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PubMed1987

The complement system in type 1 (insulin-dependent) diabetes.

The complement proteins C1q, r, s, C2, C4, C3, factor B, C5, C6, and the inhibitors, C1 inhibitors, factors I and H were measured in 35 patients with recently diagnosed Type 1 (insulin-dependent) diabetes, 76 patients with longer-duration disease (30 with complications) and 43 first-degree healthy relatives. We found that C1q, C4 and C3 were reduced significantly in all groups of patients (p less than 0.001 for each protein in recent onset and uncomplicated patients; p less than 0.01, p less than 0.01 and p less than 0.05 respectively, for patients with complications) compared to 60 control subjects and that C4 was also reduced in healthy relatives (p less than 0.001). C4 allotypes were examined in 63 subjects (selected from the patient groups) in order to clarify the role of null alleles in the production of the C4 abnormality. These showed serum C4 to be reduced significantly in 50 patients without null alleles (patient mean 0.24 g/l; control subject mean 0.34 g/l) (p less than 0.0001), although levels were lowest in the 13 patients with one or more null alleles (mean 0.19 g/l). Finally, to examine the metabolic basis for the low concentrations of C4 and C3, the turnover of highly-purified, radiolabelled C4 and C3 was measured in seven recently diagnosed patients; four of these had low levels of C4. The data showed that three out of four of these patients had reduced synthesis of C3 and C4 and normal values for fractional catabolic rate. Two patients showed features of C4 hypercatabolism. We conclude that several early complement proteins are reduced in Type 1 diabetes, irrespective of duration or complications.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed2005

Human macrophages simultaneously express membrane-C1q and Fc-receptors for IgG.

Membrane C1q (mC1q) of macrophages (MPhi) is a precursor of the IgG-binding serum protein C1q. Thus, mC1q potentially provides one of several Fcgamma binding sites of mature MPhi and we analyzed whether simultaneous expression occurs of established receptors for IgG, FcgammaRI, II, and III, and mC1q during in vitro differentiation of MPhi. Using flow cytometry, immunoprecipitation combined with Western blotting and Northern blot analysis mC1q was hardly detected in freshly isolated blood monocytes, but increasingly in developing monocyte-derived MPhi. Laser scanning fluorescence microscopy confirmed the membrane localization of mC1q. Two-color-staining flow cytometry experiments indicated that mC1q and all three types of FcgammaRs are simultaneously expressed on mature monocyte-derived MPhi. A high correlation was found for the expression of mC1q and FcgammaRs, in particular FcgammaRII, but not mC1q and CD14, another marker of monocytes/MPhi.

Cell Differentiation↗

PubMed1982

Circulating immune complexes in idiopathic glomerular disease.

Circulating immune complexes (CIC) could be found in the majority of 271 sera from 131 patients with idiopathic minimal change, membranous and mesangial proliferative glomerulonephritis when a combination of CIC assays detecting different properties of CIC were used. In neither individual patients nor in any of the three groups as a whole did CIC levels reflect the state of the renal lesion. No correlation was found between the class of immunoglobulin in the CIC and that deposited in the kidney. With the exception of minimal change disease in which non-C1q binding IgG CIC predominated, a range of CIC was found in the patients examined. The pattern of CIC detected did not allow different forms of renal disease to be distinguished. IgA CIC could be found in mesangial proliferative glomerulonephritis both with and without IgA deposition and in some patients with membranous and minimal change disease, as well as in a high proportion of sera from 12 patients with the Henoch-Schönlein syndrome. CIC size was estimated in six patients, but only in one did a specific size of complex predominate. The CIC which may be found in the majority of sera from patients with idiopathic glomerulonepohritis provide little information of clinical value; no direct relationship can be demonstrated between the CIC found and the renal lesion.

Antigen-Antibody Complex↗

PubMed1983

Circulating immune complexes in sera of patients infected with Echinococcus granulosus.

Circulating immune complexes (CIC) were investigated by the C1q binding assay in sera of 23 patients infected with Echinococcus granulosus. For the 23 sera studied, nine were found to be positive in the test. When the samples were grouped according to the cyst localization, the highest rate of CIC positively was found in the group of sera from patients with pulmonary cyst; in this group, double diffusion (DD) and indirect haemagglutination (IHA) tests gave a low rate of positivity for antibodies directed against parasitic antigens. Rheumatoid factor, anti-nuclear and anti-mitochondrial autoantibodies were not detectable in patients' sera by indirect immunofluorescence technique (IIF). Anti-smooth muscle autoantibodies, detectable by IIF, were present in 56% of the sera and this positivity was higher in the hepatic (83%) than in the pulmonary form (40%).

Antibodies, Antinuclear↗

PubMed1993

Predictive value of IgG autoantibodies against C1q for nephritis in systemic lupus erythematosus.

OBJECTIVES: Antibodies against C1q (C1qAb) have been demonstrated in the serum of patients with several immune complex diseases. Patients, particularly those with lupus nephritis, were found to have increased serum titres of IgG C1qAb in a cross-sectional analysis. In the present prospective study correlations were sought between serum titres of IgG C1qAb and clinical as well as laboratory parameters of disease activity in patients with systemic lupus erythematosus (SLE). METHODS: Titres of IgG C1qAb in the serum of 68 SLE patients were measured serially during a three year period. At the same time clinical and laboratory parameters of disease activity were assessed. RESULTS: Increased titres of IgG C1qAb were found in the serum of 56% of SLE patients during the study. Significant correlations were found between increased titres of IgG C1qAb and renal involvement. Clinical signs of renal involvement were found to be associated with significant increases of serum titres of IgG C1qAb in the six months preceding this appearance. Fifty per cent of the increases in serum titres of IgG C1qAb were followed by the development of renal involvement. Elevated serum titres of IgG C1qAb were especially related to proliferative forms of glomerulonephritis. Furthermore, significant correlations were found between serum titres of IgG C1qAb and serum levels of immune complexes, levels of complement components, and titres of antibodies to DNA. CONCLUSIONS: The results suggest that IgG C1qAb play a pathogenic role in the development of lupus nephritis and that serial measurement of serum titres of IgG C1qAb is useful in the management of SLE patients.

Adolescent↗

PubMed2006

Identification of chromosome intervals from 129 and C57BL/6 mouse strains linked to the development of systemic lupus erythematosus.

Systemic lupus erythematosus is an autoimmune disease in which complex interactions between genes and environmental factors determine the disease phenotype. We have shown that genes from the non-autoimmune strains 129 and C57BL/6 (B6), commonly used for generating gene-targeted animals, can induce a lupus-like disease. Here, we conducted a genome-wide scan analysis of a cohort of (129 x B6)F2 C1q-deficient mice to identify loci outside the C1qa locus contributing to the autoimmune phenotype described in these mice. The results were then confirmed in a larger dataset obtained by combining the data from the C1q-deficient mice with data from previously reported wild-type mice. Both analyses showed that a 129-derived interval on distal chromosome 1 is strongly linked to autoantibody production. The B6 genome contributed to anti-nuclear autoantibody production with an interval on chromosome 3. Two regions were linked to glomerulonephritis: a 129 interval on proximal chromosome 7 and a B6 interval on chromosome 13. These findings demonstrate that interacting loci between 129 and B6 mice can cause the expression of an autoimmune phenotype in gene-targeted animals in the absence of any disrupted gene. They also indicate that some susceptibility genes can be inherited from the genome of non-autoimmune parental strains.

Animals↗

PubMed1991

[The development of a C1q-solid-phase immunoenzyme method for determining circulating immune complexes].

The method of quantitative enzyme immunoassay (EIA) for the determination of circulating immune complexes (CIC) was developed on the basis of solid-phase human C1q. The calibration curve was plotted with the use of aggregated human gamma-globulin (AHGG), the optimum range of concentration being 15-500 microg/ml. In the process of approbation on clinical material the method revealed an elevated level of CIC in the sera of patients in comparison with their level in the sera of healthy donors. Out of 40 studied serum samples from patients with Yersinia infection, in 3 serum samples the levels of CIC was 26, 65 and 94 microg of AHGG equivalents per ml. In 4 out of 46 studied serum samples obtained from patients with diagnosed Yersinia arthritis the level of CIC was 12, 27, 46 and 186 microg of AHGG per ml, and in serum samples from healthy donors this level was 8.6 microg/ml [corrected].

Antigen-Antibody Complex↗

PubMed1991

Low HIV-1 proviral DNA burden detected by negative polymerase chain reaction in seropositive individuals correlates with slower disease progression.

During 1989, 316 members of a cohort of homosexual men were tested for HIV-specific DNA by the polymerase chain reaction (PCR) using a pair of gag-region primers. Of 125 HIV-seronegative subjects, 123 (98.4%) were PCR-negative while 158 (82.7%) of 191 HIV-seropositive subjects were PCR-positive. Fewer of the 33 subjects who were seropositive and PCR-negative were at Centers for Disease Control (CDC) stage IV than the seropositive, PCR-positive subjects (6 versus 25%; P = 0.030). The seropositive, PCR-negative group had higher mean CD4 counts (640 versus 490 x 10(6) cells/l; P = 0.006), higher CD4: CD8 ratios (0.92 versus 0.64; P = 0.004), lower immunoglobulin (Ig) G levels (1290 versus 1645 mg/dl; P = 0.002), lower IgA levels (168 versus 251 mg/dl; P less than 0.001), and lower C1q binding activity (8 versus 14%; P = 0.010) than the seropositive, PCR-positive subjects. The median rate of CD4 cell decline in the 3 years preceding the PCR sample was less marked in the seropositive, PCR-negative group than the seropositive, PCR-positive group (-58 versus -77 x 10(6) cells/l per year; P = 0.028). To control for duration of infection, we restricted the analysis to the subgroups of 11 seropositive, PCR-negative subjects and 34 seropositive, PCR-positive subjects who had seroconverted earlier in the cohort study. Both subgroups had similar durations of infection, yet the same pattern of differences persisted.(ABSTRACT TRUNCATED AT 250 WORDS)

Acquired Immunodeficiency Syndrome↗

PubMed1975

The complement system in bullous pemphigoid. III. Fixation of C1q and C4 by pemphigoid antibody.

By in vitro complement immunofluorescent staining methods, 46 serum samples from bullous pemphigoid patients with titers of antibasement-membrane-zone antibodies of 320 or greater were tested for their ability to fix C1q, C4, and C3. All three staining reactions were positive with 23 of the samples; 21 samples yielded negative reactions. With one sample, the C1q and C3 staining reactions were positive but the C4 reaction was negative; one other sample gave a positive C3 staining reaction only. Absorption of anti-C1q, anti-C4, and anti-C3 with C1q, C4, and C3, respectively, blocked the specific in vitro complement staining. Therefore, bullous pemphigoid antibodies of the IgG type appear to be capable of activating the "classical" complement pathway.

Autoantibodies↗

PubMed2000

Interaction of C1q and mannan-binding lectin (MBL) with C1r, C1s, MBL-associated serine proteases 1 and 2, and the MBL-associated protein MAp19.

Mannan-binding lectin (MBL) and C1q activate the complement cascade via attached serine proteases. The proteases C1r and C1s were initially discovered in a complex with C1q, whereas the MBL-associated serine proteases 1 and 2 (MASP-1 and -2) were discovered in a complex with MBL. There is controversy as to whether MBL can utilize C1r and C1s or, inversely, whether C1q can utilize MASP-1 and 2. Serum deficient in C1r produced no complement activation in IgG-coated microwells, whereas activation was seen in mannan-coated microwells. In serum, C1r and C1s were found to be associated only with C1q, whereas MASP-1, MASP-2, and a third protein, MAp19 (19-kDa MBL-associated protein), were found to be associated only with MBL. The bulk of MASP-1 and MAp19 was found in association with each other and was not bound to MBL or MASP-2. The interactions of MASP-1, MASP-2, and MAp19 with MBL differ from those of C1r and C1s with C1q in that both high salt concentrations and calcium chelation (EDTA) are required to fully dissociate the MASPs or MAp19 from MBL. In the presence of calcium, most of the MASP-1, MASP-2, and MAp19 emerged on gel-permeation chromatography as large complexes that were not associated with MBL, whereas in the presence of EDTA most of these components formed smaller complexes. Over 95% of the total MASPs and MAp19 found in serum are not complexed with MBL.

Calcium↗

PubMed1986

Incidence of circulating immune complexes in patients with acute poststreptococcal glomerulonephritis and in patients with streptococcal impetigo.

In an attempt to further study the possible contribution of circulating immune complexes (CIC) in the pathogenesis of acute poststreptococcal glomerulonephritis, 61 patients with APSGN were studied during the first three weeks of the disease, and 13 patients with noncomplicated streptococcal impetigo as a control group. C1q solid phase ELISA and Conglutinin (K) solid phase ELISA were used to measure the levels of immune complexes. The incidence of CIC in a single serum sample from patients with APSGN was 48%. Elevated levels of immune complexes were found in 46% of the patients with streptococcal impetigo. The absolute levels of CIC were comparable in both groups of patients. No correlation was found among the presence of CIC and the clinical, immunoserological or pathological findings of the disease. Our results do not support the hypothesis that trapping of the circulating immune complexes play an important role on the renal injury poststreptococcal infection. Instead, we suggest that CIC are an epiphenomena present in APSGN, and may represent rather a systemic inflammatory immune response in patients with group A streptococcal infection.

Acute Disease↗

PubMed1982

Circulating immune complexes in Plasmodium knowlesi infected Kra, and merozoite vaccinated Rhesus monkeys.

The presence of circulating soluble immune complexes that bind the C1q component of complement has been determined in the sera of two monkey species showing different degrees of clinical immunity to Plasmodium knowlesi infection. Material binding C1q was found in the serum of both primarily infected Kra monkeys and post-vaccinated immune Rhesus monkeys following the onset of parasitaemia. The complexes then disappeared from the circulation of Kra monkeys despite continuing low-grade parasitaemia, but in Rhesus monkeys C1q binding material remained detectable for up to 3 weeks after apparent elimination of parasites. The ability of complexes to bind C1q was removed by reduction and alkylation and binding material was absorbed by staphylococcal protein A suggesting the presence of Ig. Further analysis of the binding material is required to fully establish its constitution and possible immunoregulatory function at different stages of infection in the two monkey species.

Animals↗

PubMed1993

Serologic determinants of survival in patients with head and neck cancer: validating a clinical prediction model.

Quantitative measurements of serum C1q-binding macromolecules (C1qBM) and immunoglobulin A (IgA) were done on 162 patients using previously described methodology. The measurements were compared to a previously described head and neck cancer population. Using the Cox Proportional Hazards model, the prognostic implications regarding high C1qBM and subsequent death with disease (P = .02), and regional recurrence (P = .0094) were validated, but not our previous IgA-related prognostic implications. When both study populations were combined, C1qBM was predictive of survival in those patients treated with induction chemotherapy (P = .0001). C1qBM was not a significant predictor of survival in patients treated with surgery plus postoperative radiation therapy in either this second "test" population or in the original "training" population. The findings demonstrate the confounding influence of treatment modalities and the importance of model validation.

Age Factors↗

PubMed1983

Detection of immune complexes in serum of dogs with neoplastic disease by solid-phase C1q binding, using an enzyme-linked immunosorbent assay.

A solid-phase C1q-binding assay for detection of serum immune complexes (IC) was modified for an enzyme-linked immunosorbent antibody method. The IC values were measured in sera from 25 clinically normal dogs and 74 dogs with histologically confirmed neoplastic disease. Serum IC values were expressed in micrograms of heat-aggregated canine immunoglobulin per milliliter that would produce equivalent binding under the same assay conditions. The IC concentrations in sera from normal dogs and dogs with neoplastic disease (mean +/- SD) were 98 +/- 45 and 701 +/- 1,409 micrograms of aggregated canine immunoglobulin G equivalents/ml, respectively. Concentrations in the clinically normal group appeared to be distributed normally and clustered around the middle range of IC values. Dogs with neoplasms had IC values with an irregular distribution, and in general, more dogs had high and low concentrations of IC compared with those in the clinically normal group.

Animals↗

PubMed1985

Assessment of circulating immune complexes by a solid-phase C1q-binding assay during the first hours and days after prolonged exercise.

A sensitive and specific solid-phase C1q-binding assay using porcine C1q and microtitre plates as a solid phase, served to assess the immune complexes in serum during the first hours and days after a 3-h running test. Fourteen moderately trained male subjects participated in the race and covered 36.3 +/- 3.7 (mean +/- SD) km in 3 h. Blood samples were drawn 1 day before, immediately before, immediately after, 1 and 3 h after and 1, 2 and 4 days after the race. When corrected for the changes of serum total protein, the apparent immune complex concentrations were 1 and 3 h after the race significantly higher (p less than 0.001 and p less than 0.05 respectively) than the pre-exercise values. Two days after the race the values were significantly lower (p less than 0.05) than before the race. These findings provide evidence for the formation of immune complexes after severe physical exercise.

Adult↗

PubMed1976

The kidney in progressive systemic sclerosis: immunohistochemical and antibody elution studies.

Immunologic studies were performed on 11 renal specimens from seven patients with progressive systemic sclerosis (PSS). Two patients had the chronic renal lesions of PSS and five had acute PSS renal disease. One of the latter patients underwent renal transplantation after developing acute renal failure with recurrence of lesions in the allograft. The lesions in the allograft were morphologically indistinguishable from the renal lesions of acute PSS. Immunofluorescence microscopy revealed vascular localization of IgM along with early and late acting complement components C1Q, C4, and C3 in all specimens including the allograft. Fibrinogen localization was observed in the vasculature of patients with the acute form of the disease. Antiglobulin, detected by fluorescein-labeled, heat-aggregated gamma-globulin, was also present in vascular lesions from two of the specimens; Eluates of four of the kidneys including the allograft contained antinuclear antibodies. In addition, antiglobulin activity was present in eluates from three of the four kidneys, The findings suggest that (1) renal vascular lesions in PSS may result from injury via immune complexes composed of nuclear antigens and antibody, (2) the predominance of IgM in the vascular lesions may reflect the presence of rheumatoid factor in the immune complexes, and (3) a similar pathogenetic mechanism may have resulted in allograft failure following renal transplantation of a patient with PSS.

Acute Kidney Injury↗

PubMed1994

Effect of altered CH2-associated carbohydrate structure on the functional properties and in vivo fate of chimeric mouse-human immunoglobulin G1.

Immunoglobulin G (IgG) molecules are glycosylated in CH2 at Asn297; the N-linked carbohydrates attached there have been shown to contribute to antibody (Ab) stability and various effector functions. The carbohydrate attached to the IgG constant region is a complex biantennary structure. Alterations in the structure of oligosaccharide have been associated with human diseases such as rheumatoid arthritis and osteoarthritis. To study the effects of altered carbohydrate structure on Ab effector function, we have used gene transfection techniques to produce mouse-human chimeric IgG1 Abs in the Chinese hamster ovary (CHO) cell line Lec 1, which is incapable of processing the high-mannose intermediate through the terminal glycosylation steps. We also produced IgG1 Abs in Pro-5, the wild-type CHO cell line that is the parent of Lec 1. The Pro-5-produced Ab (IgG1-Pro-5) was similar to IgG1-My 1, a myeloma-produced IgG1 Ab of the same specificity, in its biologic properties such as serum half-life, ability to effect complement-mediated cytolysis, and affinity for Fc gamma RI. Although the Lec 1-produced Ab, IgG1-Lec 1, was properly assembled and retained antigen specificity, it was incapable of complement-mediated hemolysis and was substantially deficient in complement consumption, C1q binding, and C1 activation. IgG1-Lec 1 also showed reduced but significant affinity for Fc gamma R1 receptors. The in vivo half-life of IgG1-Lec 1 was shorter than that of either the myeloma- or Pro-5-produced counterpart, with more being cleared during the alpha-phase and with more rapid clearance during the beta-phase. Clearance of IgG1-Lec 1 could be inhibited by the administration of yeast-derived mannan. Thus the uptake of IgG1-Lec 1 appears to be accelerated by the presence of terminally mannosylated oligosaccharide. Therefore, certain Ab functions as well as the in vivo fate of the protein are dramatically affected by altered carbohydrate structure. Expression of Igs in cell lines with defined glycosylation mutations is shown to be a useful technique for investigating the contribution of carbohydrate structure to Ab function.

Animals↗

PubMed1982

Clinical significance of the detection of circulating immune complexes in lupus nephritis.

32 patients (22 biopsed) with lupus nephritis (LN) were observed for circulating immune complexes (IC). Solid phase C1q (SPC1q) and polyethylene glycol (PEG) precipitation tests were used. The patients were studied during the clinical follow-up in different phases of disease activity. Comparative studies between each histological class of LN and corresponding forms of idiopathic glomerulonephritis (IGN) were made: no significant differences were found between either mesangial LN and stalk mesangial IGN, or between focal proliferative LN an focal proliferative IGN. However, a significant difference was found for SPC1q data between diffuse proliferative LN and mesangiocapillary IGN, and between membranous LN and membranous IGN. LN, with an acute nephritic syndrome and hypocomplementemia, displayed SPC1q data significantly above the levels of IC found in IGN with similar clinical features. IC serum data would seem an important element for the diagnosis and the clinical management of patients affected by LN.

Adolescent↗