Inhibition of complement by a substance isolated from human erythrocytes—II

Hoffmann, Edward M.

doi:10.1016/0019-2791(69)90297-3

Cited by 84 publications

(12 citation statements)

References 6 publications

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“…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.…”

Section: Introductionmentioning

confidence: 94%

“…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.…”

mentioning

confidence: 94%

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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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Section: Introductionmentioning

confidence: 94%

mentioning

confidence: 94%

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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“…Normal human erythrocytes have at least two membrane proteins with factor H-like activity: the C3b receptor (10), CR1, and the decay-accelerating factor, DAF (11,12). CR1 binds C3b and renders it susceptible to cleavage by factor I (10).…”

mentioning

confidence: 99%

Deficiency of an erythrocyte membrane protein with complement regulatory activity in paroxysmal nocturnal hemoglobinuria.

Pangburn¹,

Schreiber²,

Müller‐Eberhard³

1983

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

284

131

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Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hemolytic anemia in which the erythrocytes are abnormally sensitive to lysis by complement. A functional deficiency of membrane-associated complement regulators has been demonstrated on PNH erythrocytes. The two factor H-like proteins, the C3b receptor (CR1) and the decay-accelerating factor (DAF), were isolated from normal human erythrocytes, and specific antisera were prepared. Selective inhibition of the two proteins on normal erythrocytes by the antisera demonstrated (i) that the factor responsible for accelerated decay of erythrocyte-bound C3 convertase is DAF and (ii) that the cofactor required for inactivation of erythrocyte-bound C3b by factor I is CR1. PNH erythrocytes were deficient in both of these activities. Erythrocytes deficient in CR1, which were obtained from an apparently healthy individual, exhibited normal DAF activity but no factor I cofactor activity. These cells were not susceptible to complement-mediated lysis in acidified human serum, whereas PNH erythrocytes and Pronase-treated human erythrocytes (which lack DAF and CR1 activities) were lysed by this treatment. It is suggested that the protein primarily responsible for preventing complement activation on normal human erythrocytes is DAF. A Mr 73,000 protein isolated from the normal erythrocyte membranes of one PNH patient by using anti-DAF IgG was largely absent from the abnormal erythrocytes of this individual, suggesting that PNH cells lack the DAF protein. CR1 antigen, however, was present on the abnormal PNH erythrocytes. The results suggest that the primary molecular defect underlying the clinical manifestations of PNH may be the lack of the membrane-associated DAF protein and that the abnormal cells may also exhibit impaired CR1 function.

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“…In 1969, Hoffmann reported that a substance remaining in the aqueous phase from an extraction of human erythrocyte stroma with n-butanol could inhibit C-mediated hemolysis thorugh an acceleration in the decay of the classical pathway C3 convertase (7,8). More than a decade later Nicholson-We Her and colleagues (9) purified an intrinsic membrane glycoprotein that expressed decay accelerating activity from guinea pig and later human erythrocyte stroma by butanol extraction.…”

Section: Decay-accelerating Factor (Daf or Cd55)mentioning

confidence: 99%

Separation of Self From Non-Self in the Complement System: A Role for Membrane Cofactor Protein and Decay Accelerating Factor

Atkinson

Oglesby

White

et al. 1991

Clinical and Experimental Immunology

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Inhibition of complement by a substance isolated from human erythrocytes—II

Cited by 84 publications

References 6 publications

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

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

Deficiency of an erythrocyte membrane protein with complement regulatory activity in paroxysmal nocturnal hemoglobinuria.

Separation of Self From Non-Self in the Complement System: A Role for Membrane Cofactor Protein and Decay Accelerating Factor

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