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PubMed1994

Decreased plasma concentrations of the C4B complement protein in autism.

OBJECTIVE: To determine complement C4 protein concentrations in the plasmas of autistic subjects and their family members. DESIGN: Cross-sectional study. SETTING: Center for Persons with Disabilities and the Department of Biology, Utah State University, Logan. PARTICIPANTS: Forty-two autistic subjects (34 males [81%] and eight females [19%]), 50 of their biologic parents, 21 siblings, and 105 normal subjects (56 females [53%] and 49 males [47%]; all white) living in northern Utah. INTERVENTIONS: None. METHODS: The enzyme-linked immunosorbent assay was used to determine C4 protein concentrations in autistic subjects. MAIN RESULTS: Plasma concentration (median, 14.7 g/L of the C4B protein) in autistic patients was significantly (P = .01) decreased compared with that of normal subjects (median, 22.4 g/L). The C4B concentrations in parents and siblings of autistic children were decreased, but not significantly. The C4A protein concentrations in the plasma of autistic subjects and their family members were normal. CONCLUSION: Decreased protein concentrations of C4B may be associated with autism.

Adolescent↗
PubMed2004

Genetic basis of tobacco smoking: strong association of a specific major histocompatibility complex haplotype on chromosome 6 with smoking behavior.

The genetic basis for addiction to tobacco smoking--particularly that of the perception of olfactory stimuli that may be important in reinforcing smoking addiction--is largely unknown. A cluster of genes for olfactory receptors is in close proximity to the MHC region on chromosome 6. Polymorphisms of MHC class III genes (RCCX modules, TNFA promoter polymorphisms) were determined in 101 healthy subjects and 232 coronary artery disease (CAD) patients from Hungary with defined tobacco smoking habits. A highly significant association between ever smoking (past + current smokers) and a specific MHC haplotype was observed (odds ratios = 2.14-4.13; P-values = 0.012 to <0.001). This haplotype is characterized by the presence of C4A null alleles and a solitary short C4B gene linked to the TNF2 allele of the promoter for TNFA gene. This haplotype occurred more frequently in the ever smokers than in the never smokers [odds ratio: 4.97 (1.96-12.62); P = 0.001], and such associations were stronger in women (odds ratio = 13.6) than in men (odds ratio = 2.79). An independent study of complement C4 protein polymorphism and smoking habits in Icelandic subjects (n = 351) yielded similar and confirmative results. Considering the documented link between olfactory stimuli and smoking in females, and the presence of a cluster of odorant receptor genes close to the MHC class I region, our findings implicate a potential role of the MHC-linked olfactory receptor genes in the initiation of smoking.

Adult↗
PubMed2005

Mannose-binding lectin in severe acute respiratory syndrome coronavirus infection.

Little is known about the innate immune response to severe acute respiratory syndrome (SARS) coronavirus (CoV) infection. Mannose-binding lectin (MBL), a key molecule in innate immunity, functions as an ante-antibody before the specific antibody response. Here, we describe a case-control study that included 569 patients with SARS and 1188 control subjects and used in vitro assays to investigate the role that MBL plays in SARS-CoV infection. The distribution of MBL gene polymorphisms was significantly different between patients with SARS and control subjects, with a higher frequency of haplotypes associated with low or deficient serum levels of MBL in patients with SARS than in control subjects. Serum levels of MBL were also significantly lower in patients with SARS than in control subjects. There was, however, no association between MBL genotypes, which are associated with low or deficient serum levels of MBL, and mortality related to SARS. MBL could bind SARS-CoV in a dose- and calcium-dependent and mannan-inhibitable fashion in vitro, suggesting that binding is through the carbohydrate recognition domains of MBL. Furthermore, deposition of complement C4 on SARS-CoV was enhanced by MBL. Inhibition of the infectivity of SARS-CoV by MBL in fetal rhesus kidney cells (FRhK-4) was also observed. These results suggest that MBL contributes to the first-line host defense against SARS-CoV and that MBL deficiency is a susceptibility factor for acquisition of SARS.

Adult↗
PubMed1981

Autolytic fragmentation of complement components C3 and C4 under denaturing conditions, a property shared with alpha 2-macroglobulin.

The alpha polypeptide chain of the complement protein C3 splits into two fragments of 74 000 and 46 000 apparent mol.wt. under certain conditions used to prepare the protein for SDS (sodium dodecyl sulphate)/polyacrylamide-gel electrophoresis. The cleavage reaction occurs over a wide range of temperatures and from pH 4.6 to 10.6 in the presence of denaturants such as urea, SDS and guanidine hydrochloride. It is also induced by heat-denaturation of C3 in the absence of chemical denaturants. The reaction occurs only with haemolytically active C3, and is not observed with hydroxylamine-inactivated C3 or with C3b. A similar cleavage of the alpha-chain of complement component C4 occurs under the same conditions, forming fragments of 53 000 and 41 000 apparent mol.wt. This reaction is again specific for haemolytically active C4, and does not occur with C4b or hydroxylamine-inactivated C4. The complement component C5, although structurally similar to C3 and C4, does not undergo a reaction of this type. The characteristics of the denaturation-induced cleavage of C3 and C4 match those described for the 'heat-induced' cleavage of alpha 2-macroglobulin [Harpel, Hayes & Hugli (1979) J. Biol. Chem. 254, 8669-8678]. Cleavage of alpha 2-macroglobulin is also specific for the active form of the protein, and does not occur with chemically inactivated or proteinase-cleaved forms. The unusual conditions and specificity of the peptide-bond cleavage in all three proteins suggest that it is an autolytic process rather than being the result of trace proteinase contamination. The active forms of C3, C4 and alpha 2-macroglobulin have the transient ability to form covalent bonds after activation. The autolytic cleavage reaction is likely to be related to the covalent-bond-forming reactions of these proteins.

Complement C3↗
PubMed1976

Factors contributing to intra-individual variation of serum constituents: Physiological day-to-day variation in concentrations of 10 specific proteins in sera of healthy subjects.

Using an automated immunoprecipitin method, we assayed human sera for 10 proteins: haptoglobin, orosomucoid, transferrin, alpha1 antitrypsin, alpha2-macroglobulin, IgG, IGa, IgM, complement C3, and complement C4. Blood from 14 healthy subjects (25-40y) was sampled on six separate days. From each venipuncture serum was divided into four eliquots; two were assayed on the day of venipuncture and two were frozen and kept until the end of the study, when all of the frozen samples were analyzed in one batch. With this experimental design, batch-to-batch analytical variation could be estimated, and we avoided confounding it with the biological variation. Data analysis was based on the analysis of variance technique. The average physiological intra-individual coefficient of variation ranged from 2.5% for transferrin to 11.1% for orosomucoid. THe interindividual variation ranged from 9.5% for transferrin to 70.5% for haptoglobin and the ratio between intra-individual variation and interindividual variation ranged from 0.66 for IgM to 0.26 for orosomucoid and transferrin.

Adult↗
PubMed2001

Improved method for the allelic definition of C4A and C4B polymorphism (HLA class III).

The polymorphism of the fourth component of human serum complement (C4) is well established at the proteinic level; at the DNA level in the analysis of C4A and C4B gene polymorphism, the PCR technique is not widely and routinely used because it is time consuming and still presents reproducibility problems. This is a serious problem because only PCR genotyping allows the establishment of Rodgers-Chido reverse antigenicity without the need for classical family segregation studies, whose samples are not always easy to obtain. The most commonly used protocol requires an initial PCR followed by nested amplification of all the products supposed positive or negative. The two reactions are set up using differing cycling conditions, primers, and magnesium chloride concentrations. We developed a simplified procedure to easily obtain reproducible results and used a single protocol for all reactions. Nested PCR is made using only the positive samples, so we decrease the number of samples to handle, the time spent for the work, and the reagents used for the reactions. Moreover, we increased the reproducibility of the experiments.

Alleles↗
PubMed1996

Restriction fragment length polymorphism analysis in the HLA class III genes of patients with diffuse panbronchiolitis.

Although diffuse panbronchiolitis (DPB) is known to be positively associated with certain major histocompatibility complex (MHC) class I antigens, e.g., HLA-B54 in Japanese patients, it is not clear whether the MHC genes predispose to the disease or are markers for other disease susceptibility gene(s). Because the HLA class III genes such as tumor necrosis factor (TNF) or the fourth component of complement (C4) are localized in the proximity of the HLA-B locus, one or more of these genes might be responsible for susceptibility to DPB. To analyze the role of HLA class III genes in DPB patients, we first evaluated the HLA-B54 association in 32 patients with DPB, and subsequently, studied the restriction fragment length polymorphism (RFLP) of the TNF-alpha and -beta (TNF-alpha/beta) genes as well as the C4A and B (C4A/B) genes in DPB patients and normal individuals. The HLA-B54 antigen was significantly more frequent in DPB patients than in normal individuals (40.3% vs 13.0%, p < 0.001), however, we did not detect a significant association between DPB and gene polymorphisms of either TNF-alpha/beta or C4A/B. Furthermore, there was no evidence of C4A gene deletion in patients with DPB. These results suggest that the HLA-B54 antigen itself might be directly involved in the pathogenesis of DPB.

Bronchiolitis↗
PubMed2004

Complement receptors and the shaping of the natural antibody repertoire.

Complement and complement receptors have been known for several decades to play important roles in immune effector mechanisms related to pathogen elimination and tissue inflammation. In addition, studies over the last 10 years have clearly demonstrated a key role for the complement C3d activation fragment receptor designated CR2 (complement receptor type 2) in the switched-isotype, high-affinity and memory humoral immune responses to T-dependent foreign antigens. More recent studies have extended those observations to include a key role for CR2 and C3d in the humoral immune response to T-independent foreign antigens. Conversely, as these studies have proceeded, a parallel series of analyses have linked defects in expression or function of complement C4 and other classical pathway activation pathway proteins, as well as CR2 and the closely related CR1, to the loss of self tolerance to nuclear antigens such as double-stranded DNA and chromatin in systemic lupus erythematosus. With regard to the topic of this issue, it is now becoming increasingly clear that CR2 also plays a major role in the development of the natural antibody repertoire. Specifically, in the absence of this receptor natural IgM and IgG develop in the naïve animal that demonstrate clearly altered recognition patterns for specific natural antibody targets. This repertoire change is important physiologically in at least one setting because these CR2-dependent natural antibodies are necessary for the recognition of ischemic self tissues. In addition, it is possible that certain of the phenotypes manifest by CR2-deficient mice may be strongly influenced not only by effects on later stages of B cell activation and maturation, as commonly thought, but also by alterations in the pre-existing pool of natural antibodies that are influenced by this receptor. This review will examine the evidence that has accumulated over the last few years supporting these hypotheses.

Animals↗
PubMed1979

Inhibition of in vitro synthesis of the second (C2) and fourth (C4) components of complement in guinea pig peritoneal macrophages by a soybean oil emulsion.

Recently a soybean oil emulsion (Intralipid) (IL) has been released in the United States for use as a parenteral nutrient. The study reported here was undertaken to determine the effect of ingestion of IL on the synthesis and secretion of the second (C2) and fourth (C4) components of complement by guinea pig peritoneal macrophages in vitro. Cells exposed to IL had extensive Oil Red 0-positive granular-appearing accumulations of neutral lipid within the cytoplasm. Control cells did not stain with Oil Red 0. Incubation of the cells with concentrations of IL from 2.3--37.5 mg/100 ml resulted in a significant decrease in the production of both C2 and C4, which could not be explained by variability between plates. The decrease in total C2 or C4 production by cells incubated with IL for 4 hr was similar to the decrease in production by cells incubated with IL for 48 hr. Several lines of evidence indicated that the decrease of C2 or C4 was the result of decreased synthesis of these proteins and not interference of IL with the detection of the proteins or their secretion from the cells. Exposure of the cells to IL at all concentrations caused reduction of the number of cells having pseudopodia and a rounding-up of the cells. IL did not affect the rate of detachment of the cells from the plates through the 48-hr incubation period or the ability of the cells to exclude trypan blue. Total protein synthesis and total lysozyme production by control and IL-treated cells was similar.

Animals↗
PubMed1984

Birdshot retinochoroidopathy.

Nine patients had birdshot retinochoroidopathy. Associated ophthalmologic findings included rhegmatogenous retinal detachment, rubeosis iridis, glaucoma, and a high incidence of disciform macular degeneration. Four patterns of birdshot spot distribution were noted on fundus examination. Immunologic studies showed a significantly elevated percentage of EA rosettes and an elevated C4 complement level. Electroretinograms showed b-wave amplitude reduction, with a disproportionate implicit time prolongation. The etiology of this syndrome remains unknown.

Adult↗
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↗
PubMed1988

Effects of cardiopulmonary bypass on pulmonary leukostasis and complement activation.

We measured white blood cell counts and complement component (C3a, C4a, and C5a) and prostacyclin levels, and studied lung biopsy specimens, in 16 patients undergoing cardiopulmonary bypass and compared them with four patients undergoing other pulmonary procedures. Bypass caused no significant elevation in peripheral venous white blood cell counts. Higher counts were present in the right atrium compared with the left atrium. Patients who underwent bypass had elevated complement component and prostacyclin concentrations before operation and these levels increased further during operation. Trapping of polymorphonuclear leukocytes occurred in pulmonary alveolar capillaries and venules after bypass. We conclude that bypass activates complement components primarily of the alternative pathway and leads to increased blood prostacyclin levels. These changes are accompanied by polymorphonuclear leukocyte accumulation in the lungs and may be important in initiation of the adult respiratory distress syndrome in these patients.

6-Ketoprostaglandin F1 alpha↗
PubMed1986

Regulation of complement protein biosynthesis in mononuclear phagocytes.

Proteins of the complement system (with the exception of the terminal components C6-9) are synthesized in mononuclear phagocytes. The extrahepatic macrophage is therefore an important local source of the complement proteins which may serve as a first-line host defence mechanism. Net synthesis and secretion of complement by these cells is a function of maturation of the mononuclear phagocytic series, the tissue from which the cells are isolated, and the state of macrophage activation. To define some of the mechanisms for regulation of complement gene expression in mononuclear phagocytes, the major histocompatibility complex class III genes and C3 have been investigated. These genes are expressed constitutively in hepatocytes and monocytes/macrophages. In the mononuclear phagocyte, interferon-gamma, at physiological concentrations, effects a dose- and time-dependent increase in factor B and C2 mRNA and a corresponding increase in factor B and C2 biosynthesis. This effect is specific inasmuch as the expression of other genes (e.g. C3) is decreased by interferon-gamma, and interferon-alpha and beta at concentrations one to two logs greater have only a minimal effect on C2 and factor B gene expression. Endotoxin acting directly on monocytes has qualitatively different effects on expression of the complement genes. These complex regulatory mechanisms are being investigated with the use of murine fibroblasts transfected with human DNA bearing the relevent complement genes.

Animals↗
PubMed1994

Autoimmune-thrombocytopenia and SLE in a patient with 5q-anomaly and deletion of the c-fms oncogene.

Autoimmune-thrombocytopenia was the striking feature in a patient with typical clinical symptoms of systemic lupus erythematosus (SLE), complement C4 deficiency, and positive lupus serology. However, myelodysplasia was found in the bone marrow and chromosome analysis revealed a deletion of the long arm of chromosome 5 (5q-anomaly), which was confirmed by a hemizygosity for the c-fms oncogene (CSF-1-receptor) on Southern blot. Autoimmune phenomena reported in conjunction with myelodysplastic syndromes (MDS), e.g., an elevation of antinuclear antibodies, are usually regarded as nonspecific. This case report suggests that SLE can occur in patients with MDS and that a concomitant autoimmune-thrombocytopenia may mask the typical signs of the 5q- syndrome.

Adult↗
PubMed1995

Biphasic response of complement to heparin: fluid-phase generation of neoantigens in human serum and in a reconstituted alternative pathway amplification cycle.

We describe a study of the effects of heparin on complement activation through the use of assays for fragment C4d, fragment Bb, and the S-C5b-9 complex (S-MAC). In sera from healthy volunteers, virtually no change was observed in C4d either as a function of time or of heparin concentration, whereas changes in Bb and S-MAC were biphasic. This observation was explored in greater detail in the heparin concentration range 0.001-5.0 u/ml (5 x 10(-3) to 25 micrograms/ml). For both Bb and S-MAC, a significant (P < 0.05) increase in production was noted in the heparin concentration range, 0.01-0.5 u/ml (5 x 10(-2) to 2.5 micrograms/ml). At higher heparin concentrations, Bb and S-MAC production decreased markedly (P < 0.05). We reconstituted the alternative pathway amplification cycle (C3, factor B, and factor D) and studied Bb generation. With reactants at concentrations one tenth those of normal serum, we observed a maximum generation of 13.2 micrograms/ml Bb. Control and heparin at 5 x 10(-4) micrograms/ml generated Bb concentrations of 6.8 and 6.1 micrograms/ml, respectively, for a 2-min incubation; at 5 x 10(-3) micrograms/ml heparin, Bb was increased to 9.8 micrograms/ml. Using isoelectric focusing to study anionic pI shifts in heparin-bound factors B and D, it was found that factor B bound heparin only at the highest heparin concentration studied, i.e., 50 micrograms/ml; factor D, however, bound heparin at a much lower concentration (0.05 micrograms/ml). We conclude that, at low concentrations, heparin activates complement due to potentiation of the alternative pathway amplification cycle in the fluid phase.

Adult↗
PubMed1989

The clinical significance of iC3b neoantigen expression in plasma from patients with systemic lupus erythematosus.

We studied the expression of an iC3b neoantigen (iC3b-NEO) in plasma from patients with systemic lupus erythematosus (SLE), by using a monoclonal antibody specific for iC3b/C3dg/C3d, to investigate the activation of the third component of complement in SLE. The plasma iC3b-NEO level in 40 untreated patients with active SLE was significantly higher than that in 36 normal subjects (mean +/- SD 31.5 +/- 13.9 micrograms/ml versus 12.3 +/- 3.3 micrograms/ml; P less than 0.001). The plasma iC3b-NEO level was highly correlated with clinical disease activity (tau = 0.62, P less than 0.0001), and it was the parameter most closely correlated with renal histologic activity in lupus nephritis (tau = 0.52, P less than 0.0001). Also, patients with diffuse proliferative lupus nephritis had the highest levels of plasma iC3b-NEO among all World Health Organization classes of lupus nephritis (P less than 0.01). We conclude that the plasma iC3b-NEO level is strongly associated with clinical disease activity and renal histologic activity in patients with SLE, and that plasma iC3b-NEO may be a sensitive and useful measure of complement activation in SLE.

Antibodies, Monoclonal↗
PubMed1979

Demonstration of beta 1H globulin together with C3 in the dermal-epidermal junction of patients with systemic lupus erythematosus.

Skin lesions and clinically normal skin from 10 patients with systemic lupus erythematosus (SLE) were examined by immunofluorescence for the presence of C3 and its control protein, beta 1H globulin. beta 1Hwas always found in association with deposited C3; in the instance where C3 deposits were not found beta 1H was also not found. Granular deposits of C3 and beta 1H were found in the dermal-epidermal junction (DEJ) in all of the 5 nonlesional skins studied. In the lesional skin, C3 was found in 4 of 5; in 2 of these 4, beta 1H was also found. As previously demonstrated for in vitro systems, beta 1H also binds in vivo to fragments of C3, presumably C3b, generated during activation of the complement system.

Adolescent↗