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PubMed1987

HLA and C4 in subacute sclerosing panencephalitis.

The frequencies of HLA-A, B, C, DR and DQ antigens were studied in 63 Japanese patients with subacute sclerosing panencephalitis (SSPE). The results could not confirm the statistical association between SSPE and HLA antigens. In addition, the allele frequencies of complement components C4, C2 and BF were determined in the 20 haplotypes with 10 unrelated SSPE patients. A significant association of C4A QO with SSPE in Caucasians was not found in Japanese.

Complement C2↗

PubMed1991

A rare complement component C4 restriction fragment length polymorphism in two families with systemic lupus erythematosus.

C4 null alleles with or without C4A,21-OHA gene deletions are associated with systemic lupus erythematosus (SLE) in various populations. We describe a new, rare C4 restriction fragment length polymorphism (RFLP), a Taq I 3.5 kb fragment, in 2 patients with SLE and their families. This RFLP is not associated with one particular major histocompatibility complex (MHC) haplotype and has not been reported in patients with SLE, patients with congenital adrenal insufficiency, or in healthy individuals.

Adult↗

PubMed1979

The purification and characterization of bovine C4, the fourth component of complement.

The fourth component of complement, C4, was isolated from bovine plasma in high yield, by using simple purification techniques. The protein, like human component C4, is a beta-globulin with a mol.wt. of about 200 000 and consists of three polypeptide chains, alpha, beta and gamma, with apparent mol. wts. of 98 000, 82 000 and 32 000 respectively. The chains of C4 have been separated by methods previously used for human C4. Their amino acid compositions are very similar to those of the human component, but differences in carbohydrate distribution have been observed. The haemolytic activity of bovine C4 is totally destroyed by incubation with bovine C1s, the activated subcomponent of the first component of complement. Component C4, treated in this way, was shown to be cleaved in the alpha chain, which was decreased in mol.wt. by about 9000, corresponding to the removal of subcomponent C4a.

Amino Acids↗

PubMed1984

Allergic reactions to antimicrobial agents: a review of reactions to drugs not in the beta lactam antibiotic class.

Allergic reactions to antimicrobial drugs are common causes of morbidity but rarely of death. Despite the lack of proven immunodiagnostic tests for reactions to the non-beta-lactam drugs, the agents that cause reactions usually can be identified by analysis of their propensity to cause reactions, temporal relationships of exposure to reactions, and remission of reactions when the drugs are discontinued. Measurements of plasma histamine levels, high-molecular-weight neutrophil chemotactic factor, and heparin-like activity and of urinary histamine and prostaglandin D2 metabolites should help clarify the role of mast cell mediator release in the various forms of these reactions. Measurements of C3a, C4a, and C5a, in biologic fluids should facilitate analysis of the contributions of complement activation to the reactions observed. Assessment of these pathophysiologic parameters should provide a more rational basis for the selection of specific pharmacologic interventions to suppress allergic reactions. If no alternative drugs are available, infected patients who are allergic often can be gradually desensitized with the agents to which they are allergic. While much important work remains to be completed, current approaches can minimize the morbidity and mortality rates associated with allergic reactions to antimicrobial agents.

Anti-Bacterial Agents↗

PubMed1991

The systemic complement activation caused by interleukin-2/lymphokine-activated killer-cell therapy of cancer causes minimal systemic neutrophil activation.

Twenty-three cancer patients undergoing therapy with interleukin-2 and lymphokine-activated killer cells were studied for evidence of complement activation and systemic neutrophil activation occurring during the course of therapy. Patient plasma samples demonstrated evidence of marked complement activation, with 3-fold elevations of C3a desArg concentrations by the 8th day of therapy. Concentrations of C4a desArg were also elevated by the end of therapy. In vitro chemotaxis of patients' neutrophils both to C5a and to the synthetic peptide chemotaxin, FMLP, was initially normal and then fell progressively to 60% of normal by the end of treatment. Mean neutrophil cell-surface expression of complement receptor Type 1 and complement receptor Type 3 increased in inverse temporal relationship to the deficit in chemotaxis, but showed no consistent pattern for individuals and was only doubled at maximum. Thus, despite a degree of complement activation which should have produced pronounced neutrophil activation, the response of the circulating neutrophils was diminished. In view of this discrepancy, the toxicity of this therapy may not be mediated by activation of circulating neutrophils.

Chemotaxis, Leukocyte↗

PubMed1983

Analysis of active and inactive complement C4 complotypes associated with subtypes of HLA-B17 in different racial groups.

HLA-A, B, and C antigens and the HLA-linked markers BF, C2, and C4 were determined in 1,799 unrelated Caucasians, 140 North American blacks, 140 Chinese, and 66 Japanese. One allele of the C4A locus (Rodgers), C4A*6, was found to code for a functionally inactive product in HLA-B17 (Bw57)-positive individuals, but for a functionally active product in HLA-B37- or HLA-B27-positive individuals. Further studies revealed that the functionally inactive C4A*6 gene product was found only in one subtype of HLA-B17, namely, 17.1 (Bw57, long). In addition, it was found that the frequency of the other subtype of HLA-B17, namely, 17.2(Bw58, short) varies greatly in different populations and that HLA-Bw58 is associated with either C4A*3,B*1 or C4A*3,B*Q0.

Alleles↗

PubMed2005

Is immunity in diabetic patients influencing the susceptibility to infections? Immunoglobulins, complement and phagocytic function in children and adolescents with type 1 diabetes mellitus.

OBJECTIVE: Previous reports suggest an increased susceptibility of diabetes patients to infections, but little information is available on possible underlying immunologic dysfunctions. The aim of this study was to evaluate humoral factors in pediatric patients with type 1 diabetes mellitus. METHODS: There were 66 diabetic patients (39 males:27 females; 5-17 yr) classified into two groups according to levels of glycohemoglobin (limit 9%): Group C - controlled (n = 33) and Group UC - uncontrolled (n = 33). We evaluated five patients in C and six in UC who reported previous infections. Immunologic analysis included measurement of plasma concentrations of immunoglobulins (Ig), C3, and C4 levels (turbidimetry); functional hemolytic assays for complement evaluation (CPH for classical and APH for alternative pathways), quantification of C4 isotypes C4A and C4B (ELISA), phagocytosis assays, measurement of bactericidal activity against Staphylococcus aureus, as well as tests of fungicidal capacity for Candida albicans. RESULTS: The UC Group had higher mean age, received higher insulin doses, and had higher concentrations of glycohemoglobin than the C Group. No significant differences in duration of the disease or nutritional conditions were detected between the groups. Lower IgA values in C (10/33) and lower IgG levels in UC (23/33) were detected, and there were inverse relationship with HbA1c values. Analysis of CPH, APH, C3, and C4 showed normal levels in both groups and no statistical correlation with the HbA1c. However, 9/33 children of the UC Group had decreased C3 values. C4B levels were below the normal range in 8/20 and correlated with higher HbA1c. Both phagocytic assays for S. aureus and Candida albicans were within normal limits. CONCLUSIONS: Low IgG concentrations and to some degree reduction in C4B levels were related to impaired metabolic control. No strong link between the immunological alterations was found in diabetic patients and the occurrence of infections.

Adolescent↗

PubMed1982

A molecular basis for the two locus model of human complement component C4.

The major histocompatibility complex(MHC)-linked fourth component of complement (C4) shows a high degree of polymorphism in several animal species. In man C4 polymorphism was detected by distinct charge differences of the variants. O'Neill et al. showed that this C4 polymorphism was controlled by two closely linked genetic loci, F (C4A) and S (C4B) and these results were extended by Awdeh et al. with an improved typing method. Biochemical analysis of human C4 has revealed that it consists of three polypeptide chains, alpha, beta and gamma. In all reports so far on the molecular analysis of human C4, no molecular weight differences between the A and B locus-encoded molecules have been noticed. Here we demonstrate that the C4A and C4B locus-encoded alpha-chains have a molecular weight (MW) of 96,000 and 94,000, respectively, presenting for the first time a molecular basis for the difference between all C4A and C4B variants tested. Even rare variants that are difficult to allocate to the A or B locus on the basis of charge differences could be identified as C4A or C4B variants in this way, thereby providing new insights into the relationships between the C4A and C4B loci.

Complement C4↗

PubMed1996

Inherited deficiencies of complement in rheumatic diseases.

Inherited complement deficiencies are rare but occur with increased frequency in systemic lupus erythematosus. This selective review summarizes the fundamentals of complement activation and biology and focuses on recent findings. system lupus erythematosus is highly associated with homozygous C1q deficiencies and with C4A null allotypes, and homozygous C2 and C3 deficiencies are less uniformly associated with autoimmune disease. This hierarchy of disease associations suggests the importance of an intact early classic activation pathway in preventing systemic lupus erythematosus. Assays of complement activation products may have greater sensitivity and specificity for systemic lupus erythematosus disease activity and lupus flares.

Autoimmune Diseases↗

PubMed2000

Genetics of the complement system.

After a brief history of complement genetics, general considerations and applications to our understanding of immune function, evolution, population structure and migration and forensic medicine, selected topics in complement genetics are presented. For individual complement proteins, genetic polymorphisms and deficiency states are described, as are the molecular bases of some of them. The clinical abnormalities exhibited by some patients with complement deficiency states are discussed, as are possible pathophysiologic mechanisms for them. The chromosomal location and the close linkage and a sharing of structural features by groups of complement proteins, such as the complotypes of the major histocompatibility complex, the regulators of complement activation, Clr and Cls, and the terminal components C6, C7 and C9, are presented in some detail. From these facts, the broad outlines are drawn of the evolution of the classical and alternative complement pathways from the lectin pathway and the terminal pathway from a common progenitor. From markers within the complotype region, rough conclusions are delineated regarding the evolution of C2, factor B, C4A and C4B alleles.

Animals↗

PubMed1986

Are major histocompatibility system class III products independent markers for susceptibility to rheumatoid arthritis?

Three components of the complement pathway C2, Factor B, and C4 are coded for by four genes C2, Bf, C4A, and C4B in the class III region of the major histocompatibility system in man. Studies of the polymorphism of these plasma proteins have shown associations of BfS, C2C, and C4B3 (2.9) with RA. Family studies have shown that these markers occur together, usually on DR4 positive haplotypes and in particular on the A2-Cw3-Bw62-C4B3-C4A3-BfS-C2C-DR4 haplotype. It is argued that Class III gene products are unlikely to be independent markers of susceptibility to RA.

Arthritis, Rheumatoid↗

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↗

PubMed1992

Cold-dependent activation of complement: recognition, assessment, and mechanism.

Cold-dependent activation of complement (CDAC) is a phenomenon characterized by low hemolytic complement activity in chilled serum. Complement component levels are normal when measured immunologically, and there is normal hemolytic activity in EDTA plasma or serum maintained at 37 degrees C. Little attention has been paid to CDAC except in Japan, and current unfamiliarity with it, even by clinical immunologists, can lead to confusion and unnecessary laboratory tests. A 66-year-old patient with a complex medical history is described whose complement tests showed abnormalities characteristic of CDAC. Evidence for classical complement pathway activation in the cold was obtained by CH50 measurements, by hemolytic C4 determinations, by C4a, C3a, and C4d generation, and by quantitating C1s-C1r-(C1 inhibitor)2 complexes. A good correlation was observed among these parameters. Cryoprecipitates were absent. CDAC activity has persisted for over 5 years and is greater at 13 than at 4 degrees C. Activation is ablated by heating at 56 degrees C and restored by the addition of C1 to the heated serum. Adsorption by streptococcal protein G-Sepharose and precipitation by 2.5% polyethylene glycol support the hypothesis that CDAC is caused by aggregated IgG. The CDAC factor(s) also induces complement activation in normal serum but has not interfered with Raji cell or C1q binding tests or with FACS analysis. More limited studies of a second individual experiencing CDAC yielded similar results.

Adult↗

PubMed1990

C4 alpha-chain reference typing report.

Previously it was shown that C4A and C4B alpha-chains after separation on SDS-PAGE can provide valuable information on presence and absence, as well as the number of C4A and C4B genes expressed in an individual. All samples submitted for C4 reference typing were also subjected to C4 alpha-chain separation; the results were included in the Final C4 Reference Typing List [Complement Inflamm 1990;7:193-212]. In addition, in selected cases with assumed 'reversed antigenicity', Western blots of C4 alpha-chains with monoclonal anti-C4A and B antibodies were obtained. As a result, subtypic differences of C4B allotypes were detected by the comparison of monoclonal antibodies 1217 and 1228.

Antibodies, Monoclonal↗

PubMed1988

Complement deficiency. Predisposing factor to autoimmune syndromes.

The recognition of the association between complete and partial complement (C) deficiencies and immune complex-mediated diseases is of clinical and etiopathologic interest. From studies of sera deficient in C1, C4, C2, or C3, the crucial role of these complement components in promoting the solubility and clearance of immune complexes has been elucidated. Moreover, partial C4 deficiency appears to be a common risk factor for the development of systemic lupus erythematosus, with complete C4A deficiency (C4A null) being present in 10 to 15 percent and heterozygous C4A deficiency present in 50 to 80 percent of patients with systemic lupus erythematosus. Most importantly, there is an obvious pathophysiologic relationship between the function of complement relative to immune complex processing and the disease that results from their deficiency. Systemic lupus erythematosus is characterized by excessive quantities of inappropriately deposited immune complexes. More subtle complement component and receptor deficiencies are likely to be predisposing factors for autoimmune disease. The complement deficiencies provide us with a unique opportunity to investigate the origin and development of immune complex excess syndromes.

Antigen-Antibody Complex↗

PubMed1995

Binding to erythrocyte complement receptor type 1 of BSA/anti-BSA complexes opsonized by C4A3 or C4B1 in the presence of serum.

An in vitro model with human serum and human 0 Rh-negative erythrocytes was used for studies on preformed BSA/anti-BSA complex binding to complement receptor type 1 (CR1). The serum used was first depleted of Clq, factor D and properdin, then of C3, C4 or both and finally reconstituted with the desired proteins (serum reagent). With varying C4 concentrations and 100% C3 present, binding curves obtained for the two C4 isotypes were similar. When the serum reagent was not reconstituted with factor D and properdin there was no difference between the CR1 binding of normal serum and the partially reconstituted serum reagent, nor between the two C4 isotypes in this serum reagent. When C3 at 50% or 100% of normal concentrations was added to the serum reagent together with 100% C4A3 or C4B1, the C4B1-opsonized complexes showed more binding than the C4A3-opsonized complexes. At very low levels of C3 (< 25%) the binding could not be distinguished from the background. The results suggest that the binding of complement opsonized antigen/antibody complexes to erythrocyte CR1 is mediated mainly by C3, originating from activation of the classical pathway, and that the difference in properties between C4A and C4B does not have a major influence.

Animals↗

PubMed1990

Functional consequences of the genetic polymorphism of the third component of complement.

The third component of complement, the central protein of the complement cascade, occurs in two principal allotypes, C3S and C3F. An excess frequency of the F allotype has been implicated in a number of disease states, including some forms of glomerulonephritis. These associations have been explained by functional differences between C3S and C3F. We examined several complement functions, using purified preparations of C3S or C3F. The C3S allotype was 1.3 times more efficient than C3F in a hemolytic assay employing sensitized sheep erythrocytes; this difference was shown to arise from a slightly more efficient deposition of C3F on the cell surface. These differences are trivial and of much less magnitude than the functional differences between C4A and C4B. There were no differences between allotypes in their ability to be converted to inactive C3b (C3bi) by complement factors H and I or by CR1 and factor I. No significant differences were seen between the allotypes and their ability to support solubilization of preformed immune complexes.

Animals↗

PubMed1986

Complement genes of the major histocompatibility complex (complotypes), extended haplotypes and disease markers.

The human major histocompatibility complex (MHC)-linked genes C2,BF,C4A,C4B occur in populations and segregate in families as single genetic units or complotypes. Analysis for significant three-point linkage disequilibrium between HLA-B, DR and complotype on normal caucasian chromosomes 6p yields about a dozen haplotypes that account for most of the known HLA-B/HLA-DR linkage disequilibrium pairs previously noted in normal caucasian populations. We refer to the HLA-B/DR/complotype sets with significant linkage disequilibrium as extended haplotypes since they often show limited variation at other MHC-linked loci. From the study of MHC haplotypes in 21-hydroxylase deficiency, C2 deficiency and type 1 diabetes, it is becoming apparent that it is extended haplotypes rather than their individual alleles that are markers for these MHC-associated diseases.

Adrenal Hyperplasia, Congenital↗