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PubMedDate not supplied

[Beta2 microglobulin, antibeta2 microglobulin activity and circulating immune complexes in rheumatoid arthritis. Serum and synovial study].

In this work, the authors found significantly raised serum Beta2m microglobulin values in a group of 120 cases of rheumatoid arthritis, without any difference between the serum positive group (55 cases) and the serum negative group (65 cases). Such a rise was found in the synovial fluids with a beta2 serum synovial fluid greater than unity in 81 % of cases of rheumatoid arthritis as against 6 % in a control group. The comparative study and the main immunological disorders permits one to note a correlation between the levels of circulating immune complexes (CIC) fixing the Clq and the serum beta2m in serum negative cases of rheumatoid arthritis (RA) (r = 0.52 p < 0.001) whereas this link does not exist in the serum positive group (r = 0.08). These conclusions led the authors to an anti-serum beta2m activity in the serum positive and negative groups of RA, which were very significantly different from the control groups. Furthermore, a study of complement activation, by titration of C3d showed a significant correlation between the levels of CIC and of C3d in RA -, but not in RA +. The authors discuss the participation of beta2m in the formatiton of CIC during RA and its role in the activation of complement.

Antigen-Antibody Complex↗
PubMed2001

Complement activation in the human brain after traumatic head injury.

The complement cascade has been suggested to be involved in the development of secondary brain injuries following brain contusions, based on animal experiments. The aim of the present study was to examine the possible involvement of the complement cascade following traumatic head injury in the human brain. Sixteen patients were included in this study, 12-77 years of age, treated at the neurointensive care unit for traumatic brain contusions. All of these patients were operated with frontal or temporal lobe resection due to intractable intracranial hypertension. The resected tissue was analyzed with regard to components related to complement activation. The time interval between accident and operation was 2-82 h. Brain tissue from three patients operated with hippocampectomy due to epilepsy, including temporal lobe resection, were used as controls. We found increased immunoreactivity for complement components C1q, C3b, and C3d and the membrane attack complex (MAC), C5b-9, in the immediate vicinity of neurons in the penumbra area of the contusion. These findings constitute histological evidence for activation of the complement cascade in the penumbra of cortical contusions in the human brain. Using in situ hybridization, we also found C3-mRNA in the penumbra, suggesting a local synthesis of complement. Furthermore, upregulation of the endogenous complement regulator clusterin was found in some neurons in the same area. We suggest that unknown compounds in the debris from injured neurons or myelin breakdown products trigger complement activation, including formation of C5b-9. Activated complement components may stimulate accumulation of inflammatory cells and formation of brain edema, as well as having membrane destructive effects by the end product MAC, thereby being mediators in the development of secondary brain damage.

Adolescent↗
PubMed1991

Characterization of the human complement receptor 2 (CR2, CD21) promoter reveals sequences shared with regulatory regions of other developmentally restricted B cell proteins.

Expression of human complement receptor 2 (CR2, CD21, C3d,g/EBV receptor) is developmentally restricted on human B lymphocytes to cells of the late-pre and mature stages. CR2 is also a member of the genetically linked regulators of complement activation family found on human chromosome 1q32. Regulators of complement activation proteins are variably expressed in plasma, on cell membranes, and in nonvascular extracellular fluid sites. To begin to understand the mechanisms that control both tissue specific and B cell developmental restriction of CR2 expression, we have cloned and characterized the CR2 promoter upstream of a single apparent transcriptional initiation site. Within this region are sequences with significant similarity to previously characterized TATA, SP1, AP-2, AP-1-like, and Ig enhancer E motif DNA protein binding sites, in addition to direct and inverted repeats. Significant regions of identity are also found between CR2 promoter sequences and those of the CD23 promoter, another protein whose expression is developmentally restricted on B cells. The CR2 promoter will direct transcription of the reporter gene chloramphenicol acyltransferase when transiently transfected into the human Raji B cell line. Therefore, we have identified the promoter for a human B cell protein whose expression is developmentally restricted. Further analysis of this region and the transcriptional regulation of CR2 gene expression should lead to significant insights into the molecular mechanisms by which B cells mature and are activated.

Antigens, CD↗
PubMed1986

Complement activation and spleen function in erythema multiforme associated with herpes simplex virus reactivation.

Plasma C3d concentrations were measured in patients with erythema multiforme (EM) complicating herpes labialis. C3d levels were raised during cold sores but not during EM. Heat damaged red cell clearance was prolonged during EM. These observations support the concept that immune complexes disseminate herpes simplex virus (HSV) antigens to skin before the onset of EM.

Adult↗
PubMed1998

Human heart generates complement proteins that are upregulated and activated after myocardial infarction.

In human heart, we detected mRNAs and proteins for C1q, C1r, C1s, C2, C3, C4, C5, C6, C7, C8, and C9 with the use of reverse transcriptase-polymerase chain reaction, Western blotting, and immunohistochemical techniques. We found an upregulation of both mRNAs and proteins in areas of recent and old myocardial infarctions. In both situations, the classical complement pathway was activated, with C4d, C3d, and the membrane attack complex (C5b-9) being deposited on damaged cardiac myocytes. These activated complement components were also identified on Western blots of infarcted tissue. Complement mRNAs in infarcted heart tissue were higher than those in liver, and liver complement mRNAs were not upregulated in cases with infarcted hearts. Our results establish that (1) complement proteins are endogenously produced by human heart; (2) the classical complement pathway is fully activated after myocardial infarction; (3) complement activation is directly involved in myocardial damage after ischemic insults; and (4) damage from complement activation may be chronically sustained. These data suggest that inhibition of the complement system should be effective in treating myocardial infarction.

Adult↗
PubMed2006

Functional characterization of the complement control protein homolog of herpesvirus saimiri: ARG-118 is critical for factor I cofactor activities.

Herpesvirus saimiri (HVS) is a lymphotropic virus that causes T-cell lymphomas in New World primates. It encodes a structural homolog of complement control proteins named complement control protein homolog (CCPH). Previously, CCPH has been shown to inhibit C3d deposition on target cells exposed to complement. Here we have studied the mechanism by which it inactivates complement. We have expressed the soluble form of CCPH in Escherichia coli, purified to homogeneity and compared its activity to vaccinia virus complement control protein (VCP) and human complement regulators factor H and soluble complement receptor 1. The expressed soluble form of CCPH bound to C3b (KD = 19.2 microm) as well as to C4b (KD = 0.8 microm) and accelerated the decay of the classical/lectin as well as alternative pathway C3-convertases. In addition, it also served as factor I cofactor and supported factor I-mediated inactivation of both C3b and C4b. Time course analysis indicated that although its rate of inactivation of C4b is comparable with VCP, it is 14-fold more potent than VCP in inactivating C3b. Site-directed mutagenesis revealed that Arg-118, which corresponds to Lys-120 of variola virus complement regulator SPICE (a residue critical for its enhanced C3b cofactor activity), contributes significantly in enhancing this activity. Thus, our data indicate that HVS encodes a potent complement inhibitor that allows HVS to evade the host complement attack.

Arginine↗
PubMedDate not supplied

Delayed hemolytic transfusion reactions. Evidence for complement activation involving allogeneic and autologous red cells.

Twenty-six patients with delayed hemolytic transfusion reactions ( DHTR ) were investigated. The reaction of hemolysis often was concealed by other disorders that were usually associated with signs of hemolysis or blood loss. Coating of red cells was analyzed with regard to IgG and/or complement bound in vivo. Although many of the alloantibodies involved (K [8]; E [5]; Fya [2]; Fyb [2]; D [1]; c [1]; multiple [7]) are usually thought to be incapable of complement activation, a strongly positive direct antiglobulin test (DAT) due to C3d was found in all cases. On first examination after transfusion, C3d was present on circulating red cells in large amounts and remained discernible for weeks and even months. IgG on red cells was detected by the DAT in only 10 out of 26 cases. By means of a sensitive radioimmunoassay, IgG was demonstrated in 16 out of 17 cases, but usually in small quantities. Despite the low IgG concentrations, the causative alloantibodies could be eluted in 25 of 26 cases, and, as shown by sequential investigations, in six cases were recoverable from circulating red cells for over 100 days posttransfusion. Since the antiglobulin reactions due to anti-complement were usually strong, not of the "mixed-field" type, and in some cases remained detectable on circulating red cells for months, we conclude that complement is regularly activated in DHTR and binds not only to donated but probably also to autologous red cells.

Adult↗
PubMed1988

Expression of CR2 (C3d receptor) on the cell membranes of adult T cell leukemia.

MT-2 cells, which produce human T-cell lymphotropic virus type I (HTLV-I), are known to have a complement receptor. We have established that the complement receptor is CR2 which binds C3d on immune complexes but not CR1. CR2 was also detected on ATL-3I cells but no complement receptor was detected on ATL-1K cells which lack ATL antigen (ATLA). Since CR2 is not detectable on normal T lymphocytes, the presence of CR2 on some ATL cells might suggest that ATL cells were derived from a particular minor lineage of T cells, or HTLV-I has a capacity to induce CR2, which has been demonstrated to be an a-type growth factor for B lymphocytes and to be a receptor for Epstein-Barr virus.

Antigens, Differentiation, B-Lymphocyte↗
PubMed1982

Biological significance of the C3 nephritic factor in membranoproliferative glomerulonephritis.

Serum levels of the C3 nephritic factor (C3NeF), an IgG autoantibody directed against the C3bBb convertase of the alternative complement pathway, and of eight complement components (C1q, C4, C3, C3d, C5, C9, fB and properdin) were measured in 109 serum samples from 27 patients with idiopathic membranoproliferative glomerulonephritis (MPGN) (type I, 20 cases, and type II, 7 cases) and 14 patients with secondary MPGN. Correlations between the concentrations of C3NeF, serum complement levels and progression of the renal damage were studied during the course of the disease in 14 patients with C3NeF activity. The results showed that (1) C3NeF activity was more frequent in patients with type II MPGN than in patients with type I disease; nevertheless there was a high incidence of this splitting activity in patients with secondary MPGN, (2) high levels of the complement components were present in patients with MPGN, (3) low levels of C3 occurred frequently in type II disease and in secondary MPGN, (4) there was no correlation between C3, fB and C3NeF levels, (5) the presence of C3NeF was associated with a more rapid deterioration of renal function. Longitudinal studies showed that serum levels of C3NeF were not satisfactory for monitoring the clinical course of the illness and, in this respect, are similar to the levels of other autoantibodies in patients with autoimmune disease. As MPGN is a clinical syndrome with various pathogeneses, we suggest that the autoantibody, C3NeF, should be considered only as a marker of some forms of MPGN.

Autoantibodies↗
PubMed1993

Complement deposits in epidermal cells after ultraviolet B exposure.

Ultraviolet B (UVB) radiation is known to induce formation of sunburn cells (SBC) in the epidermis. Since it was unknown whether this process might be accompanied by complement (C) activation, we analyzed C-deposition in skin biopsies taken before and 24 h and 48 h after UVB exposure (fourfold minimal erythema dose or fourfold minimal phototoxic dose) from 14 patients (5 receiving potentially photosensitizing drugs and 9 without such medication) by immunohistology. Local C-activation was visualized by direct or indirect immunofluorescence staining with polyclonal antibodies against C3b, C3d, C5, C9 and monoclonal antibodies to C3b, C3d, C9 and neoantigens on the terminal complement complex (TCC). Neutrophils were identified immunohistologically by antibodies to polymorphonuclear elastase. All but one specimen taken before UVB irradiation were completely negative; biopsies obtained 24 h after UVB revealed complement C3b- and/or C3d-deposits within scattered cells of the epidermis, with wide individual variations in the number of C3-positive cells. C3b and TCC were found predominantly in the cytoplasma; C3d deposits were more often accentuated at the cell surface of C-positive cells. A significantly higher number of keratinocytes was C3d-positive 48 h after UVB exposure than in specimens taken 24 h after UVB. Such a reactivity pattern might indicate a rapid decay of intracellular C3b to C3d. Patients medicated with potentially photosensitizing drugs developed significantly higher numbers of strongly C3-positive cells than those without such medication. Infiltration with elastase-positive cells, presumably representing neutrophils, was observed in the upper third of the dermis and the epidermis in all but one biopsy (n = 9) after UVB.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Release of granulocyte elastase and complement changes during hysterectomy.

Complement activation and release of granulocyte elastase has been previously reported during major vascular surgery and has been ascribed to plasma/cell interactions with foreign surfaces or to administration of blood or plasma. The effect of uncomplicated general anaesthesia and surgery, not requiring blood or plasma, on complement activation and signs of proteinase release was assessed by measuring C3d and elastase-alpha-1 PI, respectively, in nine patients undergoing elective hysterectomy. There was a minor decrease in plasma C3d during anaesthesia, surgery and in the post-operative period caused by the diluting effect of intravenous fluids. Elastase alpha-1 PI remained largely unchanged until the first post-operative day, when a significant increase was seen (p less than 0.05); on the second and third day significant elevated values were still observed. Release of granulocyte elastase seems to be a generalized response to surgical trauma and may be a part of the endocrine-metabolic stress response.

Adult↗
PubMed1988

Complement and leukocyte changes during major vascular surgery.

To gain further insight into the effects of major vascular surgery involving the abdominal aorta on complement and leukocytes, serial measurements of leukocyte and differential counts, plasma concentrations of C3d, and granulocyte elastase bound to alpha1 proteinase inhibitor (E-alpha1PI) were made after aorta declamping in a group of patients not receiving blood or plasma. In the hours after declamping, lymphocyte count decreased, whereas an increase was noticed in leukocytes, neutrophils, and plasma E-alpha1PI. Complement activation was not found. Previous reports on complement activation during aortic surgery probably reflect the administration of blood and plasma during the surgical procedures. Whether aortic cross-clamping or interaction between granulocytes and the aortic prothesis is responsible for the release of lysosomal enzymes during the procedure warrants further studies.

Aorta, Abdominal↗
PubMed1990

The terminal complement complex (sC5b-9) is not specifically associated with the development of the adult respiratory distress syndrome.

Previous investigators suggested that increased plasma levels of the terminal complement complex (sC5b-9) are an early marker for the development of adult respiratory distress syndrome (ARDS) in septic patients. We asked whether an increase in sC5b-9 was also associated with the development of ARDS from other etiologies and whether sC5b-9 measurements consistently reflected complement activation in vivo. We evaluated 75 patients with sepsis, trauma, hypertransfusion, multiple fractures, aspiration, or pancreatitis who were at risk for ARDS but did not develop the syndrome and 23 patients with similar histories who did develop ARDS. Of the latter patients, seven were identified and studied both when they were at risk and when they had ARDS. Serial blood samples were obtained and analyzed for the complement activation products Bb, Ba, C4d, C3d, IC3b, and sC5b-9. All but one of the patients studied had levels of one or more complement fragments that were greater than 2 SD above the mean obtained from 18 normal subjects. In contrast to the report referred to previously, none of the fragments measured, including sC5b-9, was a specific indicator of ARDS, and no combination of complement fragments predicted which patients at risk would develop ARDS. Patients demonstrated evidence of activation of the classical pathway only, alternative pathway only, or both pathways, but none of these was associated with greater risk or severity of disease. In addition, in several patients only late components were activated, suggesting that enzymes other than those derived from complement activation may be responsible. In conclusion, complement can be activated by a variety of mechanisms in critically ill patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Complement Activation↗
PubMed1986

Complement activation in systemic lupus erythematosus: a marker of inflammation.

Previous investigators have established that complement activation occurs in patients with systemic lupus erythematosus (SLE). Utilizing a new rapid method, an ELISA for C3d as a measure of activation products, 83 SLE plasmas and 24 controls were assayed. A retrospective correlation of C3d levels with the clinical assessment defined 4 subgroups of SLE patients: Group 1--clinically well with normal C3d levels (25%), Group 2--clinically ill with elevated C3d levels (34%), Group 3--clinically well with elevated C3d levels (39%), the largest group, and Group IV--clinically ill with normal C3d levels (2%). In the group of overtly ill patients with elevated C3d levels (Group 2) who were studied serially, C3d levels correlated with disease activity, suggesting that elevated C3d levels may be a marker for active SLE. Further prospective study is required to determine the significance of elevated C3d levels in clinically well patients.

Adult↗
PubMed1989

Activation of the complement system in systemic sclerosis. Relationship to clinical severity.

Using newly developed techniques, we investigated the complement pathways and the extent of their activation in patients with systemic sclerosis (SSc) of both the diffuse cutaneous and limited cutaneous types. Plasma levels of the fragments C3d, C4d, and Ba were measured in patients with SSc and in matched control subjects. All fragments and ratios were higher in SSc patients than in controls (P less than 0.05), demonstrating that complement activation occurs in SSc. Levels of C3d, C3d:C3, Ba, and Ba:factor B were higher in patients with diffuse cutaneous SSc patients than in controls (P less than 0.01). C3d, C3d:C3, C4d, and C4d:C4 levels were also higher in patients with limited cutaneous SSc than in controls (P less than 0.05). These results show that complement activation occurs in SSc patients and that it reflects clinical severity. Complement activation may therefore have a pathogenetic role in SSc, and its measurement may prove useful in monitoring the disease.

Adult↗
PubMed1997

Local and systemic complement activity in small intestinal bacterial overgrowth.

It is unknown whether bacteriolysis due to luminal complement activation contributes to local defense mechanisms against small intestinal bacterial overgrowth, particularly with gram-negative bacteria. This study addressed this issue. Thirty adult subjects were investigated with culture of luminal secretions adherent to proximal small intestinal mucosa. Luminal and plasma concentrations of C3 and C3d and C3d/C3 ratios were determined. Activated terminal complement complex was sought in surface epithelium to which aspirated secretions had been adherent. Small intestinal bacterial overgrowth with gram-negative bacteria was present in 12/30 (40.0%) subjects. C3, C3d, and C3d/C3 profile indicated that increased local but not systemic C3 activation occurs in this group. Conversely, no activation of terminal complement complex was evident in this circumstance. Thus, complement-mediated bacteriolysis is unlike to contribute to local defense mechanisms against small intestinal bacterial overgrowth, even when overgrowth flora includes gram-negative bacteria. Factors preventing full local activation of the complement cascade in this circumstance require investigation.

Adult↗
PubMed1992

A sensitive method for the detection of immune complexes in human gingival crevicular fluid.

An assay for immune complexes [ICs] in gingival crevicular fluid [GCF] could be potentially useful to ascertain the risk of periodontal disease activity at specific oral sites. This paper describes and ELISA-based method sufficiently sensitive to measure ICs in GCF samples at levels below 1 microgram/ml. Static GCF samples taken from 5 adults showed IC levels ranging from 5 to 166 micrograms/ml. Additional tests of 10 GCF samples from 1 adult were conducted with complement components and indicated that either C1q or rabbit anti-human C3d was suitable as a capture agent in the assay procedure. Further application of this assay may help to assess the usefulness of IC levels in GCF samples as possible diagnostic indicators of periodontal disease activity.

Adult↗
PubMed1981

Cryoglobulins, circulating immune complexes, and complement activation in cerebral malaria.

A total of 32 patients with Plasmodium falciparum malaria were studied. Of these, 23 had benign infections, and 9 had typical cerebral malaria. Cryoglobulins, circulating immune complexes detected by a C1q-binding assay, and hypocomplementemia were found in eight of nine patients with cerebral malaria. Raised levels of complement component 3 breakdown products (C3d) were found in the seven patients tested. Peak levels of circulating immune complexes and C3d were associated with thrombocytopenia. In contrast, in patients with benign Plasmodium falciparum malaria, cryoglobulins and circulating immune complexes were found only in 3 of 23 patients. Similarly, hypocomplementemia was detected only in 5 of 23 patients. These observations suggest that the intensity of the immune response and of the associated complement activation may be important factors in the pathogenesis of cerebral malaria.

Adult↗