Unique Expression of HRF20 (CD59) in Human Nervous Tissue

Akatsu, Hiroyasu; Yamada, Tatsuo; Okada, Noriko; Yamamoto, Takayuki; Yamashina, Manabu; Okada, Hidechika

doi:10.1111/j.1348-0421.1997.tb01208.x

Cited by 10 publications

(4 citation statements)

References 35 publications

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“…CD59 is a much smaller protein with no sequence or structural resemblance to the RCA family of proteins [27]. Several lines of evidence from human and animal studies indicate that CD59 is more relevant than CD55 and CD46 in protecting normal cells from MAC formation and MACinduced phenomena [37][38][39][40][41][42].…”

Section: Cdc the Complement Systemmentioning

confidence: 99%

The Role of Complement in the Mechanism of Action of Rituximab for B-Cell Lymphoma: Implications for Therapy

2008

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Rituximab, a genetically engineered chimeric monoclonal antibody specifically binding to CD20, was the first antibody approved by the U.S. Food and Drug Administration for the treatment of cancer. Rituximab significantly improves treatment outcome in relapsed or refractory, low-grade or follicular B-cell nonHodgkin's lymphoma (NHL). However, there are also some challenges for us to overcome: why ϳ50% of patients are unresponsive to rituximab in spite of the expression of CD20, and why some responsive patients develop resistance to further treatment. Although the antitumor mechanisms of rituximab are not completely understood, several distinct antitumor activities of rituximab have been suspected, including complementdependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), apoptosis, and direct growth arrest. To counteract resistance to rituximab therapy, several strategies have been developed to: (a) augment the CDC effect by increasing CD20 expression, heteroconjugating rituximab to cobra venom factor and C3b, and inhibiting membrane complement regulatory protein, especially CD59, function; (b) enhance the ADCC effect through some immunomodulatory cytokines and CR3-binding ␤-glucan; and (c) reduce the apoptotic threshold or induce apoptotic signaling on the tumor. Extensive studies indicate that rituximab combined with these approaches is more effective than a single rituximab approach. Herein, the mechanism of action of and resistance to rituximab therapy in B-cell NHL, in particular, the involvement of the complement system, are extensively reviewed. The Oncologist 2008;13: 954 -966

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Section: Cdc the Complement Systemmentioning

confidence: 99%

The Role of Complement in the Mechanism of Action of Rituximab for B-Cell Lymphoma: Implications for Therapy

2008

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“…Downregulation of CD55 and upregulation of C3/C5 convertase would favour complement-mediated immunopathogenic lesions in the CNS [174]. In the normal CNS CD55 is found on capillary endothelial cells although in the PNS it is expressed by Schwann cells [175]. We do not as yet know if CNS glial cells are able to express DAF under any conditions.…”

Section: Complement Pathway Componentsmentioning

confidence: 99%

Differential effects of Th1, monocyte/macrophage and Th2 cytokine mixtures on early gene expression for immune-related molecules by central nervous system mixed glial cell cultures

et al. 2006

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Cytokines secreted within the central nervous system (CNS) are important in the development of multiple sclerosis (MS) lesions. The balance between Th1, monocyte/macrophage (M/M) and Th2 cytokines in the CNS may be pivotal in determining the outcome of lesion development. We examined the effects of mixtures of cytokines on gene expression by CNS glial cells, as mixtures of cytokines are present in MS lesions, which in turn contain mixtures of glial cells. In this initial analysis by gene array, we examined changes at 6 hours to identify early changes in gene expression that represent primary responses to the cytokines. Rat glial cells were incubated with mixtures of Th1, M/M and Th2 cytokines for 6 hours and examined for changes in early gene expression employing microarray gene chip technology. A minimum of 814 genes were differentially regulated by one or more of the cytokine mixtures in comparison to controls, including changes in expression in a large number of genes for immune system-related proteins. Expression of the proteins for these genes likely influences development and inhibition of MS lesions as well as protective and regenerative processes. Analysing gene expression for the effects of various combinations of exogenous cytokines on glial cells in the absence of the confounding effects of inflammatory cells themselves should increase our understanding of cytokine-induced pathways in the CNS.

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“…Expression of CD59 has recently been demonstrated in the human central nervous system (Shen et al 1995; Akatsu et al 1997; Zhang et al 1998; Singhrao et al 1999 a ), and it has been found that this molecule is slightly upregulated in neurons and glial cells in neurodegenerative diseases associated with local inflammation and chronic complement activation, such as Alzheimer's and Huntington's disease (McGeer et al 1991; Yasojima et al 1999; Singhrao et al 1999 b ). If complement activation plays a direct role in these diseases by enhancing MAC formation on neuronal cells, then CD59 upregulation would certainly be insufficient to protect these cells since neurons seem to be uniquely vulnerable to ionic imbalance caused by complement attack.…”

mentioning

confidence: 99%

CD59 blocks not only the insertion of C9 into MAC but inhibits ion channel formation by homologous C5b‐8 as well as C5b‐9

Farkas

Baranyi

Ishikawa

et al. 2002

The Journal of Physiology

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111

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Activation of the complement system on the cell surface results in the insertion of pore forming membrane attack complexes (MAC, C5b‐9). In order to protect themselves from the complement attack, the cells express several regulatory molecules, including the terminal complex regulator CD59 that inhibits assembly of the large MACs by inhibiting the insertion of additional C9 molecules into the C5b‐9 complex. Using the whole cell patch clamp method, we were able to measure accumulation of homologous MACs in the membrane of CD59− human B‐cells, which formed non‐selective ion channels with a total conductance of 360 ± 24 pS as measured at the beginning of the steady‐state phase of the inward currents. C5b‐8 and small‐size MAC (MAC containing only a single C9) can also form ion channels. Nevertheless, in CD59+ human B‐cells in spite of small‐size MAC formation, an ion current could not be detected. In addition, restoring CD59 to the membrane of the CD59− cells inhibited the serum‐evoked inward current. The ion channels formed by the small‐size MAC were therefore sealed, indicating that CD59 directly interfered with the pore formation of C5b‐8 as well as that of small‐size C5b‐9. These results offer an explanation as to why CD59‐expressing cells are not leaky in spite of a buildup of homologous C5b‐8 and small‐size MAC. Our experiments also confirmed that ion channel inhibition by CD59 is subject to homologous restriction and that CD59 cannot block the conductivity of MAC when generated by xenogenic (rabbit) serum.

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Unique Expression of HRF20 (CD59) in Human Nervous Tissue

Cited by 10 publications

References 35 publications

The Role of Complement in the Mechanism of Action of Rituximab for B-Cell Lymphoma: Implications for Therapy

The Role of Complement in the Mechanism of Action of Rituximab for B-Cell Lymphoma: Implications for Therapy

Differential effects of Th1, monocyte/macrophage and Th2 cytokine mixtures on early gene expression for immune-related molecules by central nervous system mixed glial cell cultures

CD59 blocks not only the insertion of C9 into MAC but inhibits ion channel formation by homologous C5b‐8 as well as C5b‐9

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