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PubMed2005

Complement C2 receptor inhibitor trispanning: a novel human complement inhibitory receptor.

The complement system presents a powerful defense against infection and is tightly regulated to prevent damage to self by functionally equivalent soluble and membrane regulators. We describe complement C2 receptor inhibitor trispanning (CRIT), a novel human complement regulatory receptor, expressed on hemopoietic cells and a wide range of tissues throughout the body. CRIT is present in human parasites through horizontal transmission. Serum complement component C2 binds to the N-terminal extracellular domain 1 of CRIT, which, in peptide form, blocks C3 convertase formation and complement-mediated inflammation. Unlike C1 inhibitor, which inhibits the cleavage of C4 and C2, CRIT only blocks C2 cleavage but, in so doing, shares with C1 inhibitor the same functional effect, of preventing classical pathway C3 convertase formation. Ab blockage of cellular CRIT reduces inhibition of cytolysis, indicating that CRIT is a novel complement regulator protecting autologous cells.

Amino Acid Sequence↗
PubMed1977

Simultaneous presence of receptors for complement and sheep red blood cells on human fetal thymocytes.

The cells of four thymus glands, two at 12 weeks, one at 16 weeks and one at 22 weeks gestational age, were examined cytochemically for enzymic activity and for surface markers. The reactions for chloroacetate esterase, peroxidase, and alkaline phosphatase were negative and the reaction for nonspecific esterase was only weakly positive in some of the cells. In contrast, nearly all thymocytes at the 12th gestational week showed strong focal acid phosphatase (acP) activity. The number of acP-stainable cells and the staining intensity declined progressively. A high percentage of thymocytes in early fetal life express a complement receptor (CR); the proportion of CR-bearing cells decreased while cells forming rosettes with sheep erythrocytes (possessing erythrocyte receptors: ER) correspondingly increased during fetal life. Using a mixed rosette assay, up to 30% of the thymocytes at 12 weeks gestation were found to bear CR and ER simultaneously. The number of CR- and ER-positive cells also declined progressively with fetal age. These findings show that CR-positive, ER-negative thymus cells mature into CR-negative, ER-positive thymocytes via a CR-positive and ER-positive intermediate cell, indicating that mature ER-positive thymocytes do not originate from another cell line lacking CR. The changes in surface markers during early T cell maturation is relevant to certain lymphomas whose cells also show strong focal acP activity and also express both CR and ER. These lymphoma cells may correspond to fetal thymocytes or T precursor cells present in small numbers after birth.

Binding Sites↗
PubMed2004

The virulence function of Streptococcus pneumoniae surface protein A involves inhibition of complement activation and impairment of complement receptor-mediated protection.

Complement is important for elimination of invasive microbes from the host, an action achieved largely through interaction of complement-decorated pathogens with various complement receptors (CR) on phagocytes. Pneumococcal surface protein A (PspA) has been shown to interfere with complement deposition onto pneumococci, but to date the impact of PspA on CR-mediated host defense is unknown. To gauge the contribution of CRs to host defense against pneumococci and to decipher the impact of PspA on CR-dependent host defense, wild-type C57BL/6J mice and mutant mice lacking CR types 1 and 2 (CR1/2(-/-)), CR3 (CR3(-/-)), or CR4 (CR4(-/-)) were challenged with WU2, a PspA(+) capsular serotype 3 pneumococcus, and its PspA(-) mutant JY1119. Pneumococci also were used to challenge factor D-deficient (FD(-/-)), LFA-1-deficient (LFA-1(-/-)), and CD18-deficient (CD18(-/-)) mice. We found that FD(-/-), CR3(-/-), and CR4(-/-) mice had significantly decreased longevity and survival rate upon infection with WU2. In comparison, PspA(-) pneumococci were virulent only in FD(-/-) and CR1/2(-/-) mice. Normal mouse serum supported more C3 deposition on pneumococci than FD(-/-) serum, and more iC3b was deposited onto the PspA(-) than the PspA(+) strain. The combined results confirm earlier conclusions that the alternative pathway of complement activation is indispensable for innate immunity against pneumococcal infection and that PspA interferes with the protective role of the alternative pathway. Our new results suggest that complement receptors CR1/2, CR3, and CR4 all play important roles in host defense against pneumococcal infection.

Animals↗
PubMed1997

Epstein-Barr virus in synergy with tumor-promoter-induced malignant transformation of immortalized human epithelial cells.

It is difficult to study how Epstein-Barr virus (EBV) causes transformation of human epithelial cells. The major difficulty is that cultured human epithelial cells do not express EBV receptor (complement receptor 2, CR2), hence EBV cannot infect such epithelial cells directly. In order to investigate the role of EBV in the transformation of human epithelial cells, pSG-CR2-Hyg carrier was transfected into immortalized human epithelial cells (293 cells) to express EBV receptor. EBV could infect these CR2-positive cells directly, and expressed EBV antigens. EBV-infected epithelial cells grew in piles with multiple cellular layers and lost contact inhibition in vitro. In soft-agar culture containing 12-0-tetradecanoylphorbol 13-acetate (TPA), EBV-infected 293 cells formed more and larger colonies. When EBV-infected 293 cells were transplanted subcutaneously into nude mice, and treated with TPA, poorly differentiated carcinoma was induced. These results suggest that EBV could induce the malignant transformation of immortalized human epithelial cells in synergy with TPA.

Animals↗
PubMed1977

[The differentiation of human peripheral blood lymphocytes by immunological methods. III. Results in acute lymphoblastic leukemia (author's transl)].

In 47 patients with acute lymphoblastic leukemia surface markers were evaluated on mononuclear cells of the peripheral blood as well as in some cases on bone marrow lymphocytes. The lymphocytes were characterized by their binding capacity for sheep red blood cells, the demonstration of Fc-receptors, complement receptors as well as surface immunoglobulins. In 6 of 23 untreated patients the blasts bound sheep red blood cells spontaneously (T-ALL), in two of these six cases the lymphoblasts had simultaneously receptors for complement. In a further patients the lymphoblasts had complement- and Fc-receptors. The blasts of 16 of 23 patients were negative in respect to the markers tested (O-ALL). By comparing two groups of patients--one with positive cells, one unreactive--the clinical features differed: the marker positive group showed a predominance of male patients, 5 of 7 patients had a massive mediastinal mass and the remission rate was lower than in the group with positive blasts. 24 patients in remission under maintance treatment had a decreased percentage of rosette forming lymphocytes as well as lymphocytes with surface immunoglobulins and Fc-receptors. There existed some correlation between the percentage of rosette forming lymphocytes and the clinical course: patients with complications had lower percentages of rosette forming lymphocytes than patients with a favourable course.

Adolescent↗
PubMed1988

Epstein-Barr virus (EBV) infection of murine L cells expressing recombinant human EBV/C3d receptor.

The normal host range of Epstein-Barr virus (EBV) is limited to primate B lymphocytes and certain epithelial cells that express the C3d/EBV receptor [complement receptor 2 (CR2, CD21)]. In the present study, expansion of the tissue tropism of EBV has been accomplished by stably transfecting the murine fibroblast L cell line with pMT.CR2. neo.1, a eukaryotic expression vector promoting the transcription of a complementary DNA insert encoding human CR2. High CR2-expressing transfected L cells were selected by fluorescence-activated cell sorting. The recombinant CR2 was shown to have the same molecular weight as wild-type CR2 from Raji cells and to mediate the binding by the transfectants of particles bearing the iC3b and C3d fragments of the third component of complement. All CR2-expressing L cells, but not nontransfected controls, also bound EBV, as assessed by indirect immunofluorescence. After a 60-hr culture, approximately 0.5% of the CR2-expressing cells preincubated with EBV demonstrated immunofluorescent staining of EBV nuclear antigen with serum from a patient with nasopharyngeal carcinoma. No fluorescent staining of cells was seen with monoclonal antibodies to the early antigen complex or to gp350/220, indicating that the infection was predominantly latent. Infected cells cultured for up to 4 weeks remained EBV nuclear antigen-positive. The capacity of recombinant human CR2 to confer on murine L cells susceptibility to stable latent infection by EBV indicates that this receptor is a primary determinant of the tissue tropism of EBV and may facilitate studies of cell-specific factors that regulate the viral growth cycle.

Animals↗
PubMed1980

Enhanced expression of human monocyte complement (C3b) receptors by chemoattractants.

The capacity of various leucoattractants to enhance, or unfold, receptors for complement (C3b) on human blood monocytes has been studied. A number of recognized monocyte chemoattractants including casein, supernatants from C. parvum 10390 and from human lymphocytes (cultured either in the presence or absence of phytohaemagglutinin) and the formyl-methionyl peptides, F-Met-Leu-Phe, F-Met-Met-Phe and F-Met-Phe, increased the percentage of monocytes which formed rosettes with IgM-sensitized sheep erythrocytes coated with complement. Comparable results were achieved irrespective of whether purified components of whole serum was used as a source of complement. In contrast, there was no significant increase in EAG (Fc) rosettes with those doses of casein which gave enhancement of C3b receptors. A small degree of complement receptor enhancement was observed with histamine but the unformylated peptides, Met-Leu-Phe and Met-Met-Phe, were without apparent effect. Maximal receptor enhancement was obtained at 30 min but when the leucoattractant was removed, enhancement was reversible, returning to normal values in approximately 120 min. Monocyte complement receptor enhancement increased with temperatures between 0 degrees C and 37 degrees C. These data (1) confirm and extend our previous findings on leucoattractant-induced enhancement of complement receptors on human monocytes; (2) indicate that the phenomenon may have potential as a clinical test for monocyte function both in health and disease.

Caseins↗
PubMed1983

Identification of the membrane receptor for the complement fragment C3d by means of a monoclonal antibody.

The B2 antigen characterized by means of a monoclonal antibody (14) is a 140,000 Mr protein expressed only in certain stages of the differentiation of lymphocytes of the B lineage. Here we examine the relationship between B2 and the membrane complement receptor type 2 (CR2) for the complement fragment C3d (11, 12), which is also associated only with B cells. Both phenotypic markers are distributed in a similar manner among B cell malignancies and, as shown here, among established cell lines. A polypeptide with binding affinity for C3d was isolated from the membrane of B2-positive cells, i.e., tonsil lymphocytes and Raji cells. We found that this C3d-binding protein not only had the same Mr and isoelectric point (pI) as the B2 antigen, but that it was recognized by the monoclonal antibody to B2. However, anti-B2 does not mask the ligand-binding site of CR2 since it does not prevent the interaction of the purified 140,000 Mr polypeptide with immobilized C3d. Rosette formation between tonsil lymphocytes and erythrocyte intermediates bearing C3d was specifically inhibited by anti-B2. In the case of Raji cells, rosette formation was strongly inhibited only when the lymphocytes were sequentially treated with anti-B2 and with a polyclonal antibody against mouse Ig. In short, B2 and CR2 have a similar distribution among normal and malignant cells, have the same Mr and pI under denaturing conditions, and react with a single monoclonal antibody. We conclude that B2 is identical to CR2.

Animals↗
PubMed1991

[The relationship between complement C3 receptors (CR1, CR3) on polymorphonuclear leukocytes and complement fragments during hemodialysis].

The expression of complement receptor type 1 (CR1) and type 3 (CR3) on polymorphonuclear leukocytes (PMNs) and generation of complement fragments, C3a, C5a, C4d, iC3b and Bb, were studied in patients during hemodialysis using cuprammonium rayon (Cu) membranes. Furthermore, the relation between the expression of CR1 and CR3 on PMNs from healthy donors and complement fragments was investigated. The expression of CR1 and CR3 on PMNs increased during hemodialysis. Plasma C3a, C5a and iC3b levels increased in the first 15 minutes and then decreased at 120 minutes of dialysis. But plasma Bb level remained high until the end of hemodialysis. Purified Bb had no effect on the expression of CR1 and CR3 on PMNs, but C5a augmented those expression in vitro. Nafamostat mesilate, an artificial proteinase inhibitor, inhibited augmentation of complement receptors on PMNs in concentration dependent fashion. C5a generated through the activation of complement was thought to take an important role in the increased expression of CR1 and CR3 on PMNs.

Aged↗
PubMed2002

Immunoglobulin A-associated lymphocytic vasculopathy: a clinicopathologic study of eight patients.

INTRODUCTION: Cutaneous IgA-associated vasculitis can be a clue to Henoch-Schönlein purpura (HSP), which typically comprises renal and gastrointestinal tract disease and arthritis, whereby prominent and predominant IgA deposits within the cutaneous vasculature provoke a pustular leukocytoclastic vasculitis. DESIGN: We describe eight patients with a novel expression of a cutaneous IgA vascular injury syndrome, namely a lymphoid vasculopathy which clinically and light microscopically resembled a pigmentary purpura (PP) in six, and correlate direct immunofluorescence (DIF) and clinical features to light microscopy. RESULTS: Among associated diseases were prior viral infection, an HSP symptom complex, an undifferentiated connective tissue disease syndrome, lupus erythematosus profundus (LEP), Degos' disease and Berger's disease. Skin lesions comprised non-palpable petechial lesions involving lower extremities in all cases and also the upper extremities in two. A superficial perivascular lymphocytic infiltrate unaccompanied by vascular fibrin deposits was associated with prominent erythrocyte extravasation including into the epidermis. Mural and extravascular fibrin deposition was seen in one biopsy from a PP-like lesion and mural fibrinoid necrosis was seen in the cases of LEP and Degos' disease; in biopsies from these three cases, the presence of fibrin deposition warranted use of the appellation 'lymphocytic vasculitis'. In all patients, DIF showed prominent and predominant IgA deposits. CONCLUSIONS: A non-necrotizing lymphocytic purpuric vascular reaction is one manifestation of vascular IgA deposition in the skin. A subpopulation of human lymphocytes bear surface Fc receptor and/or C3 receptors ('complement receptor lymphocytes') which can bind circulating immune complexes (ICs) or C3 generated via activation of the alternative complement cascade. Thus, circulating ICs are a potential pathogenic basis of this eruption, the histologic differential diagnosis of which is idiopathic PP and PP of drug or viral etiology.

Adolescent↗
PubMed1979

Correlated expression of a B-lymphocyte-specific glycoprotein (gp27/35) and the EBV receptor/C3 receptor complex in sublines from the same Burkitt lymphoma.

A series of virus-producer and non-producer sublines, derived from the Burkitt lymphoma line Jijoye and its P3HR-1 clone, were previously found to differ in the expression of EBV receptors and, in parallel, C3 receptors. The differences could be related to an "internal selection" caused by the cytopathic P3HR-1 virus variant, favouring the growth of receptor-negative cells. We have now analyzed the same lines for the expression of a B-lymphocyte-specific glycoprotein (gp27/35). A close parallellism was found between the expression of the EBV receptor-complement receptor complex and the glycoprotein, measured by quantitative absorption. The results favour a relationship between gp27/35 and EBV/C3 receptor expression.

Antigen-Antibody Complex↗
PubMed1984

Local opsonization by secreted macrophage complement components. Role of receptors for complement in uptake of zymosan.

We have examined the role of macrophage (M phi plasma membrane receptors for the cleaved third complement component (iC3b; CR3) and mannosyl, fucosyl terminated glycoproteins (MFR) in uptake of unopsonized zymosan. Monoclonal antibodies against CR3, M1/70 (Mac-1) and MO1, each inhibited approximately 50% of uptake of 125I-zymosan by murine and human M phi, respectively. Yeast mannan inhibited 0-50% of zymosan uptake in various M phi, in parallel with their expression of MFR. We demonstrated that M phi were the source of C3 in our assay and that the activity of other components of the complement system, namely a C3 convertase, factor I, and a factor I cofactor were also present in serum-free cultures of human monocytes. Macrophage C3 was deposited rapidly, within 10 min, on the zymosan particles and mediated binding, ingestion, and stimulation of superoxide release in BCG-activated and thioglycollate-elicited peritoneal M phi via CR3. Local secretion of complement proteins by M phi themselves can therefore opsonize pathogens and cells able to activate the alternative pathway and effect their destruction.

Animals↗
PubMed1976

Production of specific antisera to human B lymphocytes.

Antisera have been prepared, in mice and rabbits, to membrane and sub-membrane fractions of human B lymphocyte derived lymphoid lines. Antisera to a protein subfraction were, after only minimal absorption, specific for human peripheral B lymphocytes, monocytes and B cell derived lymphoid lines. The antigen(s) recognised by these antisera were not the same as the previously described B-cell markers; immunoglobulin, Fc receptor, complement receptor and Ia antigens. The antigen(s) could not be removed from cells by lysostrip with anti- beta2 microglobulin.

Absorption↗
PubMed1981

Localization of the receptors for activated complement on the visceral epithelial cells by the human renal glomerulus by immunoenzymatic microscopy.

Horseradish peroxidase-labeled IgG-anti-IgG immune complexes bearing activated third component of complement, C3, were used as indicator particles for the localization of the complement receptor in the human renal glomerulus. The HRP-labeled IgG-anti-IgG complexes were coated with activated C3 by exposing them to fresh human serum as a source of complement. This represents a more physiologic indicator particle for complement receptor-bearing structures than the synthetic immune complexes previously used. By light microscopy, the deposition of the complexes was restricted to the glomeruli. By transmission electron microscopy, the complexes were selectively associated with the surface of the visceral epithelial cells (podocytes). Complexes exposed to buffer alone or to heat-inactivated human serum failed to adhere to any of the renal structures examined.

Binding Sites↗
PubMed2003

Beta-glucan functions as an adjuvant for monoclonal antibody immunotherapy by recruiting tumoricidal granulocytes as killer cells.

The tumor-killing mechanisms available to monoclonal antibodies (mAbs; e.g., antagonism of growth factor receptors, antibody-dependent cell-mediated cytotoxicity) limit efficacy. Previous studies suggested that i.v. beta-glucan might function as an adjuvant for antitumor mAbs. beta- Glucan had been shown to function via the iC3b-receptor complement receptor 3 (CR3; CD11b/CD18) thereby enhancing leukocyte killing of tumor cells coated with iC3b via naturally occurring antitumor antibodies. Therapy with beta-glucans was limited by levels of natural antibodies and by tumor escape through elimination of antigen-positive cells. Accordingly, it was hypothesized that beta-glucan responses could be improved by combined administration with antitumor mAbs. Five tumor models were explored in BALB/c or C57Bl/6 mice using tumors that expressed either high levels of naturally occurring antigens (e.g., G(D2) ganglioside) or recombinant human MUC1. In comparison with antitumor mAb or beta-glucan alone, combined treatment with mAb plus beta-glucan produced significantly greater tumor regression in all models that included mammary, s.c., and hepatic tumors. Tumor-free survival only occurred in models that incorporated stable expression of the target antigen. beta-Glucan enhancement of the mAb tumoricidal response did not occur in mice deficient in either leukocyte CR3 (CD11b(-/-)) or serum C3, confirming the requirement for CR3 on leukocytes and iC3b on tumors. Granulocytes appeared to be primarily responsible for tumoricidal activity, because beta-glucan therapeutic responses did not occur in granulocyte-depleted mice. These data suggest that the therapeutic efficacy of mAbs known to activate complement (e.g., Herceptin, Rituxan, and Erbitux) could be significantly enhanced if they were combined with beta-glucan.

Adenocarcinoma↗
PubMed1977

Cellular requirements for the induction of cytotoxic T cells in vitro.

The stimulator and accessory cell requirements for the induction of cytotoxic T cell responses to alloantigens in vitro are reviewed. The ability of lymphocytes to stimulate was acquired early in development and was found to be a property of both Ig+ and Ig- cells. The presence of Fc receptors, complement receptors or Ia antigens on lymphocytes did not confer superior stimulator capacity. In contrast to lymphocytes mature macrophages were poor stimulators. When resting lymphocytes were used as a source of stimulator cells there was an additional requirement for an adherent accessory cell population for the induction of cytotoxic T cells. The accessory cell population functioned whether syngeneic or allogeneic with the responder and was required for the induction rather than the maintenance of the response. It was further characterized as an Ig+, theta, FcR+/-, CR +/-, Ia- cell which was not a mature macrophage. Accessory cells could be replaced to some extent by supernatants from spleen cell cultures. A model for T cell induction is proposed where only cells which produce unique inductive stimuli are able to function as stimulator cells. Stimulator cells are defined as those cells capable of stimulating cytotoxic T cell precursors directly and independently. Stimulator capacity is suggested to be a function of activated cells only, thus lymphocytes only stimulate following activation by accessory cells. Cells lacking innate stimulator capacity but exhibiting Ia antigens are suggested to stimulate via an alternative means.

Animals↗
PubMed1979

Human megakaryocytes. I. Characterization of the membrane and cytoplasmic components of isolated marrow megakaryocytes.

Human marrow megakaryocytes have been isolated with high purity and yield by processing marrow cells sequentially through density centrifugation and velocity sedimentation. Analysis of the isolated cells for various platelet-associated components by immunofluorescence demonstrated that fibrinogen, plasma factor VIII antigen (factor VIII:AGN) platelet myosin, platelet glycoproteins I and III are present on the membrane and in the cytoplasm of over 90% of marrow megakaryocytes. Parallel studies of human and mouse megakaryocytes and platelets for IgG receptor (FcR), complement receptor type one (CR1) (C3b receptor), complement receptor type two (CR2) (C3d receptor), and Ia antigen by fluorescence and (or) rosette formation methods were performed. FcR were present on most human megakaryocytes and platelets. The Ia antigen was detected on a proportion (10-15%) of human megakaryocytes but it was undetectable on human platelets. CR1 was found on 20-40% of mouse megakaryocytes and also on a proportion of mouse platelets. These differentiation markers may be of use in monitoring megakaryocyte maturation.

Animals↗