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At least 19 recordsLinked to original sources
PubMed1992

Human adipsin is identical to complement factor D and is expressed at high levels in adipose tissue.

A cDNA for human adipsin was isolated and shown to encode a protein sharing 98% amino acid sequence similarity with the protein sequence previously determined for purified natural human complement factor D. Like mouse adipsin, recombinant human adipsin displays the enzymatic activity of human complement factor D, cleaving complement factor B only when B is complexed with activated complement component C3. We conclude that human adipsin is equivalent to complement factor D and that adipsin is the homologue of factor D in rodents. Adipose tissue is a major site of synthesis of human adipsin/complement factor D mRNA, but unlike the case in rodents, human adipsin mRNA is also expressed in monocytes/macrophages. The data presented here, demonstrating the equivalence of human adipsin to complement factor D and its high level of expression in fat, suggest a previously unsuspected role for adipose tissue in immune system biology.

Adipose Tissue↗
PubMed1991

Purification of human complement factor D from the peritoneal fluid of patients on chronic ambulatory peritoneal dialysis.

We describe a simple procedure for the purification of human factor D from the peritoneal fluid (PF) of patients with end stage renal failure (ESRF) on chronic ambulatory peritoneal dialysis (CAPD). The main advantages of this method are: (1) a relative enrichment of factor D in PF versus plasma (factor D/total protein enriched 3.8-fold); thus, added to the elevated concentration of factor D in ESRF, the enrichment compared to normal human serum is approximately 50 fold. (2) This biological source of factor D is almost unlimited, since around 10 liters of PF are removed per day from each patient. The purification is performed in three simple steps-Bio Rex 70, Heparin Sepharose CL 6B and Mono S FPLC- and milligrams of highly purified factor D are obtained. Peritoneal fluid might be a valuable source for the purification of other low MW proteins which accumulate in renal failure.

Antibodies, Monoclonal↗
PubMed1991

[Factor D of complement: Uremic toxin?].

Factor D is an essential enzyme of the alternative pathway of complement. Its catabolism is mainly renal. The concentration of factor D increases with renal failure, and is approximately 10-fold higher in patients with end-stage renal disease. The accumulation of factor D is responsible for an enhancement of alternative pathway activation. Whether this excess of factor D has pathophysiological consequences remains to be determined, however, complement activation might participate in adverse effects during hemodialysis and in the progression of renal injury.

Complement Factor D↗
PubMed1991

Crystallization and preliminary X-ray investigation of factor D of human complement.

Human factor D, an essential enzyme of the alternative pathway of complement activation, has been crystallized. Crystals were grown by vapor diffusion using polyethylene glycol 6000 and NaCl as precipitants. The factor D crystals are triclinic and the space group is P1 with unit cell dimensions a = 40.8 A, b = 64.7 A, c = 40.3 A, alpha = 101.0 degrees, beta = 109.7 degrees, gamma = 74.3 degrees. The unit cell contains two molecules of factor D related by a non-crystallographic 2-fold axis. The crystals grow to dimensions of 0.8 mm x 0.5 mm x 0.2 mm within five days, are stable in the X-ray beam and diffract beyond 2.5 A.

Complement Factor D↗
PubMed1978

Mechanism of action of factor D of the alternative complement pathway.

Factor D (C3 proactivator convertase) of human serum has been shown to be absolutely necessary for alternative pathway function, for activation of the C3/C5 convertase of that pathway and not to be a subunit of this enzyme. Factor D was found to be present in human plasma in active form only, at a concentration of 2 microgram/ml, and not to be controlled by plasma protease inhibitors or by spontaneous decay. Unlike trypsin, factor D cleaves and activates factor B only when it is in Mg++-dependent complex with C3b, has no esterolytic activity, and is unable to cleave the B chain of insulin. The alleged functional and antigenic relationship of factor D to alpha-thrombin could not be verified. The results of this study led to the description of the mechanism of action of factor D in terms of the cryptic site hypothesis.

Complement Activating Enzymes↗
PubMed1991

Complement factor D-like activity of Porphyromonas gingivalis W83.

Porphyromonas gingivalis is a proteolytic gram-negative anaerobic bacterium that is frequently isolated from lesions of human periodontal disease. Previous studies have shown that P. gingivalis strain W83 inactivates C3 in pooled normal human serum (NHS) by a mechanism that is inhibitable by EDTA, yet it degrades purified complement proteins by a mechanism that is not EDTA-inhibitable. Furthermore, during complement activation, only a small number of C3 molecules accumulate on the surface of this organism unless the bacteria are treated with the protease inhibitor TLCK prior to complement activation. The hypothesis was tested that P. gingivalis W83 contains protease activity mimicking that of complement factor D, thus enabling it to activate C3 in serum without significant C3 accumulation on the cell surface. It was first noted that incubation of P. gingivalis W83 in absorbed human serum that was depleted of factor D resulted in C3 consumption that was reversed in the presence of the protease inhibitor TLCK. To directly demonstrate that factor B-dependent C3 consumption occurs in the absence of factor D, P. gingivalis W83 was incubated with purified C3 or a mixture of C3 and B. Although some proteolysis of C3 was noted, increased C3 consumption was noted in mixtures containing both C3 and B. This increment in C3 consumption was inhibited by both EDTA and TLCK. Furthermore, the addition of purified factor H to this mixture inhibited the increment in C3 consumption, indicating that a C3 convertase was probably formed.(ABSTRACT TRUNCATED AT 250 WORDS)

Chromatography, Gel↗
PubMed1991

Deterioration of immune complex solubilization activity of serum by increased concentration of factor D.

We investigated the effect of excess complement factor D on the immune complex solubilization activity (ICSA) of serum. First, we estimated the concentration of factor D, ICSA and the hemolytic activity via the classical complement pathway (CH50) in the sera of 16 healthy individuals and 36 patients on hemodialysis for end-stage renal failure. The serum concentration of factor D in these patients (mean +/- SD: 12.12 +/- 2.38 micrograms/ml) was significantly higher (p less than 0.001) than that in the healthy subjects (1.02 +/- 0.11 micrograms/ml). In this study, peroxidase and antiperoxidase rabbit IgG were used as immune precipitates for ICSA. The ICSA in patients (45.8 +/- 7.4 normal human serum %, NHS%) was significantly lower (p less than 0.001) than that in the healthy subjects (100.2 +/- 12.5 NHS%). There was no difference in CH50 between the sera of the patients (31.8 +/- 2.5) and that of the healthy group (32.4 +/- 2.6). Second, we determined that increasing amounts of purified factor D added to fresh serum resulted in a decrease in ICSA. This occurred in the serum of a healthy individual as well as in that of a patient. CH50 did not change regardless of the concentration of factor D used. There was an increase in C3 conversion in the sera to which purified factor D had been added, as observed by crossed immunoelectrophoresis. It is suggested that ICSA had deteriorated due to the excess of factor D, which had activated the alternative pathway of complement.

Antigen-Antibody Complex↗
PubMed1990

Quantitation of components of the alternative pathway of complement (APC) by enzyme-linked immunosorbent assays.

Sensitive enzyme-linked immunosorbent assays (ELISA) using monoclonal antibodies have been developed to specifically detect components of the alternative pathway of complement in human blood plasma. Normal values of the factor B split products Ba (1.01 +/- 0.30 micrograms/ml, mean +/- SD), Bb (0.65 +/- 0.23 micrograms/ml), of the C3-fragments C3b/iC3b/C3dg (17.9 +/- 5.7 micrograms/ml), native factor B (238 +/- 48 micrograms/ml), factor D (1.05 +/- 0.27 micrograms/ml), and factor H (702 +/- 292 micrograms/ml) were determined in the EDTA-plasma of healthy probands (n = 55). The simultaneous quantitation of the main cleavage products and of control proteins in the plasma samples permits precise analysis of the activation of the alternative pathway of complement in various disease states. In addition, we describe a method for the specific depletion of factor B prior to fragment-specific assays utilizing monoclonal antibodies conjugated to paramagnetic beads. The latter should permit the quantitation of other complement split products.

Animals↗
PubMed1990

Inherited complement deficiency states: implications for immunity and immunological disease.

The study of complement deficiency states and their influence on immune function has generated new insights and still provides a challenge to continued investigation. The association of classical pathway deficiencies (C1, C4, C2 or C3) with immunological diseases such as SLE and glomerulonephritis has contributed to current knowledge concerning complement-dependent immune complex handling and elimination. Susceptibility to systemic infection with encapsulated bacteria is encountered in most forms of inherited complement deficiency. Recurrent neisserial infection is the only clinical manifestation clearly associated with defects of the membranolytic sequence C5-C9, while deficiency of properdin, a component of the alternative activation pathway, appears to predispose to nonrecurrent meningococcal disease. Inherited complement deficiency is rare, but the perspective is widened by the more common occurence of acquired defects in immunological diseases, and the apparent requirement for efficient complement recruitment in host defense. Another aspect is the possibility that complement deficiency might alleviate or prevent inflammatory symptoms. Notably, complement deficiency has not been reported in classical rheumatoid arthritis. Considerations of this kind would be refuted or modified by findings of complement deficiency in single patients.

Animals↗
PubMed1992

Adipsin and an endogenous pathway of complement from adipose cells.

The alternative complement pathway is best known for its role in humoral suppression of infectious agents. We have previously shown that adipose cells synthesize adipsin, the mouse homolog of human complement factor D, and that the synthesis of this protein is reduced in several rodent models of obesity. We show here that adipose cells and adipose tissue also synthesize two other essential components of the alternative pathway of complement, factors C3 and B, and activate the proximal portion of this pathway. This activation occurs in the absence of infectious agents and without triggering the terminal, lytic part of this pathway. We demonstrate the production in vitro of several polypeptides characteristic of complement activation that are known to have potent biological activities, including the anaphylatoxin C3a. Cultured adipocytes require stimulation with cytokines to activate complement, while explanted adipose tissue has no such requirement. The adipose tissue from obese mice is deficient in this localized activation of the alternative pathway. These results indicate that complement activation occurs in a localized site, adipose tissue, in normal mice and is impaired in a state of metabolic dysfunction. This suggests a novel function for the proximal portion of this complement pathway related to adipose cell biology or energy balance.

3T3 Cells↗
PubMed1992

Serum levels of the soluble interleukin-2 receptor are dependent on the kidney function.

We have investigated the influence of kidney function on soluble interleukin-2 receptor (S-IL-2R) serum levels. S-IL-2R is a glycoprotein with a molecular weight of 45 kDa. The serum concentration of S-IL-2R was positively correlated to serum creatinine (r = 0.35) and complement factor D (r = 0.30), a low molecular weight protein, and the reciprocal value of S-IL-2R was negatively correlated to 51Cr-EDTA clearance (r = -0.35). When measuring S-IL-2R and factor D in a wide range of serum creatinine (140-1,380 mumol/l), a high positive correlation was found between factor D and serum creatinine. S-IL-2R and serum creatinine had r = 0.92 and r = 0.79, p = 0.0001, respectively. The correlation coefficient between factor D and S-IL-2R was 0.86. S-IL-2R is used as a marker for an increased activity of the immune system and in a variety of lymphoproliferative disorders. However, it is important to keep in mind that a reduced kidney function may contribute to the increased S-IL-2R levels seen in different immune diseases. Therefore, renal function should be taken into account in the interpretation of elevated plasma concentrations of S-IL-2R.

Complement Factor D↗
PubMed1990

Differentiation dependent biphasic regulation of adipsin gene expression by insulin and insulin-like growth factor-1 in 3T3-F442A adipocytes.

Adipsin is a serine protease with complement factor D activity that is synthesized by adipocytes and secreted into the blood stream. Expression of adipsin is deficient in models of genetic (ob/ob, db/db) and acquired (monosodium glutamate-lesioned) obesity, but the cellular mechanisms responsible for this deficiency are unknown. Because hyperinsulinemia is frequently associated with obesity, we evaluated the effects of this hormone and insulin-like growth factor 1 (IGF-1) on adipsin secretion and adipsin messenger RNA (mRNA) levels in 3T3-F442A adipocytes. In the present study, we report that in fully differentiated adipocytes (after 11 days post confluence), insulin exposure progressively decreases adipsin secretion by 40%, 67%, and 78% after 2, 4, and 6 days of treatment. The inhibition of adipsin secretion by insulin is the result of a corresponding decrease in adipsin mRNA and is specific since two other differentiation-dependent fat cell mRNAs encoding aP2 (a fatty acid binding protein) and glycerophosphate dehydrogenase (GPD), are unaffected. Insulin suppresses adipsin gene expression via high affinity insulin receptors, because physiological levels of insulin produce this effect, and dose-response curves for insulin stimulation of 2-deoxyglucose uptake and glucose utilization are similar to insulin's effect on adipsin. In contrast, insulin when present during days 1-8 post confluence (during differentiation) markedly increases adipsin secretion and adipsin mRNA levels. This stimulation is due to the ability of insulin to accelerate differentiation as evidenced by corresponding increases in aP2 and GPD mRNAs as well. Insulin and IGF-1 are equipotent in this effect, suggesting that both insulin and IGF-1 receptors can mediate this response. In summary, during the differentiation of 3T3-F442A adipocytes, insulin stimulates adipsin gene expression by accelerating differentiation. As the cells become mature adipocytes, they acquire some differentiation-dependent factor, which couples insulin receptor stimulation to inhibition of adipsin gene expression. This model should aid our search for the molecular links between insulin receptor stimulation and altered gene expression.

Adipose Tissue↗
PubMed1978

Initiation of the alternative pathway of complement: recognition of activators by bound C3b and assembly of the entire pathway from six isolated proteins.

An intact alternative pathway of complement activation was assembled from six isolated proteins present at their respective physiological concentrations (C3, 1200 microgram/ml: factor B, 200 microgram/ml; factor D, 2 microgram/ml; beta1H, 560 microgram/ml; C3b inactivator, 34 microgram/ml; and native properdin, 20 microgram/ml). Initiation of the pathway required the presence of five of these proteins not including properdin. The initial C3 convertase of the system was shown to be a fluid-phase rather than a surface-bound enzyme. The ability of the pathway to discriminate between activator and nonactivator was found to reside in the bound C3b molecule. When bound to the surface of an activator through its labile binding site, C3b interacts with surface structures of the activator through another site on the molecule. This interaction results in diminished beta1H binding to C3b and thereby allows the bound C3b molecule to escape control and participate in C3 convertase formation. Thus, initiation of the alternative pathway is a two-step process, the first being non-specific and the second being discriminatory.

Binding Sites↗
PubMed1992

Fluid-phase activation of the alternative pathway of complement by excess factor D in regularly dialyzed patients.

We examined the effect of excess factor D on the alternative pathway of complement (APC). First, we demonstrated that the production of C3a is accelerated in the fluid-phase with the addition of purified factor D. Analysis by sodium dodecylsulfate polyacrylamide gel electrophoresis under reducing conditions showed that the serum iC3b level was elevated when incubated with excess factor D. Secondly, we demonstrated, by measuring the C5a-des-Arg level, that the generation of C5a was promoted in the fluid-phase with the addition of purified factor D. We then studied whether activation of APC is elevated in the blood of patients on maintenance hemodialysis whose sera contained a high concentration of factor D. First, we detected, by fluorescence activated cell sorter analysis, greater amounts of C3d on erythrocytes from the patients (mean fluorescence intensity +/- SD: 7.7 +/- 1.7 arbitrary units) than those from healthy individuals (5.4 +/- 0.5 arbitrary units; p less than 0.001). Secondly, serum C3 level was significantly lower (p less than 0.001) in patients (mean +/- SD: 63.3 +/- 8.2 mg/dl) than in healthy individuals (84.8 +/- 9.5 mg/dl), whereas there was no difference in serum C4 level between patients (32.4 +/- 6.9 mg/dl) and healthy individuals (33.0 +/- 7.4 mg/dl). Serum C5 level was almost the same in patients (10.5 +/- 1.5 mg/dl) and in healthy individuals (11.2 +/- 1.3 mg/dl). These results provide supportive evidence of elevated APC activation in patients with high serum factor D.

Blood Circulation↗