Hereditary deficiency of the second component of complement (C'2) in man.

Klemperer, Martin R.; Woodworth, Harold C.; Rosen, Fred S.; Austen, K. Frank

doi:10.1172/jci105403

Cited by 143 publications

(52 citation statements)

References 26 publications

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“…Although the function of this pathway is as yet unknown, it has been observed that animals with C4 deficiency and humans with C2 deficiency are relatively free of infection, but patients with nonfunctional C1 have a bactericidal defect and are prone to infection despite an apparent intact alternate complement pathway (7,18,19). Perhaps the repeated infections observed in these patients are secondary to a block in the cytotoxic pathway reported here.…”

Section: Resultsmentioning

confidence: 72%

A New Complement-Mediated Cytolytic Mechanism—the C1-Bypass Activation Pathway

May

Frank

1973

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

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A new cytolytic pathway is described whereby cells sensitized with cytotoxic antibody can be specifically iysed in the complete absence of intact, classical complement pathway function. Evaluation of this model with sera deficient in the 4th (C4), 2nd (C2), and 6th (C6) components of complement has revealed that this new Iytic mechanism, termed the Cl-bypass activation pathway, is initiated by the antibody-mediated activation of C1. Utilizing components of the previously described alternate complement pathway, this pathway bypasses C4 and C2 to activate the third to ninth components of complement (C3-9) with induction of membrane damage.Serum complement (C) is the principal humoral cytotoxic effector system within the body, and a principal mediator of the biological events of inflammation. Until recently, complement activity was thought to result from the sequential activation of a single series of effector proteins. That is, antigen-antibody complexes were shown to activate in turn the first three components of complement C1, C4, and C2, termed the early components, and activation of these early components led to activation of C3-9, the later components in the complement sequence. A few years ago work from several laboratories established the existence of an alternate pathway of complement activation that bypassed C1, C4, and C2 of the "classical" pathway to enter the complement sequence at the level of C3 (1-4).Previous studies from our laboratory have shown that the alternate pathway is very inefficient at mediating the lysis of both erythrocytes and nucleated cells sensitized with cytotoxic antibody (5). In this report, for the first time, a new cytolytic system is described whereby cells sensitized with cytotoxic antibody can be specifically lysed in the complete absence of intact classical pathway function. Examination of this model has disclosed the existence of a novel cytotoxic complement pathway that is initiated by the attachment of C1 to membrane-bound antibody. The formation of an antigen-antibody-Cl complex (EAC1) leads to activation of components of the bypass or alternate complement pathway, and these in turn activate C3 and the later components of the complement sequence. MATERIALS AND METHODSPreparation of Anti-Forssman Antiserum and Purification of IgG Immunoglobulin. Anti-Forssman antiserum was prepared in a New Zealand white rabbit by repeated intravenous injections of increasing quantities of boiled sheep erythrocyte stromata over a 2.5-week period (10). 2 Weeks after the last intravenous injection of antigen, the rabbit was injected in each footpad with 0.2 ml of an emulsion containing equal volumes of antigen and Freund's complete adjuvant. 2 Weeks later, the animal was bled and the serum was used as a source of IgG hemolytic antibody. The IgG fraction of this antiserum was purified by gel filtration on Sephadex G-200 followed by sucrose density ultracentrifugation as described (6). 0.1 ml of a 1:1280 dilution of this antiserum was sufficient to produce 50% hemolysis of 0.1 ml of ...

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Section: Resultsmentioning

confidence: 72%

A New Complement-Mediated Cytolytic Mechanism—the C1-Bypass Activation Pathway

May

Frank

1973

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

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“…There are inbred strains of rabbits with C'6 deficiency (4, 5), of mice with C'5 deficiency (6,7), and a strain of guinea pigs deficient in one of the proteins comprising the classical third component of complement (8,9). C'2 deficiency has now been well characterized in at least two families (10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

Inherited deficiency of the third component of human complement (C′3)

Alper¹,

Propp²,

Klemperer³

et al. 1969

J. Clin. Invest.

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“…Hereditary defects of complement components reported thus far mostly involved the classical pathway in human, including Clr (Pickering et al, 1971), Cls (Pondman et al, 1968), C4 (Hauptmann et al, 1974), C2 (Klemperer et al, 1966), C3 (Ballow et al, 1975), C5 (Rosenfeld et al, 1976), C6 (Leddy et al, 1974), C7 (Boyer et al, 1975;Gelgge et aI,, 1977;Nemerow et aL, 1978), and C8 (Petersen et al, 1976), and two inactivators of the complement system, C1 inhibitor (Donaldson and Evans, 1963), and C3b inactivator (Abramson et al, 1971;Thompson and Lachmann, 1977). Few cases of ninth component (C9), the terminal component of the complement sequence, have been reported.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, levels of C9 protein in serum of normal homozygote (C9, C9), heterozygote (C9, C9), and deficient homozygote (C9, C~) approximately reflected the dosage effect of the wild type and mutant gene. Some of the known defects of complement components in man, including C2 (Klemperer et al, 1966;Fu et al, 1974;Day et al, 1975), C3 (Alper and Rosen, 1979), C5 (Rosenfeld et aI., 1976;Snyderman et al, 1979), C6 (Leddy et al, 1974;Lim et al, 1976;Glass et al, 1978), C7 (Boyer et al, 1975;Gelftge et al, 1977;Nemerow et al, 1978), and C8 (Petersen et al, 1976) appear to be inherited in the same mode as is C9. One of the well documented exceptions to this mode of inheritance is the deficiency of C1 inhibitor (Donaldson and Evans, 1963), causative pathogenesis of hereditary angioedema.…”

Section: Discussionmentioning

confidence: 99%