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PubMed1985

Null alleles of the fourth component of complement and HLA haplotypes in familial systemic lupus erythematosus.

Eight families (121 individuals) with two or more members affected with systemic lupus erythematosus (SLE) were analyzed for histocompatibility antigens (HLA-A, B, C, DR, MT, and MB) and complement antigens (C4A, C4B, and BF). These data were correlated with serological markers (antinuclear antibodies, single- and double-stranded anti-DNA, anti-SM, anti-nRNP, anti-Ro [SS-A], anti-La [SS-B], and biological false-positive tests for syphilis and clinical features. Fifteen members had SLE, and 19 had other immune diseases (subacute cutaneous lupus erythematosus, discoid lupus erythematosus, hypothyroidism, insulin-dependent diabetes mellitus, primary Sjogren's syndrome, immune thrombocytopenic purpura, rheumatoid arthritis, and multiple sclerosis). Twenty-three healthy relatives (seroreactors) had significant titers of circulating antibodies, as did 2 of 17 spouses. There was an increased frequency of null C4 alleles in those individuals with SLE (60%) and healthy relatives (50%) as compared with spouses (24%). Multivariate analysis showed a significant association between SLE and female sex (P =.006), whereas there was no significant association revealed between female sex and other immune diseases. Patients with SLE also had a higher frequency of either C4A or C4B null alleles (P = .01) than those with immune diseases. The C4A homozygous null phenotype was more common in SLE patients than in seroreactors (P = .02). There was a higher frequency of HLA-DR2 and DR3 in individuals with SLE than in those with immune disease (P = .08), seroreactors (P = .02) and normal relatives (P = .002). One totally C4-deficient patient with SLE was identified. These families demonstrate an important association between SLE and the C4 null allele and the HLA-DR2 and DR3. These risk factors, however, cannot account for the development of disease in all individuals.

Adult↗
PubMed1989

Complement phenotypes in patients with psoriasis.

Phenotype frequencies for the complement proteins C4A, C4B, Bf (factor B) and C3 were performed for 49 Caucasian patients with psoriasis. The C4*A6 allele was present in 26.6% of the patients as compared to 5.4% of healthy regional Caucasian controls, p less than 0.001, relative risk = 6.28. The C4*A6 allele is known to be in linkage disequilibrium with the HLA B17 allele and to produce a non-functional gene product when it occurs with the B17 allele. HLA B17 is known to be associated with psoriasis in many Caucasian populations. Additional findings in the present study were a significant reduction in the C4B*2 allele frequency, a non-significant increase in the Bf*F allele frequency and no difference for Bf or C3 phenotype frequencies in the patients with psoriasis as compared to the controls.

Complement C3↗
PubMed1992

Shared HLA class II-associated genetic susceptibility and resistance, related to the HLA-DQB1 gene, in IgA deficiency and common variable immunodeficiency.

Most cases of selective IgA deficiency (IgA-D) and common variable immunodeficiency (CVID) occur sporadically. However, familial clustering is not uncommon, and the two disorders can occur within the same family. We have previously described positive associations with three DR-DQ haplotypes as well as a strong negative association with DRw15,DQw6,Dw2 in IgA-D. Different amino acids at position 57 of the HLA-DQ beta chain were found to be related to susceptibility and resistance to IgA-D. Now we have found identical, although somewhat weaker, positive and negative DR-DQ associations in a large group of CVID patients (n = 86), as well as the same associations with codon 57 of the DQB1 gene. In addition, we have confirmed our earlier observations in an independent group of IgA-D individuals (n = 69), and in sib-pair analysis we have found linkage of the genetic susceptibility to IgA-D to the HLA class II region. In IgA-D individuals not carrying the three overrepresented DR-DQ haplotypes, the same positive association with a non-aspartic acid residue at position 57 of the HLA-DQ beta chain was seen. The previously reported associations with deletions of the HLA class III genes C4A (fourth component of complement) and CYP21P (steroid 21-hydroxylase pseudogene) were, in our groups of immunodeficient individuals, statistically secondary to the association with the DQB1 allele 0201. The shared HLA class II associations in the two humoral immunodeficiencies support the hypothesis that IgA-D and CVID are related disorders. Disease susceptibility and resistance are most closely associated with a gene(s) within the DR-DQ region, alleles of the DQB1 locus being candidate genes.

Alleles↗
PubMed1989

Demonstration of neutrophil chemotactic anaphylatoxins in human dandruff.

In contrast to scales collected from the scalps of nine healthy individuals where a few parakeratotic cells are observable, a large number of parakeratotic cells associated with some infiltrated polymorphonuclear leukocytes (PMNLs) were found in the scales obtained from 11 individuals complaining of dandruff. Therefore, we determined the neutrophil chemotactic properties of the water-soluble extracts of dandruff scales and normal control scalp scales. Aqeous extracts fractionated by Sephadex G-75 showed a potent chemotactic activity only in the fractions of the dandruff patients that eluted with cytochrome C marker (cyt C; molecular weight, 12 kDa). It was comparatively stable to heat but was greatly inhibited by the addition of anti-C5 antiserum. Radioimmunoassay demonstrated that, although small amounts of C5a and C4a anaphylatoxins were demonstratable even in the extracts of normal scalp, they were found in significantly increased amounts in the extracts of dandruff. Moreover, there was a significantly positive correlation between C5a and C4a concentrations in these extracts. These results suggest that classical complement pathway activation with resultant production of C5a anaphylatoxin is involved in the migration of PMNLs into the lesional skin of dandruff.

Adult↗
PubMed1984

A comparison of the properties of two classes, C4A and C4B, of the human complement component C4.

A remarkable difference has been observed between the reactivity of the two forms of human complement component C4. C4B binds twice as effectively as C4A to antibody-coated red cells, but the reverse occurs with protein-antigen complexes. C4B reacts much more effectively with hydroxyl groups than C4A and this is reversed for reaction with amino groups in spite of the very small difference in amino acid sequence between the two forms of C4. No other differences in stability, activation or inactivation were observed. These findings emphasise the biological advantage of the duplication of the C4 gene in its reaction with a wide range of antigenic structures. The correlation of the presence of different forms of C4 with susceptibility to autoimmune diseases may be explicable by these big differences in binding reactivity.

Amino Acid Sequence↗
PubMed1987

Three Chido determinants detected on the B5Rg+ allotype of human C4: their expression in Ch-typed donors and families.

A study was made of polyspecific human allo-anti-C4, anti-Chido (Ch), which reacts with determinants usually located on C4B protein. Some anti-Ch reagents are capable of reacting with Ch- red cells coated with C4 from Ch:-1,-2,-3 donors. A complex serologic pattern demonstrated three more Ch determinants, Ch4, Ch5, and Ch6, which were detected by haemagglutination-inhibition tests. All Ch:1,2,3 samples were Ch:4,5,6 but samples lacking one or more of the Ch1,Ch2,Ch3 series of determinants also lacked some of the new determinants. MHC typed families demonstrated the inheritance of the new determinants as part of the Ch haplotype, and associations with C4 allotypes and haplotypes have been established. Ch4 always associates with C4B protein. Ch5 and Ch6, normally detected on C4B protein, were detected in several individuals who lacked C4B (BQO allotypes) and were therefore presumed in these instances to be located on the accompanying C4A protein.

Antigens, Surface↗
PubMed1989

Two isotypes of human C4, C4A and C4B have different structure and function.

The two types of human C4, C4A and C4B, differ in their amino acid sequence and in their capacity to bind to different acceptor sites. C4B is more efficient than C4A in haemolytic assays; by contrast C4A binds preferentially to immune complexes. In assays comparing haemolysis to processing of immune complexes the two types of C4 differ more than fivefold. Thus, the classical pathway is a duplicated system that allows the formation of a C3 convertase on various substrates: this duplication may be of vital importance to eliminate invading microorganisms. In addition, the clinical observation of an increased incidence of homozygous C4A null alleles in systemic lupus erythematosus may be explained in part by defective processing of immune complexes in the absence of C4A.

Antigen-Antibody Complex↗
PubMed1986

[A new case of bronchospasm under extracorporeal circulation].

A case of bronchospasm occurring after the termination of cardiopulmonary bypass is reported. The complement fractions C3a, C4a and C5a were measured before and right after CPB. Complement activation is not specific to CPB but may occur in any thoracotomy. The statistically significant increase in complement C3a without any pulmonary symptomatology has been reported by several authors. Complement activation cannot therefore be considered as the explanation of this bronchospasm.

Bronchial Spasm↗
PubMed1979

C4a: the third anaphylatoxin of the human complement system.

The activation peptide C4a was isolated from C1s-cleaved C4, the fourth component of complement. The peptide appeared to be homogeneous by electrophoresis on cellulose acetate and by polyacrylamide gel electrophoresis. C4a has a molecular weight of 8650 and an electrophoretic mobility at pH 8.6 of +2.1 x 10(-5) cm2V-1 sec-1. Carboxypeptidase B released approximately 1 mol of arginine per mol of C4a. The partial COOH-terminal sequence was determined to be Leu-Gln-Arg-COOH. The isolated C4a was spasmogenic for guinea pig ileum at a concentration of 1 microM and it desensitized the muscle (i.e., produced tachyphylaxis) with respect to human C3a anaphylatoxin (at 0.33 microM) but not with respect to human C5a anaphylatoxin. Increased vascular permeability was observed in human skin after intradermal injection of 1 nmol of C4a, as evidenced by immediate erythema and edema formation. The spasmogenic, tachyphylactic, and vascular activities of C4a were abrogated by removal of the COOH-terminal arginine, a property that is characteristic also of the C3a and C5a anaphylatoxins. Contamination of C4a with either C3a or C5a has been ruled out by using radioimmunoassays for these peptides. Although C4a is considerably less active than are C3a and C5a, the present observations suggest that C4a constitutes a heretofore unrecognized anaphylatoxin that is related biologically and chemically to the activation peptides of C3 and C5.

Amino Acid Sequence↗
PubMed1987

Relation between complement activation and susceptibility to decompression sickness.

The consequences of complement activation and the symptoms of decompression sickness are similar. Consequently, the relation between the sensitivity of individuals to complement activation by air bubbles and their susceptibility to decompression sickness has been examined. Plasma samples from 34 individuals were incubated with air bubbles, and the concentration of the fluid phase metabolites of complement activation C3a, C4a, and C5a were measured with radioimmunoassays. It was found that both the anaphylatoxins C3a and C5a were produced by the presence of air bubbles but that the anaphylatoxin C4a was not. This finding indicates that air bubbles activate the complement system by the alternate pathway. One group of individuals was found to be particularly sensitive to complement activation by this pathway. They produced 3.3 times more C3a and 5.3 times more C5a in their plasma samples incubated with air bubbles as did the other group. Sixteen individuals were subjected to a series of pressure profiles that were severe enough to produce bubbles in their circulatory system that could be detected by Doppler ultrasonic monitoring. The group of individuals that had been identified as being more sensitive to complement activation by the alternate pathway was also found to be more susceptible to decompression sickness.

Adult↗
PubMed1995

Anti-HBV neonatal immunization with recombinant vaccine. Part II. Molecular basis of the impaired alloreactivity.

HLA study was performed in 9 absolute non-responder (serum titre of anti-HBsAg < 2 mIU ml-1) and 8 hyporesponder (serum antibody level between 2 and 9.9 mIU ml-1) babies who underwent, in neonatal period, HBV vaccination with Engerix B recombinant vaccine. The investigation pointed out that many of these subjects carry HLA haplotypes classically involved in autoimmune diseases: namely HLADR7; DQ2, DR4; DQ8 and DR3; DQ2. The genomic typing for DRB1, DRB3, DRB4, DRB5, DQA1, DQB1 and DPB1 genes revealed an increased frequency of the DRB1*0701; DQA1*0201; DQB1*0201 haplotype (23.5 vs 9.9% of the controls) and of DPB*0201 allele (42.3 vs 13.2% of controls). The polymorphism of Bf, C4A and C4B complement serum components, recognized as important "immune-function-related genes", pointed out an increased frequency of the null allele C4AQ0 (34.3 vs 6.8% of the controls) stressing the role of C4A serum complement component in response to foreign peptide. The immunogenetic investigation has been extended to 23 responder babies (titre of anti-HBsAg > 50 mIU ml-1), vaccinated with the same trial as the poor responders. The HLA frequencies observed in this group were comparable to those of control population and, with respect to the HLA markers cited above, absolutely different from the non/hyporesponder infants. From the HLA class II sequence analysis in the group of poor-responder babies some characteristics, peculiar to autoimmune diseases, have been observed: the majority of the infants showed at least an arginine at the 52 residue of the alpha chain of DQ molecule and a non-aspartic acid at the 57 position of the DQ beta chain.(ABSTRACT TRUNCATED AT 250 WORDS)

Alleles↗
PubMed1986

Determination of anaphylatoxin concentrations in suction blisters in patients with psoriasis.

Concentrations of C3a and C4a anaphylatoxins in suction blister fluids were determined by radioimmunoassay in patients with psoriasis and normal controls. Comparison of anaphylatoxin levels between serum samples and blister contents in the same subjects revealed that the levels of both C3a and C4a anaphylatoxins were significantly higher in the former than the latter even in those raised on normal skin, suggesting that the classic complement pathway is activated during suction procedure. Therefore we cannot regard suction blister fluid to be simply representative of undisturbed interstitial tissue fluid as far as the complement system is concerned. There was no difference in anaphylatoxin levels between those from uninvolved skin of psoriatic patients and those from normal controls. However, significantly high anaphylatoxin levels were noted in fluids of suction blisters raised on lesional skin as compared with those produced on uninvolved skin in psoriatic patients.

Adolescent↗
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↗
PubMed1987

Activation of the complement system by recombinant tissue plasminogen activator.

Recent trials have shown that recombinant tissue plasminogen activator (rt-PA) is an effective thrombolytic agent in patients with acute myocardial infarction. Because rt-PA converts plasminogen to plasmin, which is known to activate complement in vitro, we tested the hypothesis that rt-PA can induce in vivo activation of complement. Studies were performed in 12 patients with acute myocardial infarction. Six control patients had patent coronary arteries and did not receive rt-PA; these patients had normal values of the components of the complement system C4a (409 +/- 111 ng/ml) and C5a (8.8 +/- 1.8 ng/ml) with a slight elevation of C3a (204 +/- 6.6 ng/ml) in samples collected before coronary arteriography (253 +/- 25 minutes after onset of pain). After coronary arteriography, there was a slight decrease in the values of C4a (224 +/- 37 ng/ml), C5a (7.3 +/- 1.3 ng/ml) and C3a (164 +/- 35 ng/ml). The remaining six patients had complete coronary occlusion and received rt-PA (80 to 150 mg intravenously). In this treated group, before coronary arteriography the values of C4a (406 +/- 51.6 ng/ml) and C5a (8.1 +/- 1.9 ng/ml) were normal, and those of C3a were slightly elevated (250 +/- 76 ng/ml). All complement values obtained before rt-PA were similar to those in the untreated group. However, after administration of rt-PA (but before any angiographically detectable reperfusion), there was a striking increase in C4a (2,265 +/- 480 ng/ml; p less than 0.01), C3a (600 +/- 89 ng/ml; p less than 0.05) and C5a (30.0 +/- 4.5 ng/ml; p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1991

Immunoblotting human C4 bound to human erythrocytes in vivo and in vitro.

A study of C4 bound to human erythrocytes in vitro and in vivo has been made by immunoblotting with mouse monoclonal anti-C4c and anti-C4d and human polyclonal anti-C4d (Rodgers and Chido) following SDS-PAGE. Multi-banded patterns differentiated between C4A and C4B isotypes. Treatment of EC4b with trypsin eliminated immunoblotting but not agglutination reactions. Serum inactivation (factor I) of EC4b resulted in banding patterns similar to those obtained from patients' EC4d. Treatment of EC4b membranes with NH2OH affected many of the bands, two were lost, one was markedly reduced and others had altered SDS-PAGE mobility. Interpretation of the bands has been made in terms of C4-acceptor complexes and inactivation fragments of C4. A distinct difference in the banding of C4A and C4B isotypes has been detected.

Ammonium Hydroxide↗