The Experts below are selected from a list of 1758924 Experts worldwide ranked by ideXlab platform
Jose A Halperin - One of the best experts on this subject based on the ideXlab platform.
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glycation of the complement regulatory protein CD59 is a novel biomarker for glucose handling in humans
The Journal of Clinical Endocrinology and Metabolism, 2014Co-Authors: Pamela Ghosh, Rupam Sahoo, Anand Vaidya, Allison B Goldfine, Neil Herring, Lynn Bry, Michael Chorev, Jose A HalperinAbstract:Context: Human CD59, an inhibitor of the membrane attack complex of complement, is inactivated by glycation. Glycation inactivation of CD59 enhances complement-mediated injury in target organs of diabetes complications. Objective: We hypothesized that circulating soluble glycated CD59 (GCD59) represents a novel biomarker of blood glucose handling and aimed to conduct human study protocols to test this hypothesis. Design, Setting, Participants, and Outcome Measures: Using a newly developed ELISA, we measured circulating soluble GCD59 in samples from 3 separate human studies evaluating acute and chronic glucose handling and glucose responses to insulin therapy. Study 1 (normal vs diabetic subjects) evaluated the cross-sectional association between GCD59 and glycated hemoglobin (HbA1c) in 400 subjects with and without type 2 diabetes. Study 2 (oral glucose tolerance test [OGTT] in nondiabetics) evaluated whether fasting GCD59 independently predicted the 2-hour glucose response to an OGTT in 109 subjects with...
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daf cd55 and protectin CD59 modulate adaptive immunity and disease outcome in experimental autoimmune myasthenia gravis
Journal of Neuroimmunology, 2012Co-Authors: Jindrich Soltys, Jose A Halperin, Qin XuebinAbstract:The role of regulators of complement activity (RCA) involving CD55 and CD59 in the pathogenesis of experimental autoimmune myasthenia gravis (EAMG) remains unclear. CD55 and CD59 restrict complement activation by inhibiting C3/C5 convertases' activities and membrane attack complex formation, respectively. Actively immunized EAMG mice deficient in either CD55 or CD59 showed significant differences in adaptive immune responses and worsened disease outcome associated with increased levels of serum cytokines, modified production of acetylcholine receptor antibodies, and more complement deposition at the neuromuscular junction. We conclude that modulation of complement activity by RCA represents an alternative in controlling of autoimmune processes in EAMG.
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human CD59 inhibitor sensitizes rituximab resistant lymphoma cells to complement mediated cytolysis
Cancer Research, 2011Co-Authors: Tao You, Jose A Halperin, Michael Chorev, Jinyan Zhang, Zhihai Peng, Bertal H Aktas, Jennifer R Brown, Xuebin QinAbstract:Rituximab efficacy in cancer therapy depends in part on induction of complement-dependent cytotoxicity (CDC). Human CD59 (hCD59) is a key complement regulatory protein that restricts the formation of the membrane attack complex, thereby inhibiting induction of CDC. hCD59 is highly expressed in B-cell non-Hodgkin's lymphoma (NHL) and up-regulation of hCD59 is an important determinant of the sensitivity of NHL cells to rituximab treatment. Here we report that the potent hCD59 inhibitor rILYd4 enhances CDC in vitro and in vivo, thereby sensitizing rituximab-resistant lymphoma cells and primary chronic lymphocytic leukemia cells (CLL) to rituximab treatment. By defining PK/PD profiles of rILYd4 in mice, we showed that by itself rILYd4 does not adversely mediate in vivo hemolysis of hCD59-expressing erythrocytes. Increasing expression levels of the complement regulators CD59 and CD55 in rituximab-resistant cells occurs due to selection of pre-existing clones, rather than de novo induction of these proteins. Moreover, lymphoma cells overexpressing CD59 were directly responsible for the resistance to rituximab-mediated CDC therapy. Our results rationalize the use of rILYd4 as a therapeutic adjuvant for rituximab treatment of rituximab-resistant lymphoma and CLL. Further, they suggest that preemptive elimination of CD59 overexpressing subpopulations along with rituximab treatment may be a useful approach to ablate or conquer rituximab resistance.
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analysis of the promoters and 5 utr of mouse CD59 genes and of their functional activity in erythrocytes
Genes and Immunity, 2006Co-Authors: Xuebin Qin, Jose A Halperin, Sean P Ferris, F Guo, Gudrun ZiegelerAbstract:The complement regulatory protein CD59 inhibits formation of the membrane attack complex (MAC), the terminal effector of the complement system. There are two mouse CD59 genes in mice but only one in humans. In the work reported here we (a) mapped the promoter regions of both mCD59a and mCD59b genes, (b) identified two different promoters for each mCD59 gene, (c) defined a previously unrecognized additional exon 1 in each mCD59 gene, (d) identified that each mCD59 gene expresses two different tissue-specific transcripts that differ in their 5'-UTR, and (e) confirmed the presence of mCD59b mRNA in multiple tissues. At the functional level, comparison of the sensitivity of mCD59ab(-/-) and mCD59a(-/-) red blood cells to MAC-mediated lysis revealed that mCD59b protects RBC from MAC-mediated lysis, at least in the setting of mCD59a deficiency. Together these findings indicate that the mCD59 genes may have complex and perhaps different regulatory mechanisms in different tissues.
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glycation inactivation of the complement regulatory protein CD59 a possible role in the pathogenesis of the vascular complications of human diabetes
Diabetes, 2004Co-Authors: Xuebin Qin, Allison B Goldfine, Michael Chorev, Nicole Krumrei, Luciano Grubissich, Juan A Acosta, Arthur P Hays, Jose A HalperinAbstract:Micro- and macrovascular diseases are major causes of morbidity and mortality in the diabetic population, but the cellular and molecular mechanisms that link hyperglycemia to these complications remain incompletely understood. We proposed that in human diabetes, inhibition by glycation of the complement regulatory protein CD59 increases deposition of the membrane attack complex (MAC) of complement, contributing to the higher vascular risk. We report here 1) the generation and characterization of an anti-glycated human CD59 (hCD59) specific antibody, 2) the detection with this antibody of glycated hCD59 colocalized with MAC in kidneys and nerves from diabetic but not from nondiabetic subjects, and 3) a significantly reduced activity of hCD59 in erythrocytes from diabetic subjects, a finding consistent with glycation inactivation of hCD59 in vivo. Because hCD59 acts as a specific inhibitor of MAC formation, these findings provide a molecular explanation for the increased MAC deposition reportedly found in the target organs of diabetic complications. We conclude that glycation inactivation of hCD59 that leads to increased MAC deposition may contribute to the extensive vascular pathology that complicates human diabetes.
Wenchao Song - One of the best experts on this subject based on the ideXlab platform.
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absence of CD59 exacerbates systemic autoimmunity in mrl lpr mice
Journal of Immunology, 2012Co-Authors: Takashi Miwa, Lin Zhou, Michael A Maldonado, Michael P Madaio, Robert A Eisenberg, Wenchao SongAbstract:CD59 is a GPI-anchored membrane regulator of complement expressed on blood cells as well as peripheral tissues. It protects host cells from complement injury by inhibiting formation of the membrane attack complex. Recent studies in mice have suggested also a role of CD59 in T cell immune response that was mechanistically independent of complement. In the present study, we investigated the function of CD59 in the MRL/lpr model of murine lupus. We backcrossed the CD59a knockout (CD59a−/−) mouse onto the MRL/lpr background and compared CD59a+/+-MRL/lpr and CD59a−/−-MRL/lpr littermates for the development of systemic autoimmunity. We found that CD59a deficiency significantly exacerbated the skin disease and lymphoproliferation characteristic of MRL/lpr mice. It also increased autoantibody titers and caused a higher level of proteinuria in male MRL/lpr mice. Bone marrow transfer experiments indicated that CD59a expression on both bone marrow–derived cells and peripheral tissues played a role in lymphoproliferation, whereas the skin disease phenotype is determined mainly by local CD59a expression. Importantly, C3 gene deletion or C5 neutralization with a blocking mAb in CD59a−/−-MRL/lpr mice did not rescue the proautoimmune phenotype associated with CD59a deficiency. These results together suggest that CD59a inhibits systemic autoimmunity in MRL/lpr mice through a complement-independent mechanism.
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critical protection from renal ischemia reperfusion injury by cd55 and CD59
Journal of Immunology, 2004Co-Authors: Koei Yamada, Takashi Miwa, Jianuo Liu, Masaomi Nangaku, Wenchao SongAbstract:Renal ischemia-reperfusion injury (IRI) is a feature of ischemic acute renal failure and it impacts both short- and long-term graft survival after kidney transplantation. Complement activation has been implicated in renal IRI, but its mechanism of action is uncertain and the determinants of complement activation during IRI remain poorly understood. We engineered mice deficient in two membrane complement regulatory proteins, CD55 and CD59, and used them to investigate the role of these endogenous complement inhibitors in renal IRI. CD55-deficient (CD55(-/-)), but not CD59-deficient (CD59(-/-)), mice exhibited increased renal IRI as indicated by significantly elevated blood urea nitrogen levels, histological scores, and neutrophil infiltration. Remarkably, although CD59 deficiency alone was inconsequential, CD55/CD59 double deficiency greatly exacerbated IRI. Severe IRI in CD55(-/-)CD59(-/-) mice was accompanied by endothelial deposition of C3 and the membrane attack complex (MAC) and medullary capillary thrombosis. Complement depletion in CD55(-/-)CD59(-/-) mice with cobra venom factor prevented these effects. Thus, CD55 and CD59 act synergistically to inhibit complement-mediated renal IRI, and abrogation of their function leads to MAC-induced microvascular injury and dysfunction that may exacerbate the initial ischemic assault. Our findings suggest a rationale for anti-complement therapies aimed at preventing microvascular injury during ischemia reperfusion, and the CD55(-/-)CD59(-/-) mouse provides a useful animal model in this regard.
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identification and functional characterization of a new gene encoding the mouse terminal complement inhibitor CD59
Journal of Immunology, 2000Co-Authors: Yueming Qian, Xuebin Qin, Takashi Miwa, Xiujun Sun, Jose A Halperin, Wenchao SongAbstract:CD59 is a 18- to 20-kDa, GPI-anchored membrane protein that functions as a key regulator of the terminal step of the complement activation cascade. It restricts binding of C9 to the C5b-8 complex, thereby preventing the formation of the membrane attack complex (C5b-9 of complement). A single human CD59 gene has been identified, and corresponding genetic homologues from rat, mouse, and pig have been characterized in previous studies. In this study, we report the discovery and functional characterization of a separate CD59 gene in the mouse (referred to as CD59b, the previously characterized mouse CD59 gene as CD59a). Mouse CD59b is 85% and 63% identical to CD59a at the nucleotide and amino acid level, respectively. In cDNA transfection experiments with Chinese hamster ovary cells, peptide-tagged CD59b was detected on the cell surface by flow cytometry and was shown to be susceptible to phosphatidylinositol-specific phospholipase C cleavage. Chinese hamster ovary cells expressing CD59b were significantly more resistant than control cells to human and mouse complement-mediated lysis. These results suggest that CD59b encodes a GPI-anchored protein that is functionally active as a membrane attack complex inhibitor. Northern blot analysis revealed that CD59b is expressed selectively in the mouse testis. In contrast, the major transcript of CD59a was shown to be expressed at high levels in the heart, kidney, liver, and lung, but only minimally in the testis. These results revealed the existence of two distinct CD59 genes in the mouse that are differentially regulated and that may have nonoverlapping physiological functions in vivo.
Xuebin Qin - One of the best experts on this subject based on the ideXlab platform.
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human CD59 inhibitor sensitizes rituximab resistant lymphoma cells to complement mediated cytolysis
Cancer Research, 2011Co-Authors: Tao You, Jose A Halperin, Michael Chorev, Jinyan Zhang, Zhihai Peng, Bertal H Aktas, Jennifer R Brown, Xuebin QinAbstract:Rituximab efficacy in cancer therapy depends in part on induction of complement-dependent cytotoxicity (CDC). Human CD59 (hCD59) is a key complement regulatory protein that restricts the formation of the membrane attack complex, thereby inhibiting induction of CDC. hCD59 is highly expressed in B-cell non-Hodgkin's lymphoma (NHL) and up-regulation of hCD59 is an important determinant of the sensitivity of NHL cells to rituximab treatment. Here we report that the potent hCD59 inhibitor rILYd4 enhances CDC in vitro and in vivo, thereby sensitizing rituximab-resistant lymphoma cells and primary chronic lymphocytic leukemia cells (CLL) to rituximab treatment. By defining PK/PD profiles of rILYd4 in mice, we showed that by itself rILYd4 does not adversely mediate in vivo hemolysis of hCD59-expressing erythrocytes. Increasing expression levels of the complement regulators CD59 and CD55 in rituximab-resistant cells occurs due to selection of pre-existing clones, rather than de novo induction of these proteins. Moreover, lymphoma cells overexpressing CD59 were directly responsible for the resistance to rituximab-mediated CDC therapy. Our results rationalize the use of rILYd4 as a therapeutic adjuvant for rituximab treatment of rituximab-resistant lymphoma and CLL. Further, they suggest that preemptive elimination of CD59 overexpressing subpopulations along with rituximab treatment may be a useful approach to ablate or conquer rituximab resistance.
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analysis of the promoters and 5 utr of mouse CD59 genes and of their functional activity in erythrocytes
Genes and Immunity, 2006Co-Authors: Xuebin Qin, Jose A Halperin, Sean P Ferris, F Guo, Gudrun ZiegelerAbstract:The complement regulatory protein CD59 inhibits formation of the membrane attack complex (MAC), the terminal effector of the complement system. There are two mouse CD59 genes in mice but only one in humans. In the work reported here we (a) mapped the promoter regions of both mCD59a and mCD59b genes, (b) identified two different promoters for each mCD59 gene, (c) defined a previously unrecognized additional exon 1 in each mCD59 gene, (d) identified that each mCD59 gene expresses two different tissue-specific transcripts that differ in their 5'-UTR, and (e) confirmed the presence of mCD59b mRNA in multiple tissues. At the functional level, comparison of the sensitivity of mCD59ab(-/-) and mCD59a(-/-) red blood cells to MAC-mediated lysis revealed that mCD59b protects RBC from MAC-mediated lysis, at least in the setting of mCD59a deficiency. Together these findings indicate that the mCD59 genes may have complex and perhaps different regulatory mechanisms in different tissues.
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glycation inactivation of the complement regulatory protein CD59 a possible role in the pathogenesis of the vascular complications of human diabetes
Diabetes, 2004Co-Authors: Xuebin Qin, Allison B Goldfine, Michael Chorev, Nicole Krumrei, Luciano Grubissich, Juan A Acosta, Arthur P Hays, Jose A HalperinAbstract:Micro- and macrovascular diseases are major causes of morbidity and mortality in the diabetic population, but the cellular and molecular mechanisms that link hyperglycemia to these complications remain incompletely understood. We proposed that in human diabetes, inhibition by glycation of the complement regulatory protein CD59 increases deposition of the membrane attack complex (MAC) of complement, contributing to the higher vascular risk. We report here 1) the generation and characterization of an anti-glycated human CD59 (hCD59) specific antibody, 2) the detection with this antibody of glycated hCD59 colocalized with MAC in kidneys and nerves from diabetic but not from nondiabetic subjects, and 3) a significantly reduced activity of hCD59 in erythrocytes from diabetic subjects, a finding consistent with glycation inactivation of hCD59 in vivo. Because hCD59 acts as a specific inhibitor of MAC formation, these findings provide a molecular explanation for the increased MAC deposition reportedly found in the target organs of diabetic complications. We conclude that glycation inactivation of hCD59 that leads to increased MAC deposition may contribute to the extensive vascular pathology that complicates human diabetes.
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identification and functional characterization of a new gene encoding the mouse terminal complement inhibitor CD59
Journal of Immunology, 2000Co-Authors: Yueming Qian, Xuebin Qin, Takashi Miwa, Xiujun Sun, Jose A Halperin, Wenchao SongAbstract:CD59 is a 18- to 20-kDa, GPI-anchored membrane protein that functions as a key regulator of the terminal step of the complement activation cascade. It restricts binding of C9 to the C5b-8 complex, thereby preventing the formation of the membrane attack complex (C5b-9 of complement). A single human CD59 gene has been identified, and corresponding genetic homologues from rat, mouse, and pig have been characterized in previous studies. In this study, we report the discovery and functional characterization of a separate CD59 gene in the mouse (referred to as CD59b, the previously characterized mouse CD59 gene as CD59a). Mouse CD59b is 85% and 63% identical to CD59a at the nucleotide and amino acid level, respectively. In cDNA transfection experiments with Chinese hamster ovary cells, peptide-tagged CD59b was detected on the cell surface by flow cytometry and was shown to be susceptible to phosphatidylinositol-specific phospholipase C cleavage. Chinese hamster ovary cells expressing CD59b were significantly more resistant than control cells to human and mouse complement-mediated lysis. These results suggest that CD59b encodes a GPI-anchored protein that is functionally active as a membrane attack complex inhibitor. Northern blot analysis revealed that CD59b is expressed selectively in the mouse testis. In contrast, the major transcript of CD59a was shown to be expressed at high levels in the heart, kidney, liver, and lung, but only minimally in the testis. These results revealed the existence of two distinct CD59 genes in the mouse that are differentially regulated and that may have nonoverlapping physiological functions in vivo.
Peter J Cowan - One of the best experts on this subject based on the ideXlab platform.
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overexpression of human cd55 and CD59 or treatment with human cd55 protects against renal ischemia reperfusion injury in mice
Journal of Immunology, 2017Co-Authors: Anjan K Bongoni, E Salvaris, Veena Roberts, Doreen Fang, Jennifer L Mcrae, Nella Fisicaro, Karen M Dwyer, Peter J CowanAbstract:Deficiency in the membrane-bound complement regulators CD55 and CD59 exacerbates renal ischemia-reperfusion injury (IRI) in mouse models, but the effect of increasing CD55 and CD59 activity has not been examined. In this study, we investigated the impact of overexpression of human (h) CD55 ± hCD59 or treatment with soluble rhCD55 in a mouse model of renal IRI. Unilaterally nephrectomised mice were subjected to 18 (mild IRI) or 22 min (moderate IRI) warm renal ischemia, and analyzed 24 h after reperfusion for renal function (serum creatinine and urea), complement deposition (C3b/c and C9), and infiltration of neutrophils and macrophages. Transgenic mice expressing hCD55 alone were protected against mild renal IRI, with reduced creatinine and urea levels compared with wild type littermates. However, the renal function of the hCD55 mice was not preserved in the moderate IRI model, despite a reduction in C3b/c and C9 deposition and innate cell infiltration. Mice expressing both hCD55 and hCD59, on the other hand, were protected in the moderate IRI model, with significant reductions in all parameters measured. Wild type mice treated with rhCD55 immediately after reperfusion were also protected in the moderate IRI model. Thus, manipulation of CD55 activity to increase inhibition of the C3 and C5 convertases is protective against renal IRI, and the additional expression of hCD59, which regulates the terminal complement pathway, provides further protection. Therefore, anti-complement therapy using complement regulatory proteins may provide a potential clinical option for preventing tissue and organ damage in renal IRI.
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High‐level co‐expression of complement regulators on vascular endothelium in transgenic mice: CD55 and CD59 provide greater protection from human complement‐mediated injury than CD59 alone
Xenotransplantation, 1998Co-Authors: Peter J Cowan, Trixie A. Shinkel, Atousa Aminian, Margarita Romanella, P. L. Wigley, Andrew Lonie, Mark B. Nottle, Martin J. Pearse, Anthony J. F. D'apiceAbstract:High-level endothelial expression of the human complement regulatory factor CD59 has been shown to protect transgenic mouse hearts from human complement-mediated injury in an ex vivo perfusion model. In this study we examine whether co-expression of CD55 provides additional protection. CD55/CD59 double-transgenic mice were generated by co-injection of CD55 and CD59 expression constructs driven by the human intercellular adhesion molecule 2 (ICAM-2) promoter. A line was established from one mouse that exhibited strong expression of CD55 and CD59 on vascular endothelium in the heart and other transplantable organs. An ex vivo perfusion model was used to compare hearts from these CD55/CD59 mice with hearts from a previously established line, which expressed CD59 at a similar level to the double transgenic line. CD59 hearts displayed prolonged survival compared to wild-type hearts during perfusion with 40% human plasma and maintained approximately 20% maximum work after 60 min. CD55/CD59 hearts were further protected, with work maintained at 35% of the maximum level after 60 min. The data demonstrate that high-level endothelial co-expression of CD55 and CD59 provides greater protection from human complement-mediated injury in this model than expression of CD59 alone.
Michael Chorev - One of the best experts on this subject based on the ideXlab platform.
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glycation of the complement regulatory protein CD59 is a novel biomarker for glucose handling in humans
The Journal of Clinical Endocrinology and Metabolism, 2014Co-Authors: Pamela Ghosh, Rupam Sahoo, Anand Vaidya, Allison B Goldfine, Neil Herring, Lynn Bry, Michael Chorev, Jose A HalperinAbstract:Context: Human CD59, an inhibitor of the membrane attack complex of complement, is inactivated by glycation. Glycation inactivation of CD59 enhances complement-mediated injury in target organs of diabetes complications. Objective: We hypothesized that circulating soluble glycated CD59 (GCD59) represents a novel biomarker of blood glucose handling and aimed to conduct human study protocols to test this hypothesis. Design, Setting, Participants, and Outcome Measures: Using a newly developed ELISA, we measured circulating soluble GCD59 in samples from 3 separate human studies evaluating acute and chronic glucose handling and glucose responses to insulin therapy. Study 1 (normal vs diabetic subjects) evaluated the cross-sectional association between GCD59 and glycated hemoglobin (HbA1c) in 400 subjects with and without type 2 diabetes. Study 2 (oral glucose tolerance test [OGTT] in nondiabetics) evaluated whether fasting GCD59 independently predicted the 2-hour glucose response to an OGTT in 109 subjects with...
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a specific and sensitive assay for blood levels of glycated CD59 a novel biomarker for diabetes
American Journal of Hematology, 2013Co-Authors: Pamela Ghosh, Rupam Sahoo, Anand Vaidya, Sonia Cantel, Amol Kavishwar, Allison B Goldfine, Neil Herring, Lynn Bry, Michael ChorevAbstract:Increasing evidence links the complement system with complications of human diabetes. The complement regulatory protein CD59, an inhibitor of formation of membrane attack complex (MAC), is inhibited by hyperglycemia-induced glycation fostering increased deposition of MAC, a major effector of complement-mediated tissue damage. CD59, an ubiquitous GPI-anchored membrane protein, is shed from cell membranes by phospholipases generating a soluble form present in blood and urine. We established an enzyme-linked immunosorbent assay (ELISA) to measure serum/plasma glycated human CD59 (hCD59) (GCD59) and evaluated its potential as a diabetes biomarker. We used a synthetic peptide strategy to generate (a) a mouse monoclonal antibody to capture hCD59, (b) a rabbit monoclonal antibody to detect GCD59, and (c) a GCD59 surrogate for assay standardization. ELISA conditions were optimized for precision, reproducibility, and clinical sensitivity. The clinical utility of the assay was initially evaluated in 24 subjects with or without diabetes and further validated in a study that included 100 subjects with and 90 subjects without a diagnosis of diabetes. GCD59 (a) was significantly higher in individuals with than in individual without diabetes, (b) was independently associated with HbA1c, and (c) identified individuals with diabetes with high specificity and sensitivity. We report the development and standardization of a novel, sensitive, and specific ELISA for measuring GCD59 in blood. The assay distinguished individuals with diabetes from those without, and showed strong correlation between GCD59 and HbA1c. Because GCD59 likely contributes to the pathogenesis of diabetes complications, measurement of blood levels of GCD59 may be useful in the diagnosis and management of diabetes.
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human CD59 inhibitor sensitizes rituximab resistant lymphoma cells to complement mediated cytolysis
Cancer Research, 2011Co-Authors: Tao You, Jose A Halperin, Michael Chorev, Jinyan Zhang, Zhihai Peng, Bertal H Aktas, Jennifer R Brown, Xuebin QinAbstract:Rituximab efficacy in cancer therapy depends in part on induction of complement-dependent cytotoxicity (CDC). Human CD59 (hCD59) is a key complement regulatory protein that restricts the formation of the membrane attack complex, thereby inhibiting induction of CDC. hCD59 is highly expressed in B-cell non-Hodgkin's lymphoma (NHL) and up-regulation of hCD59 is an important determinant of the sensitivity of NHL cells to rituximab treatment. Here we report that the potent hCD59 inhibitor rILYd4 enhances CDC in vitro and in vivo, thereby sensitizing rituximab-resistant lymphoma cells and primary chronic lymphocytic leukemia cells (CLL) to rituximab treatment. By defining PK/PD profiles of rILYd4 in mice, we showed that by itself rILYd4 does not adversely mediate in vivo hemolysis of hCD59-expressing erythrocytes. Increasing expression levels of the complement regulators CD59 and CD55 in rituximab-resistant cells occurs due to selection of pre-existing clones, rather than de novo induction of these proteins. Moreover, lymphoma cells overexpressing CD59 were directly responsible for the resistance to rituximab-mediated CDC therapy. Our results rationalize the use of rILYd4 as a therapeutic adjuvant for rituximab treatment of rituximab-resistant lymphoma and CLL. Further, they suggest that preemptive elimination of CD59 overexpressing subpopulations along with rituximab treatment may be a useful approach to ablate or conquer rituximab resistance.
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glycation inactivation of the complement regulatory protein CD59 a possible role in the pathogenesis of the vascular complications of human diabetes
Diabetes, 2004Co-Authors: Xuebin Qin, Allison B Goldfine, Michael Chorev, Nicole Krumrei, Luciano Grubissich, Juan A Acosta, Arthur P Hays, Jose A HalperinAbstract:Micro- and macrovascular diseases are major causes of morbidity and mortality in the diabetic population, but the cellular and molecular mechanisms that link hyperglycemia to these complications remain incompletely understood. We proposed that in human diabetes, inhibition by glycation of the complement regulatory protein CD59 increases deposition of the membrane attack complex (MAC) of complement, contributing to the higher vascular risk. We report here 1) the generation and characterization of an anti-glycated human CD59 (hCD59) specific antibody, 2) the detection with this antibody of glycated hCD59 colocalized with MAC in kidneys and nerves from diabetic but not from nondiabetic subjects, and 3) a significantly reduced activity of hCD59 in erythrocytes from diabetic subjects, a finding consistent with glycation inactivation of hCD59 in vivo. Because hCD59 acts as a specific inhibitor of MAC formation, these findings provide a molecular explanation for the increased MAC deposition reportedly found in the target organs of diabetic complications. We conclude that glycation inactivation of hCD59 that leads to increased MAC deposition may contribute to the extensive vascular pathology that complicates human diabetes.