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PubMed1994

A new PCR-based typing of the Rodgers and Chido antigenic determinants of the fourth component of human complement.

The Rodgers (Rg) and Chido (Ch) blood groups are antigenic determinants of the fourth component of human complement C4. They are associated with the two isotypes of C4, C4A and C4B, respectively. They serve as markers to distinguish C4A from C4B as well as for the definition of subtypes of common and rare allotypes. As an alternative to the serological typing method using human alloantisera, a PCR typing procedure with sequence-specific primers (PCR-SSP) was designed. The method was tested on selected DNA samples from individuals with well-defined C4 allotypes. No false-positive or false-negative typing results were obtained and all the determinant combinations could be distinguished. The PCR genotyping allowed the detection of all Rg/Ch sequence determinants of each isotype. Thus, reverse antigenicity could also be established in the presence of other C4 allotypes without a segregation study. To exclude the possibility that PCR-typed determinants originate from a non-expressed C4 null gene, a sequence-specific PCR was established detecting a 2-bp insertion in exon 29 described previously as a cause for C4A non-expression. PCR Rg/Ch genotyping provides a fast and efficient method for routine typing in HLA haplotype and disease association studies.

Alleles↗
PubMed1988

C1 binding by murine IgM. The effect of a Pro-to-Ser exchange at residue 436 of the mu-chain.

We have examined a defect in complement activation in a mutant trinitrophenyl-binding pentameric murine monoclonal IgM which has serine replacing the proline normally found at position 436 in the protein. The mutant protein showed equivalent hapten binding but a 100-fold decreased ability to initiate complement-dependent lysis of trinitrophenyl-coupled erythrocytes at physiological ionic strength (mu = 0.15). C4b deposition mediated by the mutant protein was impaired to a similar degree. C1 bound by the mutant protein showed C1s to C1-s conversion, suggesting normal activation. When measured at reduced ionic strength (mu = 0.06), the C1 and C1q binding affinity of the mutant protein was approximately one-half that of the wild type. However, the C1 binding affinity of the mutant protein showed a greater dependence upon ionic strength such that at physiological ionic strength we estimate a 50-fold lower C1 binding affinity for the mutant molecule. Kinetic studies suggested that this difference in affinity was largely attributable to differences in association rates. In addition, a fixed proportion of the mutant molecules showed no C1 binding. We conclude that the defect in complement activation occurs at the level of C1 binding. Our data support a role for the C mu 3 domain (residues 340-440) in C1 binding by IgM.

Complement Activating Enzymes↗
PubMed1989

Individuals with IgA deficiency and common variable immunodeficiency share polymorphisms of major histocompatibility complex class III genes.

IgA deficiency and common variable immunodeficiency are heritable disorders that can occur within the same family. Both immunodeficiencies are characterized by arrests in B-cell differentiation that vary in the extent of the immunoglobulin isotypes involved. A high frequency of major histocompatibility complex supratypes associated with a null allele of the gene encoding the C4A isotype of complement component C4 has been observed in IgA-deficient individuals. In search of a genetic linkage between the two immunodeficiencies, we examined the major histocompatibility complex (MHC) class III genes encoding complement components C2, C4A, and C4B and steroid 21-hydroxylase in addition to the HLA serotypes in individuals with either common variable immunodeficiency or IgA deficiency. Twelve of 19 patients with common variable immunodeficiency (63%, P less than 0.001) and 9 of 16 patients with IgA deficiency (56%, P less than 0.01) had rare C2 alleles and/or C4A and 21-hydroxylase A deletions, whereas these gene features were seen in only 5 of 34 healthy individuals (15%) in the control group. Nine of 11 patients with C4A deletion had an HLA haplotype consistent with the MHC supratype HLA-A1, Cw7, B8, C4AQ0, C4B1, BfS, DR3 previously found to be associated with IgA deficiency. The data support the hypothesis that common variable immunodeficiency and IgA deficiency are related disorders, susceptibility to which is determined by a gene(s) within or near the MHC class III gene region on chromosome 6.

Alleles↗
PubMed1983

Monoclonal antibodies to human complement receptor (CR1) detect defects in glomerular diseases.

The complement receptor for C3b of the epithelial cells of human glomeruli is structurally and functionally very similar or identical to CR1, the complement receptor for C3b and C4b present on the membrane of red cells and leukocytes. Four monoclonal antibodies directed against separate epitopes of CR1 react with an antigen in the glomeruli, which appears to be present on the epithelial podocytes. Moreover, the monoclonal antibodies very effectively inhibit the binding of C3b-bearing red cells to the glomeruli. The pattern of immunofluorescence of the receptor was normal or slightly altered in patients with minimal change disease, mesangial proliferative glomerulonephritis (GN), or idiopathic membranous GN. Glomeruli with endocapillary proliferation showed some attenuation of staining. Glomeruli in which the capillary tuft architecture was altered, or of patients with systemic lupus erythematosus, or of patients with diffuse diabetic nephropathy tended to have few foci or no staining for the receptor. No correlation was found between the intensities of staining of the C3b receptor and of C3 antigen deposited in the glomeruli.

Amyloidosis↗
PubMed1997

Complement receptor type 1 (CR1, CD35) is a receptor for C1q.

Molecular definition of the cellular receptor for the collagen domain of C1q has been elusive. We now report that C1q binds specifically to human CR1 (CD35), the leukocyte C3b/C4b receptor, and the receptor on erythrocytes for opsonized immune complexes. Biotinylated or radioiodinated C1q (*C1q) bound specifically to transfected K562 cells expressing cell surface CR1 and to immobilized recombinant soluble CR1 (rsCR1). *C1q binding to rsCR1 was completely inhibited by unlabeled C1q and the collagen domain of C1q and was partially inhibited by C3b dimers. Kinetic analysis in physiologic saline of the interaction of unlabeled C1q with immobilized rsCR1 using surface plasmon resonance yielded an apparent equilibrium dissociation constant (K[eq2]) of 3.9 nM. Thus, CR1 is a cellular C1q receptor that recognizes all three complement opsonins, namely, C1q, C3b, and C4b.

Binding Sites↗
PubMed1989

Phylogeny of regulatory proteins of the complement system. Isolation and characterization of a C4b/C3b inhibitor and a cofactor from sand bass plasma.

We have previously demonstrated that the alpha'-chain of human activated form of the fourth (C4b) and third (C3b) component of C are cleaved by plasma or serum from vertebrate species spanning through 300,000,000 yr of evolution yielding fragments identical with those obtained with human plasma. In this study, we investigated the molecular basis of this reaction. We chose barred sand bass plasma because this is the most primitive species analyzed possessing these activities. Barred sand bass plasma proteins were separated on a Sephadex G-200 column and the eluted samples analyzed for C4b and C3b cleavage. Individual fractions were inactive, but degradation was obtained when proteins of 380 and 155 kDa were combined. In contrast to the human regulatory proteins, the sand bass proteins require Ca2+ ions. K76COOH, an inhibitor of human factor I, inhibited the function of the 155-kDa but not of the 380 kDa-fraction. Thus it appears that the 155-kDa fraction functions as the C4b/C3b cleaving enzyme (I) and the 380-kDa material as its cofactor. Further purification of the 380-kDa fraction yielded a protein that by SDS-PAGE consisted of two noncovalently linked subunits of 110 and 42 kDa at a molecular ratio of 2:1. These two chains were antigenically distinct, and constitute domains of the same protein. The 110-kDa peptide binds C4b and not C3b but it fully expresses the cofactor function for the 155-kDa fraction on the cleavage of both C4b and C3b. Limited tryptic digestion of the 110-kDa domain demonstrated C4b binding activity in fragments of 34, 25, and 23 kDa. The activity of the 34-kDa fragment was the same as that of the undigested protein. Comparison of the amino acid composition of the barred sand bass cofactor and of human C4bp shows similar high content of cysteine and proline but not of tryptophan. It differs from human factor H in cysteine, serine, proline, and tryptophan. These studies indicate that regulatory proteins for the C4b and C3b C fragments may have appeared very early phylogenetically.

Amino Acids↗
PubMed1984

Linkage disequilibrium of HLA-SB1 with the HLA-A1, B8, DR3, SCO1 and of HLA-SB4 with the HLA-A26, Bw38, Dw10, DR4, SC21 extended haplotypes.

Homozygous typing cells from 13 normal HLA-A1, B8, Dw3, DR3 and five normal HLA-A26, Bw38, Dw10, DR4 individuals were typed for the following markers: HLA-SB, MB, MT; complement proteins BF, C2, C4A, C4B; and GLO. Ninety-one percent of A1, B8, Dw3, DR3 homozygous individuals (HI) tested were homozygous for BF*S, C2*C, C4A*QO, and C4B*1 (SCO1 complotype), which indicates that the SCO1 complotype is in linkage disequilibrium with the A1, B8, DR3 haplotype in randomly selected normal populations. Sixty-seven percent of HLA-A1, B8, Dw3, DR3, SCO1 positive HI also expressed SB1; since the frequency of SB1 in random Caucasian populations is 11.2%, this finding indicates that SB1 is in linkage disequilibrium with the A1, B8, DR3, SCO1 extended haplotype. All HI with the A26, Bw38, Dw10, DR4 haplotype were homozygous for both SC21 and SB4, suggesting that SC21 and SB4 should be included in the A26, Bw38, Dw10, DR4 extended haplotype. On the other hand, neither of the GLO markers were found in association with either haplotype. The results of this study indicate that HLA-SB is included in some extended haplotypes and may be important in these markers for diseases such as insulin-dependent diabetes mellitus. This study also demonstrated an apparent influence of HLA-SB on primary mixed lymphocyte culture (MLC) responses. The mean relative response of primary MLCs between individuals matched for HLA-A, B, D, DR, MB and MT but not SB was 40% of that for the MLCs with mismatched HLA-D, significantly higher than the MLCs matched for all HLA and complotypes.

Complement System Proteins↗
PubMed1982

Complement receptor (CR1) deficiency in erythrocytes from patients with systemic lupus erythematosus.

This study reports quantitative information on the concentration of complement receptor for C3b and C4b (CR1) on erythrocytes from normal individuals and patients with immune complex disease. The measurements were performed by an immunoradiometric assay using monoclonal antibodies against CR1. The antibody specificity was confirmed by immunoprecipitation of CR1 from extracts of surface-labeled cells, by inhibition of rosette formation between B lymphocytes and the erythrocytes intermediate EAC14oxy23b, and by the characteristic distribution of the antigen among cells of human peripheral blood. The number of CR1 molecules in erythrocytes from 52 normal individuals was estimated as 1,410 +/- 620. No significant differences in CR1 levels were observed when individuals were grouped by sex, age, or blood groups. In patients with SLE and rheumatoid arthritis, the number of CR1 molecules per RBC was significantly lower, i.e., 600 +/- 307 and 903 +/- 417, respectively. CR1 levels were normal in asthmatics undergoing long-term treatment with prednisone. In SLE patients, significant correlations were found between CR1 levels, C4 hemolytic titers, and levels of circulating immune complexes. In two out of four patients with SLE, CR1 levels increased significantly during remission, showing that the deficiency is, at least in part, reversible. The deficiency in CR1 could be genetically controlled or could represent an epiphenomenon caused by the interaction of the receptor with a ligand present in the circulation of patients.

Adolescent↗
PubMed1998

Cloning and characterization of the promoter for the human complement factor I (C3b/C4b inactivator) gene.

Complement factor I is a serine proteinase that regulates the classical and alternative pathways of complement by cleaving C3b and C4b and preventing the assembly of C3 and C5 convertase enzymes. In order to understand the regulation of factor I gene expression in liver cells, 4kb of the 5' flanking region of the gene was cloned, and the 1474-bp 3'-end was sequenced and shown to contain a number of transcription factor consensus sequences. A major and two minor transcription start sites were identified, respectively, at 152, 178, and 198bp upstream of the translation start site by primer extension analysis. The transcriptional activity of the 1474-bp fragment was analyzed by fusion of 5' deletion constructs to a cat-encoding gene expression vector and transient transfections into Hep G2 cells. A 273-bp fragment located at -112 to +161 relative to the major transcription start site was sufficient for promoter activity. The 3' fragment spanning +3 to +161 and containing a TATA-like element did not demonstrate promoter activity, suggesting that the core promoter resides in a 115-bp sequence located between -112 and +3. This region contains an Inr-like element overlapping the major cap site and a CTF-NF1 element, two potential CCAAT boxes and an AP-2 element partially overlapping an Sp-1 site. Thus, factor I promoter may belong to the TATA-less Inr-driven class II promoters whose transcription is regulated by Sp-1. The transcriptional activity of the 1474-bp 5' flanking fragment was upregulated by PMA, IL-6 and TNF-alpha, suggesting that factor I may be an acute phase reactant.

Base Sequence↗
PubMed1988

Complement receptors CR1 on human peripheral nerve fibres.

Receptors for C3 and C4 in human peripheral nerve tissue were studied by examining the adherence of complement (C) coated erythrocytes (E) and by using monoclonal antibodies against epitopes on the receptors for C3b (CR1), C3d (CR2) and C3bi (CR3). E (erythrocyte)-bearing C3b or C4b adhered to sections of myelinated peripheral nerves and the binding was inhibited only by anti-CR1 antibodies. By immunofluorescence, anti-CR1 antibodies stained the nerve fibres, whereas anti-CR2 and anti-CR3 antibodies did not. The staining was apparently localized to the Schwann cell membrane. E-bearing C3bi or C3d did not adhere to myelinated or unmyelinated nerves. CR1 are therefore the only C3 receptors expressed in human peripheral nerves. E-bearing C3b or C4b did not adhere to unmyelinated nerves from adults or to nerves from fetuses at a gestational age of approximately 21 weeks, whereas monoclonal anti-CR1 antibodies stained myelinated, unmyelinated and fetal nerves equally well. The results indicate that CR1 in unmyelinated and fetal nerves are either functionally inactive or express a lower affinity for C3b/C4b than CR1 in myelinated nerves. There were no significant differences in the binding of E-bearing C3b or C4b to myelinated peripheral nerves from 50 individuals, indicating that CR1 activity is not distributed phenotypically.

Adult↗
PubMed1998

Molecular mimicry of the inflammation modulatory proteins (IMPs) of poxviruses: evasion of the inflammatory response to preserve viral habitat.

Microorganisms encode numerous immunomodulators that resemble, in structure and function, molecules captured over the millennia from their hosts [G. J. Kotwal J. Leukoc. Biol. 62, 415-429]. The vaccinia virus complement control protein (VCP) was the first soluble microbial protein to have a postulated role in the immunomodulation and evasion of host defense [G. J. Kotwal and B. Moss Nature 355, 176-179]. Purified bioactive VCP has been shown to bind to C3 and C4, block the complement cascade at multiple sites [G. J. Kotwal et al. Science 250, 827-830; R. Mckenzie, G. J. Kotwal et al. J. Infect. Dis. 166, 1245-1250] and exhibit a greater potency than the human complement 4b binding protein, C4b-BP [G. J. Kotwal, Am. Biotech. Lab. 9, 76]. The importance of this protein to poxviruses was further demonstrated in rabbits and guinea pigs through the use of recombinant virus lacking an intact DNA coding for VCP [Isaacs, G. J. Kotwal, and B. Moss Proc. Natl. Acad. Sci. 89, 628-672]. Studies in mice have shown that the homolog of VCP in cowpox virus (CPV), referred to as the inflammation modulatory protein (IMP) can, in a mouse model, significantly diminish the specific footpad swelling response [C. G. Miller, S. N. Shchelkunov, and G. J. Kotwal Virol. 229, 126-133]. To determine the precise cellular changes at the site of infection, BALB/c mice were subcutaneously injected (in the backs) with CPV or a recombinant virus lacking IMP, CPV-IMP. Differences in histology were observed by staining the adjoining skin tissue sections with hematoxylin & eosin or by removal of the connective tissue and staining with May-Grunwald-Geimsa. All mice that were injected with the CPV-IMP experienced severe tissue destruction and formation of nodular lesions compared with the mice injected with CPV. Microscopic examination indicated significantly greater cellular infiltration and destruction of skeletal muscle cells in the sections of connective tissue and adjoining skin tissue, respectively, of the mice injected with the CPV-IMP [G. J. Kotwal et al. Mol. Cell. Biochem. in press]. Thus IMP preserves the tissue at the site of infection (viral habitat). In this review, we present evidence for molecular mimicry and evolutionary relationship to other homologs of IMP and discuss their relationships with other IMPs such as the poxviral chemokine and cytokine receptor-like proteins.

Amino Acid Sequence↗
PubMed1986

Mn2+-probe ESR method for the analyses of the dissociation of charged residues on the surface of immunoglobulins.

Dissociation of charged residues on the surface of immunoglobulins was analysed by an Mn2+ probe ESR method that has been developed in our previous work. Several kinds of IgG proteins and their Fab and Fc fragments were used for the experiments. The pH dependence of the intensity of ESR signals was analysed. It was shown that the number of Asp, Glu and His residues on the surface of Fc is about twice as many as that of Fab. The accessible surface area of amino acid residues calculated using X-ray crystallographic data is quite consistent with the present ESR experiments. This indicates that the number of the Asp, Glu and His residues on the surface of IgG molecules in solution is similar to that in the crystal. The Mn2+-probe ESR method was also applied to other classes of immunoglobulins, i.e. IgA and IgM. It was demonstrated that the IgA protein, which is known to lack the ability to bind Clq, has on the surface of it a smaller number of Asp, Glu and His residues as compared to IgG and IgM proteins. On the basis of these results obtained by the Mn2+-probe ESR method, we suggest that the Clq molecule, which is a basic protein, interacts favorably with the Fc portion whose surface is more negatively charged with Asp and Glu residues, compared to the Fab portion. Fine adjustment of fitting of the head of the Clq molecule into the CH2 domain of the Fc portion presumably follows for optimum binding. It was also demonstrated that Ser and Thr residues are much more abundant on the surface of Fab than in the case of Fc. We suggest that the Ser and Thr residues on the surface of Fab play an important role for binding of C4b upon activation of the complement system.

Asparagine↗
PubMed2003

Inherited mannose-binding lectin deficiency as evidenced by genetic and immunologic analyses: association with severe recurrent infections.

BACKGROUND: Mannose-binding lectin (MBL), an acute-phase serum protein of hepatic origin, plays an essential protective role in host innate immunity in targeting microbial pathogens for destruction via opsonization, enhancement of phagocytosis and complement activation. MBL deficiency, characterized by low serum MBL, has been attributed to genetic mutations in both structural and promoter regions of the gene coding for the protein. Concomitant MBL deficiency in patients with chronic immunologic disease has been associated with increased susceptibility to complicating infections that may hasten disease progression. OBJECTIVE: Few cases of inherited MBL deficiency in adults and possible associations with recurrent infection have been reported. To address this issue, we investigated the MBL profile of four generations within a single adult family whose members have experienced a variety of persistent infections. METHODS: MBL serum levels and MBL genotypes of each participating family member were ascertained by enzyme-linked immunoadsorbent assay and reverse transcriptase-polymerase chain reaction, respectively. MBL complement activation, as measured by C4b deposition against mannan-coated wells, was assayed using an enzyme-linked immunoadsorbent assay. Routine immunologic and cellular tests were carried out to evaluate the immunologic status of each family member. RESULTS: Six of the 7 family members screened carried one or more of the variant MBL alleles in their genotype and had correspondingly low serum MBL and reduced ability to affect C4b opsonization. Medical histories of the participating family members revealed an array of mild to severe recurrent infections despite no apparent immunodeficiency. CONCLUSIONS: Our studies show that MBL deficiency is an inherited characteristic and may be a crucial factor in maintaining immunologic health.

Adult↗
PubMed2001

Molecular cloning and sequence analysis of the complestatin biosynthetic gene cluster.

Streptomyces lavendulae produces complestatin, a cyclic peptide natural product that antagonizes pharmacologically relevant protein-protein interactions including formation of the C4b,2b complex in the complement cascade and gp120-CD4 binding in the HIV life cycle. Complestatin, a member of the vancomycin group of natural products, consists of an alpha-ketoacyl hexapeptide backbone modified by oxidative phenolic couplings and halogenations. The entire complestatin biosynthetic and regulatory gene cluster spanning ca. 50 kb was cloned and sequenced. It consisted of 16 ORFs, encoding proteins homologous to nonribosomal peptide synthetases, cytochrome P450-related oxidases, ferredoxins, nonheme halogenases, four enzymes involved in 4-hydroxyphenylglycine (Hpg) biosynthesis, transcriptional regulators, and ABC transporters. The nonribosomal peptide synthetase consisted of a priming module, six extending modules, and a terminal thioesterase; their arrangement and domain content was entirely consistent with functions required for the biosynthesis of a heptapeptide or alpha-ketoacyl hexapeptide backbone. Two oxidase genes were proposed to be responsible for the construction of the unique aryl-ether-aryl-aryl linkage on the linear heptapeptide intermediate. Hpg, 3,5-dichloro-Hpg, and 3,5-dichloro-hydroxybenzoylformate are unusual building blocks that repesent five of the seven requisite monomers in the complestatin peptide. Heterologous expression and biochemical analysis of 4-hydroxyphenylglycine transaminon confirmed its role as an aminotransferase responsible for formation of all three precursors. The close similarity but functional divergence between complestatin and chloroeremomycin biosynthetic genes also presents a unique opportunity for the construction of hybrid vancomycin-type antibiotics.

Base Sequence↗
PubMedDate not supplied

The suppression effect of DNA sequences within the C4A region on the transcription activity of human CYP21.

Two CYP21 genes, the active CYP21 and the pseudogene, CYP21P, also pairs of duplicated genes including the XA, XB, XB-S; YA, YB; and ZA, ZB are arranged in tandem next to the serum complement C4 genes (C4A and C4B). In this report, we have analyzed the influence of some DNA sequences within the C4A/CYP21P region on the transcription activity of the human CYP21. After transiently transfecting the plasmid constructs into mouse adrenocarcinoma Y1 cells, mouse testis Leydig tumor MA10 cells and human liver tumor HepG2 cells, our results showed that sequences located within the -13943/-13174 and -3278/-2586 regions upstream from the CYP21P had suppression effects on the promoter activity of human CYP21. However, the short sequences spanning from -8415/-8373 and -4511/-4140 upstream from the CYP21P did not alter the basal transcription activity of the CYP21 gene. Our results indicated that specific sequences within the C4A region might function as suppressor-like elements for the transcription of human CYP21.

Adrenal Cortex↗
PubMed1994

Rabbit plasma, unlike its human counterpart, contains no complex between protein S and C4b-binding protein.

In human plasma, the anticoagulant vitamin K-dependent protein S exists in two molecular forms, as free protein and complexed to C4b-binding protein (C4BP), a complement regulatory protein. It has been suggested that rabbit plasma also contains two forms of protein S and that the interaction between protein S and C4BP in rabbits can be modulated by synthetic peptides corresponding to a sequence (residues 605-614) in the carboxy-terminal part of protein S. In this report, we provide results which challenge the conclusion that rabbit plasma contains the complexed form of protein S. The two forms of protein S in human plasma were separated by gel filtration chromatography on Sephacryl S-300 and the presence of protein S in the various fractions analyzed by Western blotting using a monoclonal antibody (HPS 21) directed against the gamma-carboxyglutamic acid rich module of human protein S. This antibody, which was found to cross-react with rabbit protein S on Western blotting, was used in affinity purification of protein S from rabbit plasma as well as of recombinant rabbit protein S. HPS 21 specifically recognized protein S in rabbit plasma and did not cross-react with the other vitamin K-dependent plasma proteins. To elucidate whether rabbit plasma contained two forms of protein S, rabbit plasma was subjected to gel-filtration chromatography followed by Western blotting of the fractions with monoclonal antibody HPS 21. Protein S was found only in fractions eluting at a position corresponding to that of free protein S.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

C4B deficiency in two siblings with IgA nephropathy.

The development of IgA nephropathy in first degree relatives is a well-described, yet relatively uncommon, occurrence. The association of a C4 isotype deficiency or partial deficiency of another complement protein has been previously documented for patients with IgA nephropathy. The present report describes a family in which two siblings and their father had biopsy-confirmed IgA nephropathy; both siblings were deficient for the C4B isotype. In addition, one of the biopsied siblings and a third sibling with microscopic hematuria but no renal biopsy apparently had a partial deficiency of the complement regulatory protein, I. The findings in this family may be compatible with the hypothesis that a C4 isotype deficiency and/or a partial deficiency of an individual complement protein allows clinical expression of IgA nephropathy in an individual with a genetic susceptibility for the disease.

Adolescent↗
PubMed1984

The molecular basis for the difference in immune hemolysis activity of the Chido and Rodgers isotypes of human complement component C4.

Human C4 displays a structural polymorphism which is consistent with there being two closely linked genetic loci coding for this protein. These give rise to two C4 isotypes, designated C4A and C4B, which can be distinguished by charge and apparent m.w. differences in their respective alpha-chains and by the presence or absence of the Chido/Rodgers blood group antigens. Previous qualitative studies of C4 immune hemolysis activity in whole plasma had suggested that the C4B isotype was functionally more active. By using purified C4A and C4B isolated from individual donors known serologically to possess only one of the C4 isotypes, we examined the molecular basis for the differences in their respective hemolytic activities. It was found that the C4B:C4A hemolytic activity ratio was approximately 4:1. This fourfold difference could not be accounted for by a commensurate difference in the cleavage rate of the two isotypes by C1s by differences in the kinetics of assembly or intrinsic decay of the respective C3 convertase enzymes, or by differences in the rate of isotypic C4b cleavage by factor I in the presence of C4bp . However, the fourfold greater deposition efficiency of nascent C4b of the C4B isotype onto the surface of C1-bearing sheep erythrocytes quantitatively accounted for the observed difference in immune hemolysis function. It was further found that the thioester bond of nascent C4b of the C4A isotype preferentially transacylates onto amino group nucleophiles, whereas in the C4B isotype, acylation of hydroxyl groups is strongly preferred. Thus, the difference in immune hemolysis activity between the two C4 isotypes does not necessarily indicate an impairment of function in C4A; it may merely be a reflection of the relative abundance at the surface of a C1-bearing target of hydroxyl and amino groups capable of being acyl acceptors for nascent C4b. Finally, we also present evidence showing that the apparent m.w. difference between the alpha-chains of the C4A and C4B isotypes is not due to differences in protein glycosylation.

Acylation↗