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Results for “Complement C4a”

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PubMed1991

Lupus erythematosus profundus with partial C4 deficiency responding to thalidomide.

A female patient with disfiguring lupus erythematosus profundus (LEP) from the age of 13 years was found to have an isolated partial C4 deficiency, with reduced levels of both allotypes, C4A and C4B. A genetic basis for the hypocomplementaemia was confirmed by a family study of complement and HLA types which revealed heterozygous null alleles for C4A and C4B in the proband. Marked improvement in her cutaneous lesions occurred with thalidomide.

Adolescent↗

PubMed1986

Genetic markers in rheumatoid arthritis relationship to toxicity from D-penicillamine.

In a 3-centre study involving 144 patients with rheumatoid arthritis (RA), a relationship between side effects from D-penicillamine and HLA antigens, allotypic markers of the IgG heavy chain (Gm) and allotypes of complement components Bf, C4A and C4B was sought. There was a significant association between proteinuria induced by D-penicillamine and the antigens DR3 and B8. However, the presence of DR2 seemed to protect against the development of proteinuria. Thrombocytopenia from D-penicillamine was significantly associated with HLA-A1 and DR4; 15 of 23 patients who possessed both antigens developed thrombocytopenia (p less than 0.001 uncorrected, approximate relative risk (RR) = 5.5). A null complement allele located at the C4B locus (C4BQO) was also associated with thrombocytopenia from D-penicillamine (p less than 0.005, RR = 17.3). Our study confirms the findings from other series which indicate that there is a genetic predisposition for the development of proteinuria from D-penicillamine in RA and suggests that this may also be the case in D-penicillamine induced thrombocytopenia.

Arthritis, Rheumatoid↗

PubMed1989

[A study on complement activation in cardiopulmonary bypass--experimental and clinical evaluations].

Complement activation in patients undergoing cardiopulmonary bypass (CPB) was studied, with particular reference to anaphylatoxins. Complement levels were compared between a bubble oxygenator group (BOG) and a membrane oxygenator group (MOG). The influence of primed homologous blood on complement activation was also evaluated. C4a levels gradually increased during CPB in the BOG, whereas in the MOG they changed little. There was a marked initial rise of C4a levels in the BOG of high H/A (primed homologous vs. circulating autologous blood volume ratio). C3a levels increased more steeply in the BOG than in the MOG. In general C5a levels remained low in both groups, but were slightly higher in the BOG than in the MOG. Complement levels were determined in monkeys (Macaca fascicularis) undergoing continuous intraaortic infusion of 1) autologous blood extracorporeally bubbled with O2, 2) blood contacted with nylon, or 3) O2 microbubbles. The results indicated 1) elevation of C4a and C3a in the bubbled blood group, 2) elevation of C3a alone in the nylon group, and 3) no elevation of either anaphylatoxin. It was thus inferred that 1) during CPB, the complement might be rather dominantly activated via the classical pathway in the BOG, and via the alternative pathway in the MOG, 2) higher anaphylatoxin levels in the BOG than in the MOG might be related to mode and grade of blood trauma including plasma denaturation, and 3) the H/A ratio might be a factor able to modify complement activation.

Adolescent↗

PubMed1985

Immunogenicity of and immune response to the human platelet antigen Zwa is strongly associated with HLA-B8 and DR3.

In a prospective study the immunogenicity of the Zwa antigen during gestation was investigated. Twenty-six out of 1,211 pregnant women were Zwa negative (2.15%). In 2 out of 23 Zwa negative mothers who delivered Zwa positive children, an antibody to Zwa was detected. To determine the relationship between the immune response of pregnant women towards Zwa and the MHC, the phenotype frequencies of HLA-A, B, C, DR, and complement BF, C2, C4A, C4B allotypes of "non-responders" without detectable Zwa antibodies (N = 20) were compared with a group of "responders", i.e. Zwa negative mothers giving birth to Zwa positive children with typical neonatal alloimmune thrombocytopenia (NAIT; N = 39) and with a normal control population. When compared to the normal control group, "non-responders" showed a significant increase of the DRw6 frequency, whereas in the "responders" group HLA-A1, B8, DR3, and C4A*QO were significantly elevated. If "non-responders" and "responders" were directly compared, only B8 and DR3 remained significantly different. The strongest association with a hypothetical immune response gene appeared to exist with DR3.

Antigens, Human Platelet↗

PubMed2002

C4A deficiency and elevated level of immune complexes: the mechanism behind increased susceptibility to systemic lupus erythematosus.

OBJECTIVE: Studies of an Icelandic cohort showed that susceptibility to systemic lupus erythematosus (SLE) in individuals with C4A deficiency was increased only in the presence of increased concentrations of immune complexes. We investigated the interaction of C4A deficiency with elevated concentrations of immune complexes in healthy individuals; i.e., how different levels of C4A affected the activation of C4 and C3 and subsequent binding of increased immune complex load to human red blood cells (RBC). METHODS: Forty-five healthy individuals having different levels of C4A were studied, 8 with homozygous C4AQ0, 12 with heterozygous C4A deficiency, and 25 with normal C4A. For comparison to the complement status present after prolonged disease activity, 5 patients with SLE homozygous for C4AQ0 were also studied. RESULTS: The results showed that intact immune complex-RBC binding is dependent on the levels of immune complex-bound C3 fragments, which correlate to the levels of IC-bound C4Ad (R = 0.677, p = 0.02), but not on levels of IC-bound total C4d (R = 0.451, p = 0.16). Immune complex binding to RBC was also evaluated in increasing immune complex load. C4A deficient sera had less ability to bind the increased immune complex load to RBC than sera with normal C4A. These results are consistent with the presence of increased amounts of poorly opsonized immune complexes in C4A deficiency, leading to increased precipitation in tissues and initiation of a self-perpetuating cycle. CONCLUSION: Susceptibility to SLE is increased in individuals with C4A deficiency as C3 opsonization of immune complexes becomes insufficient at elevated immune complex concentrations.

Antigen-Antibody Complex↗

PubMedDate not supplied

Thrombolytic treatment and complement activation.

Details of possible complement activation in acute myocardial infarction (AMI) and the in vivo effects of fibrinolytic agents on this activation are not yet known. We measured complement activation in 40 patients with AMI: 20 were treated with streptokinase, and 20 did not receive any fibrinolytic agent. Anaphylatoxin C4a, C3a and membrane attack complexes SC5b-9 increased about 10-fold (p < 0.0001) during streptokinase infusion. There were no increases in complement catabolic products in AMI patients not treated with streptokinase. Significant transient leukopenia (-29.5%, 7.0 SEM, p = 0.001) and a drop in systolic pressure (-29%, 3.4 SEM, p < 0.0001) occurred after 15 min of streptokinase infusion simultaneously with the peak of anaphylatoxins in plasma.

Anaphylatoxins↗

PubMed1997

Genetic regulation of the impaired immune response to hepatitis-B vaccine associated with low TCR density in end stage renal disease patients: contribution of complement C4 and factor B alleles.

We have studied the relationship between T-cell receptor (TCR) density, genetic factors and the specific immune response in 153 end stage renal disease (ESRD) patients on haemodialysis immunised with HBsAg vaccine. One-hundred and nineteen patients raised a protective (> 10 U/ml) antibody response to hepatitis-B vaccination (responder, R), while 34 patients were found to be non-responders (NR). The density of the T-cell receptors was determined by flow cytometry. Proliferation of the T-cells induced by autologous monocytes presenting HBsAg was also measured and expressed as a stimulation index (SI). MHC class I, II and III alleles of the patients were also determined. The densities of TCR/CD3 receptors in NR patients were found to be significantly decreased as compared to the R patients (189 +/- 22 vs. 282 +/- 58 arbitrary units, P = 1.3 x 10(-7). TCR/CD3 receptor densities were found to be strongly associated (Spearman correlation coefficient: 0.84, P < 0.000001) with the SI values. Both parameters were found to be under dual genetic control: (a) very low density of the TCR/CD3 receptors and very low SI were found mainly in NR patients carrying HLA-A1, HLA-B8 and HLA-DR3 alleles; and (b) TCR/CD3 densities and function in R group were found to be significantly lower in carriers than in non-carriers of two MHC class III complement protein alleles: C4A*6, and Bf*F. Non-responsiveness to hepatitis-B vaccination was found to be associated with extremely increased neopterin levels. These findings indicate that both genetic and acquired factors contribute to the hepatitis-B vaccination failure in ESRD patients.

Alleles↗

PubMed1985

Complement and HLA. Further definition of high-risk haplotypes in insulin-dependent diabetes.

The families of 41 probands with type I (insulin-dependent) diabetes mellitus (IDDM) were typed for HLA-A, HLA-B, and HLA-DR antigens in addition to the complement polymorphisms C2, C4A, C4B, and Bf. All of these loci are encoded on the short arm of human chromosome 6 in a narrow region. Alleles at HLA-B (8, 15, 18, and 40), HLA-DR (3 and 4), and Bf (F1) have been associated with increased relative risk (RR) for IDDM, while HLA-B7 and HLA-DR2 have been associated with decreased RR for IDDM. This study confirms those significant risks in addition to confirming increased risk for the null (silent) allele for C4A (C4AQ0) and a rare C4B variant (C4B2.9). The significantly associated antigens (alleles) and risks were: HLA-B8 (RR = 3.1), HLA-DR3 (RR = 5.2), HLA-DR4 (RR = 4.3), and BfF1 (RR = 7.1), in addition to C4AQ0 (RR = 2.8) and C4B2.9 (RR = 12.6). Significantly low risk was associated only with HLA-DR2 (RR = 0.1). In a recent study, we defined five high-risk haplotypes that were determined solely by HLA-B, Bf, and HLA-DR (B8-BfS-DR3, B8-BfS-DR4, B15-BfS-DR4, B18-BfF1-DR3, and B40-BfS-DR4). By inclusion of information from the complement polymorphism, we have defined in greater detail three of these five high-risk haplotypes. One previously identified haplotype (B40-BfS-DR4) showed no complement clustering, while the rare high-risk haplotype (B8-BfS-DR4) was seen only once in this smaller sample.(ABSTRACT TRUNCATED AT 250 WORDS)

Alleles↗

PubMed1989

Determination of deletion sizes in the MHC-linked complement C4 and steroid 21-hydroxylase genes by pulsed-field gel electrophoresis.

In man, the genes encoding the complement component C4 (C4A, C4B) of the immune system and the steroid 21-hydroxylase enzyme (CYP21A, CYP21B) of adrenal steroid biosynthesis are located in the major histocompatibility complex (MHC). Frequent gene deletions and duplications have been described in the C4 and CYP21 genes, particularly in patients with autoimmune diseases and congenital adrenal hyperplasia. Here we report the determination of deletion sizes in 11 chromosomes with six different deletions. The deletions spanned the C4A+CYP21A, C4B+CYP21A, and C4B+CYP21B gene pairs as determined by standard Southern blot analysis. The deletion size fell within the range of 30-38 kb in all the chromosomes, as determined by pulsed-field gel electrophoresis. Because the deletion sizes in most other gene clusters are more heterogeneous, the results suggest the involvement of a specific mechanism in the generation of C4+CYP21 deletions.

Chromosome Deletion↗

PubMed1991

Quantitative and antigenic differences in complement component C4 between American blacks and whites.

A population of 98 healthy Black Americans was studied in order to determine normal ranges for total C4, C4A and C4B. Mean total C4 in Blacks measured by an enzymelinked immunoassay (EIA) was 44 +/- 12.8 mg/dl which was significantly different (p less than 0.001) from Caucasian levels of 31.7 +/- 11.5 mg/dl. The difference in total C4 was due to increased levels of C4B in Blacks (means = 24.4 mg/dl) as compared to Whites (means = 15.7 mg/dl; p less than 0.001). These results remained significantly different even when 8 samples having the C4A 91 phenotype were excluded. Since EIAs using monoclonal antibodies with Ch 1 specificity may yield false results, C4 allotyping is recommended when quantitating C4A and C4B levels in Blacks.

Alleles↗

PubMed1987

Comparison of complement activation by silicone intraocular lenses and polymethylmethacrylate intraocular lenses with polypropylene loops.

Silicone intraocular lenses are undergoing clinical investigation for use in the United States. We compared the ability of silicone intraocular lenses to activate the complement system in human sera with that of polymethylmethacrylate intraocular lenses with polypropylene loops using a radioimmunoassay that measures levels of activated complement fragments. Sera incubated with polymethylmethacrylate lenses with polypropylene loops had higher levels of C3a and C5a, but not C4a, than control sera incubated without intraocular lenses. On the other hand, there were no differences in levels of C3a, C4a, and C5a between sera incubated with silicone lenses and control sera. These results suggest that polymethylmethacrylate lenses with polypropylene loops activate the alternative pathway of complement, while silicone lenses do not.

Complement Activation↗

PubMed1992

C4B deficiency is not associated with meningitis or bacteremia with encapsulated bacteria.

The two isotypes of the fourth complement component are C4A and C4B. C4B forms ester bonds more efficiently than C4A and so, in theory, is more likely than C4A to bind to polysaccharide capsules of encapsulated bacteria. Two studies have reported homozygous C4B deficiency in patients with meningitis or bacteremia caused by encapsulated organisms. In the present study the association between C4B deficiency and these disorders was evaluated in four groups: patients with bacteremia, those with meningitis, those who developed Haemophilus influenzae type b (Hib) disease after Hib polysaccharide vaccination, and patients less than 1 year old with meningitis. Healthy adults served as controls. Of the 257 patients, 2.3% had homozygous C4B deficiency compared with 3.7% of 349 controls. According to these data, there is no increase in homozygous C4B deficiency among patients with bacteremia or meningitis caused by encapsulated bacteria.

Bacteremia↗

PubMed1986

Nonresponsiveness to hepatitis B vaccine in health care workers. Results of revaccination and genetic typings.

Twenty-eight health care workers who had a poor antibody response when initially vaccinated with hepatitis B vaccine were revaccinated with three additional 20-microgram doses. Eight of the twenty nonresponders, who had levels of antibody to hepatitis B surface antigen (anti-HBs) of less than 8 estimated radioimmunoassay (RIA) units, and all 8 of the hyporesponders, who had anti-HBs levels of 8 or 16 RIA units, attained anti-HBs levels of 36 RIA units or more after revaccination. Tests for HLA-A, B, C, and DR; for complement proteins C2, C4A, C4B, and BF; and for the erythrocyte enzyme glyoxalase I were done in 17 nonresponders and 3 hyporesponders. Nine (45%) had HLA-DR7 and 8 (40%) had HLA-DR3, compared with an expected rate of 23% in the general population. At least one of two extended haplotypes (B44, DR7, FC31 or B8, DR3, SCO1) were detected in 6 of the 9 who did not respond to revaccination, compared with 2 of 11 who responded to a second course of vaccine. Poor responders to vaccine may benefit from revaccination, and genetic factors may modulate the immune response to vaccination.

Adult↗

PubMed1991

Effects of high-dose aprotinin on blood loss, platelet function, fibrinolysis, complement, and renal function after cardiopulmonary bypass.

The use of aprotinin to reduce blood loss after cardiopulmonary bypass is under debate. Concern has been raised about the renal effects of aprotinin. We administered a mean aprotinin dose of 4.2 x 10(6) kallikrein-inhibiting units to 13 patients with coronary disease undergoing cardiopulmonary bypass for 74 +/- 5 minutes (mean +/- standard error of the mean); 13 comparable patients having cardiopulmonary bypass served as control subjects, and all were studied postoperatively for 24 hours. Aprotinin reduced postoperative blood loss by 50% (p = 0.0082). Two of the 13 patients who received aprotinin needed one red cell unit each versus a total of 18 units in eight of 13 control patients (p = 0.0096). Blood pressure, hemoglobin value and serum protein concentration were higher after operation in the aprotinin group (p less than 0.05 to p less than 0.01). Platelet counts did not differ, but plasma thromboxane was lower in aprotinin recipients (p less than 0.001). In control patients fibrinogen degradation products (D dimer) doubled, and alpha 2-antiplasmin activity was halved during and after cardiopulmonary bypass (p less than 0.01 to p less than 0.001), whereas aprotinin patients showed no changes. The complement breakdown products C4a, C3a, and C3dg as well as C9 neoantigen increased from prebypass baseline in both groups (p less than 0.001); the increment of C3a and C3dg was greater in the aprotinin than in the control patients (p less than 0.001). Serum electrolytes, osmolality, and creatinine remained normal in both groups of patients. Creatinine clearance was normal or above normal and virtually identical in both groups. Osmolar clearance and fractional sodium excretion were higher in the aprotinin group than in the control group shortly after cardiopulmonary bypass (p less than 0.05 to p less than 0.01); renal function was unremarkable the next morning. No adverse clinical effects attributable to aprotinin were seen. In summary, aprotinin offers advantages for cardiopulmonary bypass.

Antithrombin III↗

PubMed1987

Plasma anaphylatoxin concentrations in inflammatory skin diseases.

To study the possible involvement of the complement system in inflammatory skin disorders, we measured the concentrations of C3a and C4a anaphylatoxins in the peripheral blood of 148 patients with various inflammatory skin disorders and 48 healthy control subjects by radioimmunoassay. Significant increases in mean levels of both C3a and C4a anaphylatoxins were found in 59 patients with psoriasis. Remarkable increases in both C3a and C4a anaphylatoxins were also noted in some patients with leukocytoclastic vasculitis, urticarial vasculitis or unspecified toxic erythema. On the other hand, elevation of C4a alone was noted in a case of systemic lupus erythematosus. In contrast, using the mean of the normal control +/- 2 S.D., no significant anaphylatoxin elevation was found in 16 patients with pustulosis palmaris et plantaris, 7 with pityriasis rosea, 3 with erythema multiforme, and 3 with erythema nodosum or autoimmune bullous dermatoses.

Anaphylatoxins↗

PubMed1994

Immunogenetics of chronic liver diseases.

The genetic background of autoimmune diseases becomes more and more evident. Immunogenetics comprises the analysis of genes and their products located at the region 6p21 on the short arm of chromosome 6, which is also known as the major histocompatibility complex (MHC). MHC class I and II genes are highly polymorphic. The complement genes C2, C4A, C4B, and BF, which are also polymorphic, became known as MHC class III genes. In autoimmune hepatitis type 1, there is a dual association for white persons with either HLA-A1-B8-DR3 or HLA-DR4. In patients from Japan, autoimmune hepatitis type 1 is predominantly associated with HLA-DR4. This dual association is confirmed at the DNA level. Whereas only limited data are available for autoimmune hepatitis type 2, the association of primary biliary cirrhosis with HLA-DR8 is based on several studies. Primary sclerosing cholangitis is associated with HLA-B8-DR3 and -DR52a. This association was confirmed at the DNA level because of a significant increase of the DRB3*0101 allele. For DRB3*0101-negative individuals, a second association with DRB5*0101 (= DR2) was described. Further analysis of the hypervariable region of the HLA class II molecule indicates that lysine at position 71 is crucial for autoimmune hepatitis type 1 in white persons, whereas position 13 is important for people from Japan. In contrast, leucine at position 35 is important for patients with primary biliary cirrhosis, whereas leucine at position 38 is an important risk factor for primary sclerosing cholangitis. The MHC class III allele C4A-QO is significantly increased in autoimmune hepatitis type 1 and 2 and in primary biliary cirrhosis. Advances in immunogenetics will certainly increase our knowledge of the etiology and pathogenesis of immune-mediated liver diseases, which hopefully will lead to more specific therapeutic interventions.

Chronic Disease↗

PubMed2026

Estimating protein isoform abundances with [Formula: see text].

A single gene can encode multiple versions of a protein, dubbed isoforms, with varying functionality. Cellular control of isoform abundances is critical for multiple aspects of biology and is only partially regulated by transcript levels. While long-read sequencing facilitates transcript quantification, quantifying the resulting protein isoforms on a large scale is a major challenge, complicating biological interpretation of transcript alterations. Standard "bottom up" mass spectrometry can assess only short portions of isoforms called peptides, and these peptides often map onto more than one isoform. We introduce [Formula: see text] (Protein isoform Abundance Quantification), a Bayesian method that leverages multiomic information from the peptidome and transcriptome to provide accurate estimates of isoform abundance even when peptide mapping is ambiguous. [Formula: see text] offers several advantages over existing methods in a unified framework. It provides uncertainty quantification, integrates multiomic information for improved accuracy, and provides a rigorous framework for hypothesis testing. Extensive simulations show that [Formula: see text] consistently outperforms competing methods in detecting differentially abundant protein isoforms and estimating their abundances. We use [Formula: see text] to investigate differences in isoform abundance levels between people with schizophrenia and control subjects, confirming a long-held hypothesis that levels of the C4A isoform of Complement Component 4 are increased in schizophrenia while C4B is not. These results demonstrate that [Formula: see text] can identify significant variations in isoform abundance levels not previously possible.

Protein Isoforms↗

PubMed1992

Familial occurrence of primary glomerulonephritis: evidence for a role of genetic factors.

Chronic glomerulonephritis was diagnosed in 23 patients born in a small valley in Northern Italy and in five additional patients with one parent or a more remote ancestor born in the same area, all belonging to three potentially related families. Eighteen patients had biopsy-proven glomerulonephritis: 11 IgA nephropathy, 3 IgM nephropathy, 2 membranoproliferative type I, and 2 mesangial proliferative glomerulonephritis with isolated C3 deposits. Ten had clinical glomerulonephritis. A community screening programme discovered six additional related patients. Two underwent renal biopsy (1 IgA nephropathy; 1 focal glomerulosclerosis); four were diagnosed as having clinical glomerulonephritis. Genealogical investigation identified five deceased family members with diagnoses of chronic nephritis recorded on their death certificates. No environmental nephrotoxic factors were identified. Restriction fragment length polymorphism (RFLP) analysis of HLA-DR beta, HLA-DQ alpha and beta genes, and complement typing for C4A, C4B, and Bf polymorphisms were carried out for 29 patients, 168 healthy relatives, and 24 local controls. The frequency of HLA-Dw8.1 specificity, related to DR beta 8, DQ beta 3b, and DQ alpha 1a RFLPs, was significantly increased more in the affected and unaffected pedigree members than in Italian controls.

Adolescent↗