Paroxysmal nocturnal hemoglobinuria type III. Lack of an erythrocyte membrane protein restricting the lysis by C5b-9.

Hänsch, G M; Schönermark, S; Roelcke, D.

doi:10.1172/jci113065

Cited by 114 publications

(28 citation statements)

References 31 publications

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“…In addition, PNH III erythrocytes have been shown to be deficient in HRF/C8bp (8,9). Based on its reported function, HRF/C8bp would be expected to offer some protection against CoFBb-initiated hemolysis.…”

Section: Resultsmentioning

confidence: 99%

Relationship between the membrane inhibitor of reactive lysis and the erythrocyte phenotypes of paroxysmal nocturnal hemoglobinuria.

Holguin¹,

Wilcox²,

Bernshaw³

et al. 1989

J. Clin. Invest.

141

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Susceptibility to hemolysis initiated by activated cobra venom factor (CoF) complexes is a characteristic that distinguishes the most complement-sensitive type III erythrocytes of paroxysmal nocturnal hemoglobinuria (PNH) from the intermediately sensitive type II and the normally sensitive type I cells. Recently we isolated a membrane constituent from normal erythrocytes that inhibits CoFBb-initiated hemolysis, and this protein was designated membrane inhibitor of reactive lysis (MIRL). To investigate the molecular basis of the variability in complement sensitivity among PNH erythrocytes, the surface expression of MIRL and decay accelerating factor (DAF) on the three phenotypes of PNH was quantified immunochemically. Both complement regulatory proteins were markedly deficient on the erythrocytes from a patient with predominately type III cells. The erythrocytes from patients with a majority of either type II or I cells were also significantly deficient in both MIRL and DAF. While cytofluorometric analysis confirmed the quantitative deficiencies, segregation of erythrocytes into discrete subpopulations that expressed either no MIRL or normal amounts of MIRL was not observed. The results of immunoprecipitation studies were consistent with quantitative, but not qualitative abnormalities of MIRL and DAF. Selective removal of the sensitive erythrocytes indicated that -20% of the normal amount of MIRL is sufficient to protect cells from CoF-initiated lysis. These studies suggest that relatively subtle quantitative differences in membrane complement regulatory proteins underlie the variability in complement sensitivity of PNH erythrocytes.

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Section: Resultsmentioning

confidence: 99%

Relationship between the membrane inhibitor of reactive lysis and the erythrocyte phenotypes of paroxysmal nocturnal hemoglobinuria.

Holguin¹,

Wilcox²,

Bernshaw³

et al. 1989

J. Clin. Invest.

141

View full text Add to dashboard Cite

show abstract

“…The physiologic basis for the increased susceptibility of affected erythrocytes to complement-dependent lysis is the absence or reduction of a number of surface glycoproteins, including DAF, CD59, and C8bp, that modulate complement deposition on host cells (149,161,247,264). The variability in sensitivity to complement-mediated lysis reflects both the number of missing proteins and the extent of their reduction (162).…”

Section: Deficiencies Of Membrane Complement Proteinsmentioning

confidence: 99%

“…Thus, although PNH type 2 and 3 cells both lack DAF, the greatly increased sensitivity to comple-VOL. 4,1991 on May 10, 2018 by guest http://cmr.asm.org/ Downloaded from ment-mediated lysis of the latter cells is due to the absence of CD59 and C8bp, which modulate the activity of the membrane attack complex (149,161,162,226,306).…”

Section: Deficiencies Of Membrane Complement Proteinsmentioning

confidence: 99%

Infectious diseases associated with complement deficiencies

1991

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The complement system consists of both plasma and membrane proteins. The former influence the inflammatory response, immune modulation, and host defense. The latter are complement receptors, which mediate the cellular effects of complement activation, and regulatory proteins, which protect host cells from complement-mediated injury. Complement activation occurs via either the classical or the alternative pathway, which converge at the level of C3 and share a sequence of terminal components. Four aspects of the complement cascade are critical to its function and regulation: (i) activation of the classical pathway, (ii) activation of the alternative pathway, (iii) C3 convertase formation and C3 deposition, and (iv) membrane attack complex assembly and insertion. In general, mechanisms evolved by pathogenic microbes to resist the effects of complement are targeted to these four steps. Because individual complement proteins subserve unique functional activities and are activated in a sequential manner, complement deficiency states are associated with predictable defects in complement-dependent functions. These deficiency states can be grouped by which of the above four mechanisms they disrupt. They are distinguished by unique epidemiologic, clinical, and microbiologic features and are most prevalent in patients with certain rheumatologic and infectious diseases. Ethnic background and the incidence of infection are important cofactors determining this prevalence. Although complement undoubtedly plays a role in host defense against many microbial pathogens, it appears most important in protection against encapsulated bacteria, especially Neisseria meningitidis but also Streptococcus pneumoniae, Haemophilus influenzae, and, to a lesser extent, Neisseria gonorrhoeae. The availability of effective polysaccharide vaccines and antibiotics provides an immunologic and chemotherapeutic rationale for preventing and treating infection in patients with these deficiencies.

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“…The class of GPI-anchored membrane proteins (reviewed in 14, 15) includes the complement-regulatory factors DAF, membrane inhibitor ofreactive lysis (16)(17)(18), and C8-binding protein/homologous restriction factor (19,20). The complement-regulatory function of DAF and the GPI anchoring both come into play in the disease paroxysmal nocturnal hemoglobinuria (PNH; reviewed in 21), an acquired hemolytic anemia.…”

Section: Introductionmentioning

confidence: 99%

Dr(a-) polymorphism of decay accelerating factor. Biochemical, functional, and molecular characterization and production of allele-specific transfectants.

Lublin¹,

Thompson²,

Green³

et al. 1991

J. Clin. Invest.

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The Dr' antigen belongs to the Cromer-related blood group system, a series ofantigens on decay accelerating factor (DAF), a glycosyl-phosphatidylinositol-anchored membrane protein that protects host cells from complement-mediated damage. We studied the rare inherited Dr(a-) phenotype to ascertain the associated biochemical and functional changes in DAF and to characterize the basis for this polymorphism. Radioimmunoassay and flow cytometric analysis ofDr(a-) erythrocytes demonstrated 40% of normal surface expression of DAF but normal levels of several other glycosyl-phosphatidylinositol-anchored proteins, distinguishing this phenotype from that of paroxysmal nocturnal hemoglobinuria. Western blots confirmed this reduced DAF expression and indicated a slightly faster mobility of the molecule on SDS-PAGE. Despite the reduced DAF expression, Dr(a-) erythrocytes functioned normally in the complement lysis sensitivity assay. Utilization of the polymerase chain reaction to amplify mononuclear cell genomic DNA from three unrelated Dr(a-) individuals demonstrated that a point mutation underlies the Dr(a-) phenotype: a C to T change in nucleotide 649 resulting in a serine'65 to leucine change. This defines the Drb allele ofDAF, which can be distinguished from Dr' by a Taq I restriction fragment length polymorphism. We created transfected Chinese hamster ovary cell lines expressing either the Dr' or the Dr' allelic form of DAF.These allele-specific transfectants were tested by inhibition of hemagglutination or flow cytometry and confirmed the specificity of anti-Dr' alloantisera. The allele-specific transfectants could form the basis of a new serological approach to immunohematology. (J. Clin. Invest. 1991.87:1945-1952

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Paroxysmal nocturnal hemoglobinuria type III. Lack of an erythrocyte membrane protein restricting the lysis by C5b-9.

Cited by 114 publications

References 31 publications

Relationship between the membrane inhibitor of reactive lysis and the erythrocyte phenotypes of paroxysmal nocturnal hemoglobinuria.

Relationship between the membrane inhibitor of reactive lysis and the erythrocyte phenotypes of paroxysmal nocturnal hemoglobinuria.

Infectious diseases associated with complement deficiencies

Dr(a-) polymorphism of decay accelerating factor. Biochemical, functional, and molecular characterization and production of allele-specific transfectants.

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