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PubMed1983

Role of human factor I and C3b receptor in the cleavage of surface-bound C3bi molecules.

Control of functions mediated by the third component of complement (C3) depends on the rate of generation and degradation of biologically active C3 fragments. To evaluate the mechanisms of degradation of active C3 fragments, the role of the control protein C3b/C4b inactivator (factor I) was investigated under conditions approximating those found in vivo, i.e. in the presence of plasma. The breakdown of human erythrocyte-bound C3bi molecules in serum or plasma was mediated only by factor I, since factor I-deficient or -depleted plasma was inactive until reconstituted with highly purified factor I. The rate of cleavage of C3bi bound to human erythrocytes by purified factor I was not affected by the presence or absence of beta 1H (factor H). The released breakdown product of C3bi has been shown to be C3c antigenically and on polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate. Two different monospecific antibodies to the human C3b receptor totally abrogated factor I-mediated cleavage of cell-bound C3bi, suggesting that the C3b receptor (but not factor H) is required as an obligate cofactor. The rate of this C3b receptor-dependent, factor I-mediated cleavage of bound C3bi is strongly regulated by the surface to which C3bi is bound. Whereas C3bi bound to particulate nonactivators of the alternative complement pathway such as human erythrocytes is rapidly degraded by this mechanism, the rate of cleavage of C3bi bound to activators is significantly slower. These data suggest a physiologic role of C3b receptors in the degradation of biologically active C3 fragments deposited on host tissues. They also suggest that C3bi molecules on restricted surfaces are relatively stable and can thereby interact with complement C3 receptors in vivo.

Animals↗
PubMed1998

Purification and characterization of a phagocytosis inducing factor: role in cell-substratum adherence.

The presence of two different signaling molecules is essential to induce opsonin-independent phagocytosis of particulate activators of the human alternative complement pathway by human monocytes. In addition to the involvement of a low M(r) peptide cytokine or phagocytosis inducing factor (PIF), we have now established that the participation of bacterial lipopolysaccharide is also required. PIF has been demonstrated to be present in human cell lines of different origins, e.g., WISH cells, Raji cells, U937 cells, HL-60 cells and M21 cells. PIF has been purified to apparent homogeneity from the U937 cell line by anion-exchange chromatography on DEAE-Sephacel followed by gel filtration chromatography on Sephadex G-50. On the basis of Tricine-sodium dodecyl sulfate-polyacrylamide gel electrophoresis, the apparent molecular mass has been estimated to be approximately 1,600 Da. PIF also plays an important role in the regulation of cell-substratum adherence.

Cell Adhesion↗
PubMed1993

Rheumatoid factor expression and complement activation in children congenitally infected with human immunodeficiency virus.

Rheumatic disease manifestations and autoimmune phenomena are common in adults infected with human immunodeficiency virus (HIV). On the other hand, rheumatic disease manifestations are rare in children congenitally infected with HIV. We studied the relationship between autoimmune phenomena and rheumatic diseases by examining HIV-infected children for the presence of rheumatoid factors (RFs), immune complexes, and complement activation fragments. RFs (principally IgA) were detected in 12 of the 24 HIV-infected patients (50%) and in none of the uninfected (HIV-exposed, seroreverted) controls (n = 22). Mean levels of complement activation fragments C3a and Bb were elevated in the HIV-infected children compared with the controls. A correlation was seen between the presence of IgA RF and alternative complement pathway activation as measured by plasma levels of Bb. None of the children had clinical or laboratory evidence of rheumatic disease.

Antigen-Antibody Complex↗
PubMed2001

Low vitamin E in diet reduces stress resistance of gilthead seabream (Sparus aurata) juveniles.

This study investigates the effect of dietary vitamin E on juveniles of gilthead seabream under stressful situations, focusing on the effects on growth, haematology, some immune parameters and plasma cortisol as indicators of stress. Two sardine meal-based experimental diets, one of them supplemented with 150 mg of alpha tocopherol kg(-1) of diet (control) and another one without vitamin E supplementation (diet NE), were assayed under two different stress conditions: overcrowding as a chronic stressor (during 15 weeks) and repetitive chasing as an acute repetitive stressor. Low levels of vitamin E in the diet depleted alternative complement pathway activity [from 167.23 U ml(-1) (control fish) down to 100.99 U ml(-1)] and also nonspecific haemagglutination. Also, fish fed a non-supplemented diet showed an elevation of plasma cortisol basal levels without a stressor influence [from 3.91 ng cortisol ml(-1) plasma (control fish) up to 21.70 ng cortisol ml(-1) plasma]. Low levels of vitamin E in the diet also produced an increase of erythrocyte fragility. Under chronic stress, fish fed the vitamin E-deficient diet showed a reduction in growth and survival, and alterations in haematological parameters, such as an additional haemoconcentration in response to overcrowding when compared with control fish. Under repetitive stress, fish fed the vitamin E deficient diet showed faster elevation of plasma cortisol levels in response to stress and a lower survival rate than control fish. Production of oxygen radicals by blood neutrophils was reduced under repetitive stress in fish fed the non-supplemented diet. These results suggest that fish fed the vitamin E-deficient diet had lower stress resistance.

Administration, Oral↗
PubMed1994

Endothelium-dependent microvascular responses to activated complement.

Infusion of Escherichia coli bacteria to cause high cardiac output bacteremia produces a differential microvascular response with constriction of large arterioles and dilation of small arterioles in skeletal muscle of rats. An important component to host-defense mechanisms during bacteremia is activation of the complement system. One part of this study explored the possibility that microvascular responses to bacteremia could be mediated by activation of the alternative complement cascade to alter skeletal muscle blood flow during sepsis. Complement activation by iv zymosan into unanesthetized (decerebrate) Sprague-Dawley rats caused constriction of large arterioles and dilation of small arterioles in cremaster muscle, while cardiac output stayed normal or was elevated. These microvascular responses mimic those during bacteremia, suggesting that components of the complement system mediate skeletal muscle microcirculatory responses to live E. coli sepsis. The vasodilation response of small arterioles in skeletal muscle during bacteremia is endothelium-dependent and is mediated at least partially by endothelial-derived relaxing factor (EDRF). Complement activation gives products which interact with endothelial cells. Thus, a second part of this study explored the role of EDRF in the vasodilation of skeletal muscle small arterioles during activation of the alternate complement pathway. Blockade of EDRF action by hydroquinone totally abolished small arteriole dilation and large arteriole constriction responses to complement activation by zymosan infusion.

Animals↗
PubMed1995

Iron mediates Trichomonas vaginalis resistance to complement lysis.

Trichomonas vaginalis, a sexually transmitted disease agent in humans, is readily lysed by activation of the alternative complement pathway. The parasite became resistant following growth in medium supplemented by iron compared to parasites grown in medium depleted of iron, which were readily killed by complement. The resistance to complement was dependent on iron concentration while divalent cations other than iron were ineffective, showing specific regulation of this property by iron. Lactoferrin, but not transferrin, rendered low-iron-parasites resistant to complement lysis, reinforcing the in vivo modulation by a known source of iron for this parasite. Pretreatment of high-iron, complement-resistant parasites with proteinase inhibitors resulted in lysis by complement, indicating that resistance was likely due to proteinase degradation of C3 on the trichomonal surface.

Animals↗
PubMed1990

Participation of C3 and its ligands in complement activation.

C3, the most abundant complement protein in blood, plays a central role in the activation sequence of the complement system as well as in host defense. Expression of the multiple functions of C3 requires its cleavage by highly specific enzymes termed C3 convertases. C3 in a conformationally altered form, C3H2O, resulting from the slow spontaneous hydrolysis of the internal thioester bond of native C3, initiates the assembly of a C3 convertase which continuously cleaves C3 in the blood at slow rates generating a constant supply of small amounts of C3b. When an activator of the alternative complement pathway is present, C3b becomes covalently attached to its surface via an ester or amide bond. Activator surface-bound C3b initiates the assembly of an "amplification" C3 convertase, C3bBb(P), which can efficiently activate C3 and generate additional convertase complexes on the surface of the activator. C3b generated by an amplification or classical pathway C3 convertase can also bind covalently to the noncatalytic subunit, C3b or C4b, respectively, resulting in the generation of a C5 convertase, an enzyme catalyzing the cleavage/activation of C5. In terms of participation in host defense, several fragments of C3, including C3a, C3b, iC3b, and C3dg, mediate a number of important functions such as increased vascular permeability, enhancement of phagocytosis, elimination of immune complexes, and perhaps also proliferative responses and/or differentiation of B cells.

Complement Activation↗
PubMed1988

Immunohistochemical study of the membrane attack complex of complement in IgA nephropathy.

The localization of the membrane attack complex of complement (MAC) was examined in the normal human kidneys and in biopsy specimens from patients with primary IgA nephropathy by immunofluorescent and immunoelectron microscopies. Immunofluorescent staining for MAC was significantly more intense than in the normal kidneys, and was observed in the mesangium and occasionally along the glomerular capillary walls of 22 of 30 patients with IgA nephropathy. By dual-staining, the MAC deposits were generally concordant with the deposits of IgA, C3, C5 and C9, or of IgG, when present. C1q or C4 was infrequently observed in the glomeruli. Immunoelectron microscopy revealed various staining patterns of glomerular MAC deposition; homogeneous fine-granular staining beneath the glomerular basement membrane (GBM) in the paramesangial zone, patchy staining within the mesangial electron dense deposits (EDD), and ring-shaped or ribbon-like staining, associated with the striated membrane structures (SMS), in the matrix of the mesangium, GBM and tubular basement membrane (TBM). This study suggests that the terminal complement system is activated, mainly by an alternative complement pathway mechanism, in the mesangium of IgA nephropathy, and is associated with the paramesangial lesion and EDD. MAC deposition in glomerular SMS may also result from in situ activation rather than trapping from the circulation. There was little correlation between glomerular MAC deposition and proteinuria or renal histology of patients with IgA nephropathy.

Complement Membrane Attack Complex↗
PubMed1988

Interaction of Alphaviruses with the serum complement system is a function of method of purification.

The interaction of Sindbis and Ross River viruses with the serum complement system in vitro was influenced by the type of density gradient used to purify them. Sindbis virus purified on sucrose gradients activated the alternate serum complement pathway while Ross River virus prepared in an identical manner had no effect on C3 turnover in non-immune serum. Both viruses purified on tartrate gradients inhibited the spontaneous cleavage of C3 in normal serum. At least some of this inhibition appeared to be due to the presence of tartrate adsorbed to the surface of virions.

Alphavirus↗
PubMed1995

Animal models for complement deficiencies.

The complement system plays a key role in host defense and in the development of autoimmunity. Three types of animal models of complement-mediated disease have traditionally been used: they involve normal animals, animals with spontaneously arising genetic deficiency, and animals treated with complement-inactivating agents. All of these approaches have had partial success in our attempts to understand complement mechanisms. Most animal models of genetic deficiency have been studied relatively little, as the availability of such animals is limited. C4, C2, and partial C3 deficiency in the guinea pig are well characterized, although only C4 deficiency in the guinea pig has been exclusively studied. C3 deficiency in the dog and C6 deficiency in the rabbit are well described, although studies are limited in number. C6 deficiency in the rat has been described recently and C5 deficiency in inbred mice strains has been studied fairly extensively. Factor H deficiency in the Yorkshire pig has also been described. Relatively few agents that inhibit complement are in use. Most widely used in animal studies is cobra venom factor. This inactivates the alternative complement pathway in the fluid phase and thereby depletes complement protein levels. The antigenicity of this protein, purified from the venom of cobras, limits its duration of use in most animal models. Complement-inhibiting agents are rare and, as yet, not widely used. We recently described the use of intravenous immune globulin for inhibiting complement in animal studies and present data on its use in animals, including discordant xenograft rejection, and its potential use in human disease. New developments in molecular biology provide the potential for a vast new array of deficiency models. A limited number of laboratories are actively engaged in the production of animals with inactivated genes. For example, gene knockout mice with no C3, and with no factor B, have been generated. Several complement control proteins have been prepared by genetic molecular biological techniques. Most promising among these is CR1, which limits complement damage in several animal models. Transgenic animals, which complement regulatory proteins expressed on their cells, have been prepared. As complement control proteins tend to be more efficient at regulating complement of the same species type as the regulatory protein, these animals may be useful in such areas as xenograft transplantation. The various animal models are reviewed and their potential application to understanding of human disease is emphasized.

Animals↗
PubMed1985

The early diagnosis of impending coagulopathies following surgery and multiple trauma.

Blood coagulation problems, either disseminated intravascular coagulation (DIC) or adult respiratory distress syndrome (ARDS) are frequent complications during the recovery of the polytraumatized surgical patient or accident victims. The key to their successful control lies in prompt recognition and aggressive treatment of the disease as soon as it appears. Unfortunately their onset is not usually well defined clinically and success in handling usually depends upon clinical expertise in recognising "high risk" situations coupled with measurements in the haematological laboratory of changes in plasma coagulation factors. It is suggested in this communication that a relatively simple examination of plasma complement profiles in the high risk, intensive care patient, may not only provide early warning of the onset of a coagulopathy but also distinguish the type. Simple tests are described, based on the assessment of plasma complement C5 levels, which have a high predictive value for the onset of ARDS, a disease with few early clinical manifestations and notably lacking in early changes in haematological parameters. In prospective trials complement tests correctly identified 18 patients who later developed ARDS but were no more effective than haematological tests in the identification of 24 patients who subsequently developed DIC.

Blood Protein Electrophoresis↗
PubMed2003

Intra- and interbacterial genetic exchange of Lyme disease spirochete erp genes generates sequence identity amidst diversity.

All isolates of the spirochete Borrelia burgdorferi contain multiple, different plasmids of the cp32 family, each of which contains a locus encoding Erp surface proteins. Many of these proteins are known to bind host complement regulatory factor H, enabling the bacteria to avoid killing by the alternative complement pathway during vertebrate infection. In the present study, we characterized the erp loci and cp32 plasmids of strains N40, Sh-2-82, and 297 and compared them to the previously determined cp32 sequences of type strain B31. Bacteria of strain N40 contain 6 different cp32s, those of Sh-2-82 contain 10, and 297 bacteria contain 9 cp32s. Significant conservation between all strains was noted for the cp32 loci responsible for plasmid maintenance, indicating close relationships that appear to correspond with incompatibility groups. In contrast, considerable diversity was found between erp gene sequences, both within individual bacteria and between different strains. However, examples of identities among erp loci were found, with strains Sh-2-82, 297, and B31 each containing three identical loci that likely arose through intrabacterial genetic rearrangements. These studies also found the first evidence of large-scale genetic exchanges between Lyme disease spirochetes in nature, including the apparent transfer of an entire cp32 plasmid between two different bacteria.

Amino Acid Sequence↗
PubMed1976

Circulating immune complexes and complement sequence activation in infectious mononucleosis.

The role of immune complex formation was investigated in a patient with infectious mononucleosis complicated by an urticarial rash. Circulating cryoprotein immune complexes were identified during the urticarial phase of the illness, and disappeared during recovery. These complexes were composed of immunoglobulins G (IgG), M (IgM) and A (IgA), complement components C3, C4 and C5, Epstein-Barr (EB) virus capsid antibody and particles resembling EB virus. The IgG subtypes identified in the immune complexes were the complement fixing IgG-1, IgG-2 and IgG-3. The C3 activator of the properdin complex was detected in serum obtained during that acute phase but not after recovery. Thus, the transient appearance of circulating complement-fixing immune complexes was associated in this patient with activation of both classic and alternate complement pathways. The findings suggest that these complexes may be involved in the rash associated with infectious mononucleosis.

Adult↗
PubMed1984

Infections in burn patients: a paradigm for cutaneous infection in the patient at risk.

The burn patient is in many ways the archetypical immunosuppressed host: the anatomic barriers have been breached and the host's defenses suppressed. Infection is the leading cause of death in hospitalized burn patients not having inhalation injury, being responsible for between 50 and 75 percent of the hospital deaths. Burn injury produces profound abnormalities in immunologic function. These changes are generally proportional to the degree of burn injury (surface area and depth). Cell-mediated immune function is suppressed. Anergy and depressed allograft rejection occur. Acute burn serum samples contain several factors that suppress cell-mediated immune functions. Antibody levels are usually mildly to moderately reduced. Complement, particularly the alternative complement pathway, may be massively activated and depleted, removing a critical defense mechanism against gram-negative rod infections for which preformed antibodies are absent. This depression is further exacerbated by malnutrition and infection. Fibronectin levels are also reduced. Phagocytic cell function is abnormal with burns. Neutrophil numbers may be depressed, and function is abnormal. Chemotactic responsiveness, cytoplasmic granule enzyme content, and oxygen radical generation are abnormal. Monocyte/macrophage dysfunction has similarly been demonstrated. Burn infections reflect abnormal host functions as well as changes in the hospital environment and microbial selection pressures. The burn patient is a model of cutaneous infection in the patient at risk.

Antibody Formation↗