Abnormality of glycophorin-alpha on paroxysmal nocturnal hemoglobinuria erythrocytes.

Parker, CJ; Soldato, Cathy M.; Rosse, Wendell F.

doi:10.1172/jci111299

Cited by 49 publications

(58 citation statements)

References 68 publications

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“…26,47 As the signaling events triggered by complement fragments engaging CR1 and GPA have opposing consequences on RBC membrane deformability, the ratio between the number of complement-ligated CR1 and GPA molecules could be important in determining the net change in RBC membrane deformability. Consequently, the genetically determined number of CR1 molecules RBCs could be relevant in certain pathologic conditions associated with significant intravascular complement activation, such as sepsis (reviewed in Markiewski et al 48 ) with high RBC CR1 expressors having functional advantage over the low RBC CR1 expressors.…”

Section: Discussionmentioning

confidence: 99%

Ligation of complement receptor 1 increases erythrocyte membrane deformability

Glodek

Mirchev

Golan

et al. 2010

Blood

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Microbes as well as immune complexes and other continuously generated inflammatory particles are efficiently removed from the human circulation by red blood cells (RBCs) through a process called immune-adherence clearance. During this process, RBCs use complement receptor 1 (CR1, CD35) to bind circulating complement-opsonized particles and transfer them to resident macrophages in the liver and spleen for removal. We here show that ligation of RBC CR1 by antibody and complement-opsonized particles induces a transient Ca ؉؉ influx that is proportional to the RBC CR1 levels and is inhibited by T1E3 pAb, a specific inhibitor of TRPC1 channels. The CR1-elicited RBC Ca ؉؉ influx is accompanied by an increase in RBC membrane deformability that positively correlates with the number of preexisting CR1 molecules on RBC membranes. Biochemically, ligation of RBC CR1 causes a significant increase in phosphorylation levels of ␤-spectrin that is inhibited by preincubation of RBCs with DMAT, a specific casein kinase II inhibitor. We hypothesize that the CR1-dependent increase in membrane deformability could be relevant for facilitating the transfer of CR1-bound particles from the RBCs to the hepatic and splenic phagocytes.(Blood. 2010;116(26): 6063-6071) IntroductionIn primates, in contrast to other vertebrates, clearing the intravascular space of complement-opsonized inflammatory particles (eg, microbes and immune complexes) is mediated by circulating red blood cells (RBCs) using complement receptor 1 (CR1, CD35). 1,2 During this process, known as immune-adherence clearance, RBCs immobilize complement-tagged particles and transport them to the liver and spleen where resident macrophages remove the complement-tagged particles and leave the RBCs intact. Immuneadherence clearance acts as a "buffer system," preventing deposition of circulating immune complexes in susceptible organs, such as the kidney, and preventing activation of circulating leukocytes by inflammatory particles. 3,4 We and others have also shown that CR1-mediated immune-adherence promotes more efficient phagocytosis and intracellular killing of complement-opsonized pathogens compared with opsonized pathogens that are free-floating in plasma and not RBC-bound. 5,6 We have previously found that, in circulating human RBCs, CR1 is disperse in RBC plasma membranes, and, after ligation by immune particles, interacts with Fas-associated phosphatase-1 and rearranges into large clusters. 7 Beneath the plasma membrane of RBCs, the spectrin cytoskeleton defines a series of "corrals" that are critical for maintaining RBC shape and deformability and for regulating the range and magnitude of lateral diffusion of most transmembrane proteins. 8 The mechanical attributes of the spectrin meshwork depend critically on the transient phosphorylation of ␤-spectrin, adducin, and protein 4.1R. 9-11 Therefore, we hypothesized that ligation-mediated CR1 clustering is an active process with CR1 directly affecting the phosphorylation status of cytoskeletal proteins and thus the mechanical p...

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Section: Discussionmentioning

confidence: 99%

Ligation of complement receptor 1 increases erythrocyte membrane deformability

Glodek

Mirchev

Golan

et al. 2010

Blood

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“…An additional possibility is that another, secondary or primary, defect in the membrane could preclude complete reversal of the lytic abnormality by DAF. For example, the large amounts of in vivo deposited C4 and C3 fragments on the PNH cells (1) or glycophorin abnormalities of the cells (19,20) would not be affected by restoration of DAF and could conceivably influence complement activation on the cell surface. In addition, there is evidence that normal human cell membranes also restrict lysis by homologous complement at the level of C9 (21,22) and that type 3 (23) PNH cells are defective in their resistance to attack by C5b-9.…”

Section: Discussionmentioning

confidence: 99%

“…In principle, DAF could be incorporated into the patients' own cells in vitro, and the autologous cells could be reinjected. However, the bound C4 and C3 fragments or other secondary (or primary) defects (1,19,20,23) in the cells might limit their survival.…”

Section: Discussionmentioning

confidence: 99%

Amelioration of lytic abnormalities of paroxysmal nocturnal hemoglobinuria with decay-accelerating factor.

Medof

Kinoshita

Silber

et al. 1985

Proc. Natl. Acad. Sci. U.S.A.

105

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Purified decay-accelerating factor (DAF), from the stroma of normal human erythrocytes, was incorporated into the membranes of erythrocytes of patients with paroxysmal nocturnal hemoglobinuria (PNH), and its effect on the complement sensitivity of the cells was investigated. Reconstitution with exogenous DAF restored the ability of the affected PNH cells to resist assembly of the homologous C3 convertase, C4b2a, on their surfaces, and decreased the susceptibility of the cells to lysis in acidified serum. Conversely, treatment of normal erythrocytes with monoclonal or polyclonal anti-DAF antibodies abrogated the capacity of the normal cells to circumvent C4b2a assembly and rendered the cells sensitive to acid lysis. These findings show that the previously reported association of DAF deficiency with PNH is causally related to the lytic abnormalities of the cells and clarify the molecular basis for restriction of autologous convertase formation on normal human erythrocytes. Recently, a 70-kilodalton membrane component (DAF; decay-accelerating factor) that can inhibit C3 activation (2) was purified from the stroma of normal human erythrocytes (3). The isolated protein resembled the complement receptor type 1 (CR1) in that it could promote dissociation by decay of preformed C3 convertases of both the classical and alternative complement pathways (3). Two groups of investigators (4-6) found that DAF was deficient or absent in cells of patients with PNH, and they suggested that this defect was involved in the heightened sensitivity of the PNH cells to lysis.In our laboratory, we examined the respective roles of CR1 and DAF in the regulation of bound C3b and C4b fragments (7)(8)(9)) and compared the function of purified DAF and of DAF incorporated within cell membranes. We found that membrane-associated DAF acts primarily to block the uptake of C2 and factor B by deposited C4b or C3b fragments rather than to regulate preformed convertases. Moreover, in contrast to CR1, which interacts extrinsically with convertases on targets, DAF acts only within the surface of the same cells-i.e., it is strictly an intrinsic membrane inhibitor. Since, in its native environment, DAF effectively inhibits the assembly of all amplifying enzymes of the cascade (C3 and C5 convertases), we suggested that it might play a central role in vivo in preventing complement-mediated damage of autologous cells.A key observation permitting the above analyses was that purified DAF could be incorporated into erythrocyte membranes and retain its functional properties (8,10). In the present study, we took advantage of this phenomenon to determine whether the DAF deficiency of the PNH erythrocytes is causally related to their increased sensitivity to complement-mediated lysis. We found that reconstitution of PNH erythrocytes with DAF restores the ability of the cells to inhibit assembly of the classical pathway C3 convertase (C4b2a) on their surfaces and markedly reduces the susceptibility of the erythrocytes to the alternative pathway-mediated lysi...

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“…1 1). For (11). Recent studies have suggested that glycophorin modulates both sensitivity of cells to reactive lysis (48) and alternative pathway activity (49).…”

Section: Resultsmentioning

confidence: 99%

“…Enhanced convertase activity may be due to several different mechanisms inasmuch as the convertase (a) has greater enzymatic activity when affixed to PNH cells (7), (b) forms more readily on PNH erythrocytes (7,8), and (c) is more stable when bound to the abnormal cell membrane (8,9). These aberrant interactions with complement appear to be related to abnormalities in glycoproteins of the cell surface, which function as regulators of the complement system (8)(9)(10)(11). The greater activity of the C3 convertase is primarily responsible for the enhanced susceptibility of PNH II cells to complement-mediated lysis, because unlike PNH III cells they do not display a marked susceptibility to cytolysis in reactive lysis systems (6).…”

Section: Introductionmentioning

confidence: 99%

Characterization of the complement sensitivity of paroxysmal nocturnal hemoglobinuria erythrocytes.

Parker¹,

Wiedmer²,

Sims³

et al. 1985

J. Clin. Invest.

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The affected erythrocytes of paroxysmal nocturnal hemoglobinuria (PNH II and PNH III cells) are abnormally sensitive to complement-mediated lysis. Normal human erythrocytes chemically modified by treatment with 2-amino-ethylisothiouronium bromide (AET) have been used as models for PNH cells inasmuch as they also exhibit an enhanced susceptibility to complement. To investigate the bases for the greater sensitivity of these abnormal cells to complement-mediated lysis, we compared binding of C3 and constituents of the membrane attack complex to normal, PNH II, PNH III, and AET-treated cells after classical pathway activation by antibody and fluidphase activation by cobra venom factor complexes. When whole serum complement was activated by antibody, there was increased binding of C3 and C9 to PNH II, PNH III, and AET-treated cells, although the binding of these complement components to PNH II and PNH III cells was considerably greater than their binding to the AET-treated cells. In addition, all of the abnormal cell types showed a greater degree of lysis per C9 bound than did the normal erythrocytes. PNH III and AET-treated cells were readily lysed by fluid-phase activation of complement, whereas normal and PNH II erythrocytes were not susceptible to bystander lysis. The greater hemolysis of PNH III and AET-treated cells in this reactive lysis system was due to a quantitative increase in binding of constituents of the membrane attack complex. This more efficient binding of the terminal components after fluid-phase activation of whole serum complement was not mediated by cell-bound C3 fragments. These investigations demonstrate that the molecular events that characterize the enhanced susceptibility of PNH II, PNH III, and AET-treated erythrocytes to complementmediated lysis are heterogeneous.

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Abnormality of glycophorin-alpha on paroxysmal nocturnal hemoglobinuria erythrocytes.

Cited by 49 publications

References 68 publications

Ligation of complement receptor 1 increases erythrocyte membrane deformability

Ligation of complement receptor 1 increases erythrocyte membrane deformability

Amelioration of lytic abnormalities of paroxysmal nocturnal hemoglobinuria with decay-accelerating factor.

Characterization of the complement sensitivity of paroxysmal nocturnal hemoglobinuria erythrocytes.

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