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PubMed1976

HLA antigen studies in a family with C2 deficiency.

Two children in a family were found to be homozygous for C2 deficiency; both parents and a third child were heterozygous. C2 deficiency was associated with the HLA haplotypes carrying the antigens B18 and DW2. Antigen A10 was absent in this family. Mixed lymphocyte culture studies among the family members confirmed the association of C2 deficiency with the HLA-D locus.

Adult↗
PubMed1994

Prenatal diagnosis of heterozygous deficiency of the second component of complement.

Genetically determined C2 deficiency predisposes an individual to recurrent and invasive bacterial infections as well as a variety of rheumatic diseases. Most C2-deficient individuals carry the same 28-bp deletion in the sixth exon of the C2 gene. The present article reports the first prenatal analysis of a sibling of a C2-deficient patient; the sibling was found to be a heterozygous carrier of the 28-bp deletion of C2.

Adult↗
PubMedDate not supplied

[Role of the classical and alternative complement pathways in chemotaxis of human C2 deficiency (author's transl)].

The roles of the classical and alternative complement pathways in the formation of chemotactic factors were comparatively evaluated in a normal serum and a serum from a child with congenital C2 deficiency. Neutrophil chemotactic index was determined by a direct microscopic observation using serum activated by an immune complex for the classical pathway, and by zymosan A or liposaccharide of Salmonella enteritidis for the alternative pathway. Chemotactic activity was observed only when the C2-deficient serum was activited by the alternative pathway in the presence of zymosan A. But, in comparison to normal serum, the chemotactic activity of C2-deficient serum was impaired by dilution or short incubation time. Addition of purified C2 resulted in the normalisation of chemotactic activity induced by activation of classical and alternative pathways. These results suggest that integrity of the classical pathway of the complement is necessary for the optimal formation of the chemotactic mediators induced by the alternative complement pathway. The implications of the alternative complement pathway alteration with regard to susceptibility to bacterial infections, are discussed.

Antigen-Antibody Complex↗
PubMed1984

Interaction of Zn2+ with guinea-pig C5 convertase and guinea-pig C5.

A comparison of two methods of C5 activation, the standard method (EAC14 + C2, C3, C5, C6, and C7) and the washed-cell intermediate method (EAC1423 + C5 and washed), demonstrated that formation of hemolytically competent SAC14235 was reduced in the washed-cell method. Addition of Zn2+ in this method increased the formation of competent SAC14235 to the approximate level of the standard method. The optimum concn range of Zn2+ was 0.006-0.025 mM. In the standard method Zn2+ had no significant enhancing effect on the formation of competent SAC14235. Zn2+ had a greater affinity for EAC1423 than for fluid-phase C5 when reacted with each separately. Maximum enhancement, however, was obtained when Zn2+ was present during the reaction of C5 with EAC1423. The effect of Zn2+ on C5 activity was not related to the stabilizing property of C6 on cell-bound C5. In the washed-cell method there was an inverse relationship between the concn of C2 or C3 and the concn of C5 required to generate one competent SAC14235/cell. Over a 10-fold range of C2 or C3 concn there was an approximate four-fold increase in the number of competent SAC14235/cell formed in the presence of Zn2+. Zn2+ enhances formation of competent SAC14235 on cells that have a limited ability to activate C5 even though the C2 and C3 on the convertase are present in excess.

Animals↗
PubMed2003

Analysis of polymorphisms affecting immune complex handling in systemic lupus erythematosus.

OBJECTIVES: Systemic lupus erythematosus (SLE) is a polygenic disorder of dysregulated inflammation. Numerous specific candidate genes have been identified and most relate to the handling of immune complexes or antigen presentation. This is consistent with the classic finding of immune complex deposition in affected end organs. We wished to examine combinatorial effects of polymorphic variants of genes involved in immune complex clearance in susceptibility to lupus. METHODS: This study examined the occurrence of polymorphisms in genes which encode proteins known to be involved in immune complex handling and clearance. Each polymorphic variant of a complement protein (C2, mannose binding protein and C4), complement receptor (CR1) or Fc receptor (FcgammaRIIA and FcgammaRIIIA) gene is known to affect function adversely. One hundred and sixty SLE patients and 212 control subjects were genotyped using polymerase chain reaction methods. RESULTS: We found an increasing association of SLE with increasing numbers of gene defects. Combinations of severe defects in FcgammaRIIA and FcgammaRIIIA were particularly deleterious for both African American and Caucasian patients, even though only one defective variant was individually statistically significantly associated with SLE. CONCLUSIONS: The results of the study suggest that genes may interact in ways that either synergize or modify the effect of a single genetic effect and imply that association studies must be interpreted within the genetic background of the populations.

Antigen-Antibody Complex↗
PubMed1992

Hormonal profiles in Italian late-onset adrenal hyperplasia correlate with HLA class III polymorphisms.

To investigate the genetic polymorphisms of the HLA region in late-onset adrenal hyperplasia, 13 Italian patients affected by the disease were analyzed for: (1) HLA-A and -B typing; (2) restriction fragment length polymorphism (RFLP) of DR beta, DQ beta, DQ alpha, 21-hydroxylase A and B genes; (3) fourth complement fraction loci A and B (C4A and C4B), second complement fraction (C2) and properdin B factor (Bf) complement typing; (4) hormonal characteristics associated with some HLA haplotypes. HLA alleles B14 and DR beta 1 were found to be significantly more frequent in patients with respect to controls (relative risk: 8.7 and 7.2, p less than 0.001 and p less than 0.0001, respectively). Also C4B*2, 1 duplication was more frequent in patients than in normal subjects (23% vs. 1.5%, p less than 0.0001). Moreover, patients carrying a duplicated C4B (as well as those having the B14 antigen) showed higher 17-hydroxyprogesterone levels after ACTH stimulation. RFLP analysis of 21-hydroxylase genes with a specific probe revealed a duplication of 21-hydroxylase A gene in 40% of patients. All these individuals carried the C4A*2 B*2,1 phenotype and 75% of them displayed a clearly recognizable duplication at the C4B locus. These data support the hypothesis that in late-onset adrenal hyperplasia the 21-hydroxylase A pseudogene, even if inactive, may play a negative role in the regulation of 21-hydroxylase biosynthesis. Furthermore, we suggest analyzing class III phenotypes to screen the enzymatic defect.

17-alpha-Hydroxyprogesterone↗
PubMed1986

Hereditary deficiency of C2 in association with linear scleroderma 'en coup de sabre'.

A 32-year-old man suffering from linear frontoparietal scleroderma was found to have low (less than 10% normal) serum classical pathway activity although C1q, C3, C4, C5, and total alternative pathway activity was normal. Addition of purified C2 led to complete restoration of the total hemolytic activity of the classical pathway. The C2 hemolytic assays showed that the patient was not totally deficient in C2. He had about 30% of the normal C2 level. Studies on his available nucleus family members in the Netherlands also showed that the deficiency was inherited; one of the patient's brothers and one of his daughters had half of the normal C2 levels. The C2 deficiency could not be corrected by a three-week regimen of danazol. To the best of our knowledge, this is the first documented case concerning an association of linear frontoparietal scleroderma with C2 deficiency.

Adult↗
PubMed1990

Quantitation of C4 nephritic factor by an enzyme-linked immunosorbent assay.

We have developed an enzyme-linked immunosorbent assay (ELISA) for the quantitation of C4 nephritic factor (C4NeF). Incubation of the C4NeF-positive serum from patient M.I. with normal human serum (NHS) in the presence of human aggregated IgG (AHG) resulted in the formation of stable C4-C2 complex. No complex was formed in EDTA or under the condition free of AHG. The reaction mixture was filtered through an ACA 22 column, from which the C4-C2 complex was eluted at the first protein peak. When IgG purified from M.I. serum was incubated with NHS and AHG, C4-C2 complex also increased in proportion to dose of the purified M.I. IgG. These results show that C4NeF in M.I. serum stabilizes C4b2a convertase of the classical complement pathway, and is quantified by the ELISA. C4NeF activity was measured, using the ELISA method, in patients with various glomerular diseases, and found elevated in three of 24 patients with membranoproliferative glomerulonephritis (MPGN) type I and slightly but distinctly positive in seven of 24. No C4NeF was detected in two C3 nephritic factor-positive patients with MPGN type II and six with active systemic lupus erythematosus. The new method was more simple and quantitative than C4b2a stabilization assay for C4NeF.

Animals↗
PubMed1988

Synergism between gamma interferon and lipopolysaccharide for synthesis of factor B, but not C2, in human fibroblasts.

Four different human fibroblast cell lines synthesized C2 and factor B. Factor B synthesis was increased 12.1-fold by 50 ng/ml LPS and 7.1-fold by 100 U/ml IFN-gamma. C2 synthesis was increased only 2.1-fold by LPS, but 6.4-fold by IFN-gamma. Both LPS and IFN-gamma increased levels of factor B mRNA. LPS induced a 4.7-fold greater increase in factor B protein than in factor B mRNA, whereas IFN-gamma stimulated comparable increases in protein and mRNA. These data suggest that LPS acts to increase factor B synthesis at both pretranslational and translational sites, while IFN-gamma acts primarily at a pretranslational level. In contrast to factor B, increases in C2 protein and C2 mRNA were comparable for both stimuli. A synergistic effect between the two stimuli was observed for factor B only: protein synthesis was increased 54.5-fold or 2.8-fold greater than the additive effects of the stimuli separately. The rate of synthesis in the presence of LPS and IFN-gamma together could not be achieved by increasing concentrations of, or the times of incubation with, either stimulus separately. The synergism was not the result of an increased sensitivity of the cells to either stimulus and was not reproduced by preincubation with one stimulus before incubation with the other stimulus. Several lines of evidence suggest that the synergism, like the stimulation of factor B synthesis by LPS, was dependent on both translational and pretranslational regulation of factor B mRNA. C2 and factor B synthesized in human fibroblasts may play a role in host defense in inflammatory reactions before increases in vascular permeability and recruitment of other complement producing cells.

Cells, Cultured↗
PubMed1980

Hereditary angioneurotic edema: immunochemical 'activity' without clinical expression.

An 11-year-old white female with focal glomerulonephritis was found to have an absence of functional C1 esterase inhibitor. C1 esterase inhibitor measured by immunochemical means, however, was only slightly reduced. After an initial time period marked by variable hypocomplementemia, presumably due to immune complex formation associated with the nephritis, immunochemical signs of active and severe hereditary angioneurotic edema (HANE) developed. These have been unremitting for 3 1/2 years. Clinical signs of HANE, however, have never developed. Thus, during this time, there have been no clinical abnormalities despite the fact that free C1 esterase activity has been persistently present in this patient's serum and serum levels of functional C1 esterase inhibitor, C2 and C4 have been continuously less than 2% of normal. It appears, therefore, that this patient has an unusual form of HANE mainifested solely by the complement alterations seen during symptomatic attacks but without clinical expression of that serologic activity.

Angioedema↗
PubMed1981

On the significance of C2, C4, and factor B polymorphisms in disease.

In this review article, recent evidence is presented that some diseases like insulin-dependent diabetes mellitus, multiple sclerosis, and idiopathic membranous nephropathy, which are primarily associated with HLA-D,DR, are also related to the rare C2, C4, and Factor B alleles. Circumstantial evidence is available that at least some of these rare variants may be functionally deficient. Based on the concept of functionally interacting gene clusters, mutant complement genes may lead to impaired effector mechanisms in virus neutralization or lysis of virus-infected cells. Other mechanisms such as alteration of vascular permeability may be involved in the development of proliferative retinopathy and familial hypertension. In lepromatous lepra, an impaired cell-mediated lysis of M. leprae may be related to the hemolytically inactive C4F1 allelic product.

Arthritis, Rheumatoid↗