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PubMed1987

The effect of vitamin C nutriture on complement component C1q concentrations in guinea pig plasma.

This study shows that guinea pigs fed 100 times the amount of vitamin C needed for growth and for prevention of scurvy have elevated levels of complement component C1q. C1q is a plasma protein rich in hydroxyproline, an amino acid whose biosynthesis requires ascorbate. C1q is essential for host defense against pathogens, both as a component of the classical complement pathway and as an opsonin in the phagocytosis process. We measured C1q in vitamin C-depleted guinea pigs that had been repleted for 4 wks with the following daily doses of ascorbate (mg/100 g body wt): 0.50 (suboptimal), 2.0 (adequate), 10 (ample) and 50 (tissue saturating). We measured C1q in three ways: indirectly by quantifying protein-bound hydroxyproline and directly by hemolytic assay and by immunodiffusion against anti-C1q. Regardless of the method, plasma C1q was 30-50% higher in animals fed tissue-saturating ascorbate than in those fed adequate or suboptimal amounts of the vitamin (p less than 0.05, one-way analysis of variance, least significant difference test). These data confirm and significantly extend earlier work that provided indirect evidence for a relationship between C1q and ascorbate nutriture in the guinea pig. They are consistent with a possible relationship between ascorbate nutriture and host defense.

Animals↗
PubMed1977

The C1q binding test for soluble immune complexes: clinical correlations obtained in patients with cancer.

Sera from 134 selected patients with various types of cancer were tested for soluble antigen-antibody complexes by the C1q binding method. Sera from 85 healthy blood bank donors served as normal controls. C1q binding activity (C1q BA) values above the 95th percentile for healthy subjects were found in 83% of sera from patients with neoplastic diseases. The incidence of abnormal C1q BA values among patients with malignant melanoma was 83%, with breast cancer 74%, with colon cancer 75%, with lung cancer 88%, with leukemia and lymphoma 85%, and with miscellaneous tumors 94%. High C1q BA values were found most frequently in sera of patients who had been diagnosed relatively recently (within 5 mo) and who had evident residual disease after surgical treatment. Recurrence or progression of tumor growth occurred significantly more frequently in lung cancer patients with high C1q BA. DNA was not detected in cancer patients' sera and treatment with DNase did not decrease in C1q BA. C1q BA in sera could not be explained by the presence of antiglobulin antibodies. Sucrose density gradient ultracentrifugation studies of the serum C1q BA in 4 cancer patients showed that the major binding activity was found between 19S and 7S.

Antibodies, Anti-Idiotypic↗
PubMed1983

Antigenic interspecies cross-reaction of subcomponent C1q of the first component of complement: evidence for its cross-reaction in both collagen-like and non-collagen-like regions.

Human, bovine, and mouse C1q, a subcomponent of the first complement component, were purified, and both globular (GF) and collagen-like fragments (CLF) were isolated from human and bovine C1q. Antisera were produced in rabbits with these C1q or fragments, and F(ab')2 of immunoglobulin G (IgG) was purified from the antisera in order to avoid the possible non-specific binding of C1q of these animals to the Fc portion of rabbit IgG. Immunodiffusion analyses and radioimmune inhibition tests with these F(ab')2 showed that the definitive antigenic cross-reactivity was among C1q molecules of these animals, and that the regions participating in interspecies cross-reactions were located in both GF and CLF of C1q. These results suggest that both the C-terminal non-collagenous globular and the N-terminal collagen-like domains of C1q molecules may have remained highly conserved during evolution.

Animals↗
PubMedDate not supplied

Clinical applications of complement measurements in rheumatic diseases.

There is now convincing evidence that the complement system is involved in the pathogenesis of at least some of the manifestations of human rheumatic diseases. Complement measurements in serum and/or pathologic fluids from patients with these disorders not only reflect this involvement but also may provide important clues regarding the activity and extent of the disease processes. Future studies should provide additional information concerning the usefulness of such measurements for predicting the outcome of specific therapeutic regimens, and perhaps also be the basis for the evolution of new and more rational forms of therapy.

Antigen-Antibody Reactions↗
PubMed1980

Profile of complement components in patients with severe burns.

Twelve adults hospitalized with extensive burns formed the basis of the present study. On admission, blisterfluid and serum were collected from each patient and subsequently serum only obtained on 3rd, 7th, 14th, 21st, and 28th day of hospital stay. Complement components C1q, C3, C4, and C5 were measured in these samples by single radial immunodiffusion technique. It was observed that immediately after the thermal trauma there was a sudden and profound fall in serum levels of the early and late complement components vis-à-vis their appearance in blisterfluid. However, their levels in the latter were significantly lower than in the former. The mean serum levels of these components gradually increased up to the 14th day after burns and thenceforth leveled off, although normal serum levels for C1q and C3 were never achieved. Three patients died between 6 and 24 days after trauma. Individual variations in the complement profile were observed and no correlation between the serum levels of complement components and prognosis of burned patients was seen.

Adolescent↗
PubMed1987

The immunosuppressive activity of C1q degradation peptides.

We have previously reported the existence and activity of a collagen-like, low molecular weight, suppressive peptide complex in patients with greater than 40% BSA burns. Since C1q participates in the inflammatory response and contains a collagen-like sequence, we have tested, in vitro, the putative generation and immunologic activity of C1q peptide fragments under physical conditions present in burned patients. Nanogram quantities of heat- and enzyme-generated fragments of C1q were shown to be suppressive in vitro to neutrophil chemotaxis, and the mixed lymphocyte response (MLR). The addition of lymphocytes pretreated with C1q fragments suppressed ongoing MLR, indicating the activation of suppressor cells by the peptides. Rabbit anti-C1q globulin was found to reduce the suppressive activity of the collagen-like suppressor which was isolated from human burn sera. Our results therefore suggest that C1q may be an early source of degradation peptides which have strong nonspecific immunosuppressive activity following thermal injuries.

Burns↗
PubMed1979

The effect of age on the character of immune complex disease: a comparison of the incidence and relative size of materials reactive with Clq in sera of patients with glomerulonephritis and cancer.

The impact of aging on the severity of chronic immune-complex glomerulonephritis was studied in 144 patients from whom diagnostic renal biopsies were obtained over a 3-year period. Glomerulonephritis was related to an antecedent streptococcal infection in nine of these patients. In 58, glomerulonephritis occurred in association with a systemic disease; 27 of these had lupus erythematosus. At the time of the renal biopsy, serum creatinines were more frequently abnormal in men over 40 years of age. Similarly, histological evidence of irreversible glomerular injury was more evident in men over 40. Histological indices of renal glomerular injury correlated with the presence of intense fluorescent antibody reactions specific for C3 and C4 and IgG in the glomeruli. High serum Clq binding activities (Clq BA), an indication of the presence of circulating immune complexes, also were found significantly more often in males over 40. High serum Clq BA correlated with renal functional and biopsy evidence of severe glomerulonephritis. The renal biopsies in 89 cases were tested with fluorescein-conjugated heat-aggregated IgG (FAIgG) to determine how many contained focal immunoglobulin deposits with antiglobulin activity. Antiglobulins were detected in glomeruli of 24 patients and were found significantly more often in biopsies which revealed histological evidence of severe and irreversible histological injury. Binding of FAIgG was not selectively associated with any sex or age groups. Thus, detection of circulating immune complex-like materials in sera and the presence of glomerular deposits with antiglobulin activity were both features associated with severe glomerular injury. Both correlated with the quantity of complement deposited in the glomeruli. But only serum Clq binding activity was age and sex related. Similarly, in cancer patients, abnormal Clq BA were found more frequently in sera of older men with cancer but not in age- and sex-matched controls. Examination of selected sera by sucrose density gradient ultracentrifugation revealed that the complexes from cancer patients were relatively small (less than 19S greater than 7S) whereas those in most nephritis patients were heterogeneous in size. Sera with relatively high Clq binding activity from patients with chronic glomerulonephritis tended to contain relatively greater quantities of Clq binding materials sedimenting more rapidly than 19S.

Adolescent↗
PubMed1981

Immune complexes, complement, and anti-DNA in exacerbations of systemic lupus erythematosus (SLE).

The usefulness of serological parameters in assessing clinical exacerbations of SLE was examined. Patients with active renal disease tend to have lower levels of CH50 and C3 and highest levels of immune complexes detected by C1qBA than those patients with extrarenal manifestations only. Patients with a combination of both active extrarenal and renal disease are more likely to demonstrate the lowest levels of CH50, C4, and C3. However, immune complex levels are not higher than levels detected in patients with only active nephritis. A normal C3 level argues against active nephritis. Low complement levels without appreciably elevated levels of C1qBA suggest that significant renal disease is unlikely. The serial measurements that best reflect evolving clinical activity and which may serve as markers of impending exacerbation are, in decreasing order of usefulness: C4, CH50, C1qBA, C4, C3 and ADA. However, a combination of CH50, C4, C3 and C1qBA appeared to be the most useful. Given various serologic changes, guidelines for following patients are offered.

Antibody-Dependent Cell Cytotoxicity↗
PubMed1987

Relationship between renal pathology and the size of circulating immune complexes in patients with systemic lupus erythematosus.

Sera from 35 patients with biopsy-proven diffuse proliferative (WHO class IV) or membranous (WHO class V) lupus nephritis were analyzed for the presence and size of circulating immune complexes. Elevations of the C1q solid-phase assay (C1qSP) for immune complexes were found in sera from all patients with diffuse proliferative nephritis, with a mean +/- 1 SEM of 166.8 +/- 42.0 micrograms/AHG-equivalents/ml serum, and in 71.4% of the patients with membranous nephritis (83.1 +/- 26.7, p = 0.06). Using the WHO criteria for subclasses of membranous lupus nephritis, we also designated renal biopsies as nonproliferative (WHO classes Va and Vb) or proliferative (WHO classes IV and Vc). Employing the latter groupings, we observed significant differences between C1qSP results of patients with nonproliferative (30.3 +/- 8.8) and proliferative (172.8 +/- 36.8, p less than 0.001) lupus nephritis. These data suggest that the presence of C1q-binding material in serum is pathophysiologically related to proliferative glomerular lesions, and that levels of C1qSP binding reflect renal lesions in SLE patients. Sucrose density gradient ultracentrifugation was performed on each serum, and gradient fractions analyzed for C1qSP-binding and total IgG, using techniques to minimize losses of immune complexes. The predominant peak of C1qSP activity sedimented with the 6.6S monomeric IgG. The 6.6S C1q-binding IgG was increased only in 1 of 10 patients with membranous lupus nephritis without proliferative changes, and was elevated in 16 of 25 patients with proliferative lesions (WHO classes IV and Vc). A significant negative correlation was found between the presence of this C1q-binding material and subepithelial electron-dense deposits, suggesting that the presence of this material contributed to the absence of subepithelial immune deposits. Large-molecular-weight C1qSP-binding material was also present, mainly in sera from patients with proliferative lesions. Furthermore, highly positive correlations were found between immune deposits in interstitial blood vessels and peritubular areas, and the concentrations of C1qSP-binding IgG and rapidly sedimenting IgG in density gradient analysis. Overall, these findings are consistent with the hypotheses that circulating immune complexes contribute to the pathogenesis of glomerulonephritis and interstitial nephritis in patients with SLE, and that 6.6S C1q-binding IgG plays a role in the proliferative lesions of lupus glomerulonephritis.

Antigen-Antibody Complex↗
PubMedDate not supplied

Underlying complement deficiency in patients with disseminated gonococcal infection.

The complement system was evaluated in 22 individuals with disseminated gonococcal infection. Three of the 22 patients exhibited a total serum complement activity that was greater than 2 SD below the normal mean. Of these three, one had a complete deficiency of C1r, a second patient had pre-existing systemic lupus erythematosus with low levels of C4, and the third had a C8 concentration that was 60% of normal. We conclude that the prevalence of inherited or acquired complement deficiency among patients with disseminated gonococcal infection exceeds that among the general population and is an important host factor predisposing to systemic infection with Neisseria gonorrhoeae.

Adolescent↗
PubMed1979

Action of complement in the lysis of mouse sarcoma cells sensitized with H-2 alloantibody.

A modified cytotoxicity assay was adapted from classical erythrocytolytic assays, in which complement components were added in sequence to antibody-sensitized cells. This assay was applied to a model system in which mouse sarcoma cells were sensitized with H-2 alloantibody. The stepwise presentation of complement components combined with the stabilization of C2 by iodine treatment considerably augmented the lytic efficiency of human complement. More generally, the techniques adopted for this study provide a new model for obtaining basic information about selective reaction steps concerned in lysis of nucleated cells by alloantibody and complement. Comparisons of the lysis of sheep erythrocytes by xenoantibody with the lysis of mouse sarcoma cells by H-2 alloantibody, in our assay system with oxidized or untreated human complement, disclosed a difference in the kinetics of C142 formation, manifest in a lag phase and a protracted tmax for the sarcoma cells. These data may suggest that multiple complement-mediated functional lesions are necessary for immune lysis of nucleated cells.

Animals↗
PubMed1980

The Croonian Lecture, 1980. The complex proteases of the complement system.

The assembly and activation of the early components of complement, after their interaction with antibody-antigen complexes, are described in terms of the structures of the different proteins taking part. C1q, a molecule of unique half collagen--half globular structure, binds to the second constant domain of the antibody molecules through its six globular heads. A tetrameric complex of C1r2-C1s2 binds to the collagenous tails and leads to formation of the serine-type proteases C1r and C1s. C1s activates C4, which forms a covalent bond between its alpha' chain and the Fab section of the antibody. C2 is also activated by C1s and associates with the bound C4 molecule to form C42, a labile protease that activates C3, but which loses activity as the C2 peptide chains dissociate from C4. C2, by analogy with factor B, the equivalent component of the alternative pathway of activation, appears to be a novel type of serine protease with a similar catalytic site but different activation mechanism to the serine proteases that have been described previously.

Amino Acid Sequence↗
PubMed1976

Complement and the clinician.

The estimation of complement in serum, and in other body fluids, particularly synovial fluid, now has an established place in the assessment, prognosis and response to treatment of those diseases associated with immunological phenomena. Some knowledge of the complement sequence itself, the patterns characteristic of various disease processes and the interacting factors which may affect the levels of the various components have been summarised. Disease states closely resembling lupus erythematosus have been associated with genetically determined deficiencies of classic pathway components and deficiencies of terminal sequence components may lead to severe recurrent infections.

Collagen Diseases↗
PubMed1988

New complement fixation test with peroxidase-labeled complement Clq for direct and quantitative determination of antibodies to herpes simplex virus.

An enzyme-labeled complement fixation (ELISA-CF) test for the direct and quantitative determination of complement fixing (CF) antibodies has been developed. This paper described the introduction of the ELISA-CF test that used peroxidase-labeled Clq component of complement to detect CF antibodies which had reacted with herpes simplex virus (HSV), as a virus model. Equal volumes of heat-inactivated serum and the peroxidase-labeled Clq (P*-Clq) were simultaneously added to wells of microplates which had been coated with HSV CF antigen or with cell control antigen. The enzymatic activities of P*-Clq bound to the immune complex were determined photometrically. The ELISA-CF test allows processing of serum specimens in a 3-hr operation, with procedural simplicity and increased specificity and sensitivity compared with the conventional CF test.

Antibodies, Viral↗
PubMed1976

Complement component profiles in urticaria, dermatitis herpetiformis, and alopecia areata.

Insignificant variation was noted in the mean levels of the complement components CIQ, C4, C2, C3, C5 and C3PA between various groups of sera from patients with urticaria, angio-oedema, dermatitis herpetiformis, alopecia areata, or hay fever. No deficiencies were found. Elevated C9 levels in chronic urticaria and angio-oedema reflected its nature as an acute phase protein. The assessment of C components in single or sequential serum samples revealed only marginal variations. Similar results were recorded for plasminogen the immunoglobulins, G, A and M. Some evidence is provided for the primary involvement of the kallikrein-kinin system in urticaria.

Alopecia Areata↗
PubMed1981

Hepatitis B surface antigen deposition in the blood vessel walls of urticarial lesions in acute hepatitis B.

Urticaria is known to occur in the pre-icteric phase of acute viral hepatitis. Often such urticaria is a symptom of a serum sickness-like syndrome which can be a prodrome of viral hepatis. Immune complexes are thought to be pathogenetic in this condition. In this paper we present two patients with a serum sickness-like syndrome, urticaria and hepatitis B. By immunofluorescence techniques Hepatitis B surface antigen, CIq and C3 could be demonstrated in the blood vessels of the superficial dermis. These findings are consistent with the immune complex hypothesis.

Adult↗