutagenesis
Parul Choudhary, Paul John Whiting
Cell replacement and regenerative therapy using embryonic stem cell-derived material holds promise for the treatment of several pathologies. However, the safety of this approach is of prime importance given the teratogenic potential of residual stem cells, if present in the differentiated cell product. Using the example of embryonic stem cell-derived retinal pigment epithelium (RPE) for the treatment of age-related macular degeneration, we present a novel strategy for ensuring the absence of stem cells in the RPE population...
2016: Stem Cell Research & Therapy
Jean F Regal, Megan E Strehlke, Jenna M Peterson, Cameron R Wing, Jordan E Parker, Noel Fernando Nieto, Lynne T Bemis, Jeffrey S Gilbert, Sherry D Fleming
Preeclampsia is characterized by development of hypertension during pregnancy and reduced placental perfusion. Previous studies in a rat model of placental ischemia-induced hypertension demonstrated that inhibiting complement activation attenuated increased maternal blood pressure with C3a and C5a identified as the important products of complement activation. Given that in other forms of ischemia both natural IgM and antigen antibody complexes initiate complement activation, we hypothesized that placental ischemia exposes neoepitopes recognized by IgM to cause local complement activation and hypertension...
October 2016: Molecular Immunology
Yiyi Cao, Li Yang, Nannan Feng, Oumin Shi, Jing Xi, Xinyue You, Chunrong Yin, Huan Yang, Katsuyoshi Horibata, Masamitsu Honma, Biyun Qian, Wei Weng, Yang Luan
Erythrocyte-based PIG-A assay is sensitive and reliable in detecting exposure to mutagenetic agents in animal studies, but there are few data from human populations. In this study, we employed a method for detecting CD59 phenotypic variants, resulting from mutation in the PIG-A gene, in human red blood cells (RBCs), and determined the CD59-deficient RBC (RBC(CD59-) ) frequencies in 217 subjects from general population. The majority of subjects had a relatively low mutant frequencies (MFs) (average, 5.25 ± 3...
October 2016: Environmental and Molecular Mutagenesis
Dror Mevorach, Inna Reiner, Amir Grau, Uri Ilan, Yackov Berkun, Asaf Ta-Shma, Orly Elpeleg, Zamir Shorer, Shimon Edvardson, Adi Tabib
Objectives To report the outcome of eculizumab treatment in pediatric patients with recurrent acute predominantly motor, demyelinating neuropathy with conduction block, and chronic hemolysis due to p.Cys89Tyr mutation in the CD59 gene. Methods Four patients were recruited from our new registry of patients with homozygosity for the p.Cys89Tyr mutation on CD59. Participants received repeated intravenous eculizumab. In this 24-month open-label phase IIa study we aimed to determine whether eculizumab reduces chronic hemolysis, and cumulative doses of steroids and IV immunoglobulin (IgG), and ameliorates neurological deficits, compared to pre-treatment status...
August 29, 2016: Annals of Neurology
Wayne J Hawthorne, Andrew M Lew, Helen E Thomas
PURPOSE OF REVIEW: Despite the benefits of islet and pancreas allotransplantation, their widespread use in type 1 diabetes is limited because of the paucity of suitable donors. Porcine xenotransplantation offers an alternative, and advances in genetic modification of pigs have opened up new potential for its clinical use. This review outlines the barriers to successful islet xenotransplantation, and genetic modifications that have been tested to overcome these. RECENT FINDINGS: Islets from pigs lacking α1,3-galactosyltransferase, to prevent hyperacute rejection, are now used as a background strain for further genetic modifications...
October 2016: Current Opinion in Organ Transplantation
Sara L Lawrence, Michael A Gorman, Susanne C Feil, Terrence D Mulhern, Michael J Kuiper, Adam J Ratner, Rodney K Tweten, Craig J Morton, Michael W Parker
Cholesterol-dependent cytolysins (CDCs) are a family of pore-forming toxins that punch holes in the outer membrane of eukaryotic cells. Cholesterol serves as the receptor, but a subclass of CDCs first binds to human CD59. Here we describe the crystal structures of vaginolysin and intermedilysin complexed to CD59. These studies, together with small-angle X-ray scattering, reveal that CD59 binds to each at different, though overlapping, sites, consistent with molecular dynamics simulations and binding studies...
September 6, 2016: Structure
Tanapol Phondeechareon, Methichit Wattanapanitch, Yaowalak U-Pratya, Chanapa Damkham, Nuttha Klincumhom, Chanchao Lorthongpanich, Pakpoom Kheolamai, Chuti Laowtammathron, Surapol Issaragrisil
Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hemolytic anemia caused by lack of CD55 and CD59 on blood cell membrane leading to increased sensitivity of blood cells to complement. Hematopoietic stem cell transplantation (HSCT) is the only curative therapy for PNH, however, lack of HLA-matched donors and post-transplant complications are major concerns. Induced pluripotent stem cells (iPSCs) derived from patients are an attractive source for generating autologous HSCs to avoid adverse effects resulting from allogeneic HSCT...
October 2016: Annals of Hematology
Lucyna Kapka-Skrzypczak, Sylwia Popek, Krzysztof Sawicki, Ewa Wolińska, Magdalena Czajka, Maciej Skrzypczak
The aim of the present study was to evaluate the role of interleukin (IL)-6 and IL-8 on the expression of the membrane-bound complement inhibitors membrane attack complex-inhibitory protein (CD59) and decay-accelerating factor (CD55), in the human ovarian carcinoma A2780 cell line, which is a non-producing IL-6 cell line that does exhibit IL-6 responsiveness, due to the presence of IL-6 receptors. Extracellular levels of complement system inhibitors were evaluated by western blotting and reverse transcription-quantitative polymerase chain reaction...
August 2016: Oncology Letters
Xiaoyan Fu, Jiyu Ju, Zhijuan Lin, Weiling Xiao, Xiaofang Li, Baoxiang Zhuang, Tingting Zhang, Xiaojun Ma, Xiangyu Li, Chao Ma, Weiliang Su, Yuqi Wang, Xuebin Qin, Shujuan Liang
Terminal complement membrane attack complex (MAC) formation is induced initially by C5b, followed by the sequential condensation of the C6, C7, C8. Polymerization of C9 to the C5b-8 complex forms the C5b-9 (or MAC). The C5b-9 forms lytic or non lytic pores in the cell membrane destroys membrane integrity. The biological functionalities of MAC has been previously investigated by using either the mice deficient in C5 and C6, or MAC's regulator CD59. However, there is no available C9 deficient mice (mC9(-/-)) for directly dissecting the role of C5b-9 in the pathogenesis of human diseases...
2016: Scientific Reports
Li Xuan Tan, Kimberly A Toops, Aparna Lakkaraju
The retinal pigment epithelium (RPE) is a key site of injury in inherited and age-related macular degenerations. Abnormal activation of the complement system is a feature of these blinding diseases, yet how the RPE combats complement attack is poorly understood. The complement cascade terminates in the cell-surface assembly of membrane attack complexes (MACs), which promote inflammation by causing aberrant signal transduction. Here, we investigated mechanisms crucial for limiting MAC assembly and preserving cellular integrity in the RPE and asked how these are compromised in models of macular degeneration...
August 2, 2016: Proceedings of the National Academy of Sciences of the United States of America
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