Fc gamma receptors in human placenta

This review summarizes the status of our knowledge on the structure, expression and function of Fc gamma R in the placenta. The discovery in syncytiotrophoblast of an MHC class I--related FcR, of the type responsible for intestinal uptake of milk IgG in suckling rats and mice is also described.     

Resistance of Fc receptor- deficient mice to fatal glomerulonephritis

Immune complex-mediated inflammation is a common mechanism of various autoimmune diseases. Glomerulonephritis (GN) is one of these diseases, and the main mechanism of the induction of GN has been unclear. We examined the contribution of Fc receptors in the induction of nephrotoxic GN by establishing and analyzing mice deficient in the Fc receptor gamma chain (FcRgamma). Whereas all wild-type mice died from severe glomerulonephritis with hypernitremia by administration of anti-glomerular basement membrane (GBM) antibodies, all FcRgamma-deficient mice survived. Histologically, wild-type mice showed glomerular hypercellularity and thrombotic changes, whereas the renal tissue in FcRgamma-deficient mice was almost intact. Deposition of anti-GBM antibody as well as complement components in the GBM were equally observed in both wild-type and knockout mice. These results demonstrate that the triggering of this type of glomerulonephritis is completely dependent on FcR+ cells.     

Structure and function of human IgA Fc receptors (Fc alpha R)

Receptors for the Fc region of IgA are expressed by many human cell types, especially phagocytes located in mucosal areas, where IgA is the prevalent antibody isotype. Binding of IgA-opsonized particles (e.g., bacteria, viruses) to Fc alpha R may trigger a plethora of cell-mediated immune effector functions designed to rid the body of the foreign invader. The IgA receptor present on myeloid cells such as neutrophils, eosinophils, and monocytes (Fc alpha RI or CD89) is a transmembrane glycoprotein that binds both IgA isotypes with similar affinity. Genetic characterization showed Fc alpha RI to be a more distantly related member of the Ig receptor gene family. Recently, Fc alpha RI was found to associate with the FcR gamma-chain signaling molecule through a unique charge-based mechanism. Fc alpha RI is, thus, connected to the intracellular machinery via the ITAM signaling motifs located within the cytoplasmic tail of FcR gamma-chain. Evidence exists in support of receptors for IgA (distinct from Fc alpha RI) on human T and B cells. IgA Fc receptors may, therefore, play a role in both the induction and control of an efficient (mucosal) immune response.     

Cell surface expression of a human IgG Fc chimera activates macrophages through Fc receptors

Antibody-dependent cell-mediated cytotoxicity plays an important role in the macrophage-mediated destruction of target cells. While the selectivity is based on antibody specificity, the lytic attack is triggered by Fc receptor-mediated respiratory burst. To mimic IgG opsonization, a chimeric antibody-like molecule, containing human IgG1 Fc, was expressed on the surface of mammalian cells. The transmembrane domain of the human transferrin receptor was fused in-frame to the N-terminus of the second and third domains of human IgG1 heavy-chain constant region. This fusion molecule was designed to take advantage of the type II membrane anchor property of the transferrin receptor to express the Fc portion of the molecule in a reverse orientation, such that the Fc portion projected away from the cell surface. This is in contrast to the conventional cell surface IgG, which is anchored by a C-terminal type I transmembrane domain. The cell surface expressed reverse Fc no longer activated complement, but retained Fc receptor-binding capability and activated superoxide production by macrophages. This activity was completely blocked by an FcgammaR I-specific monoclonal antibody.     

Targeting the genes of angiotensin receptors

Gene targeting technology has produced mutant mice carrying selective null-mutation of the genes for the components of the renin-angiotensin system. Angiotensinogen null-mutant mice showed not only severe hypotension, but also several abnormal phenotypes in the kidney, including juxtaglomerular (JG) cell hypertrophy, renal arterial hypertrophy, and hypoplastic papilla. Although angiotensin type 1A (AT1A) receptor is by far the most predominant in mice, the phenotypes of AT1A null-deletion mice are much milder than those of angiotensinogen null-mutant mice. Because renin and angiotensin (ANG) production is upregulated in AT1A null-mutant mice, it is conceivable that the AT1B receptor provides compensation for the lost functions of AT1A. The observations in mice with complete absence of a gene product have not elucidated whether the abnormal phenotypes reflect direct effects caused by lack of local tissue action of ANG II or a secondary effect caused by changes in systemic milieu. We have developed chimeric mice that are made up of a mix of clusters of wild-type cells: cells homozygous for AT1A gene deletion. Within a given chimeric mouse, the expressions of renin mRNA and protein are identical between wild-type and mutant cells. In addition, all of the chimeric mice lack the renal arterial lesion observed in standard AT1A null-mutant mice. These findings indicate that both JG cell hypertrophy and renal vascular lesions are caused by systemic, rather than local, mechanism(s).     

Human placental Fc receptors and the trapping of immune complexes

Monomeric maternal antibodies are transmitted to the fetus, but most immune complexes are trapped in the placental stroma. The receptors responsible for trapping immune complexes appear to be Fc gamma RIa, Fc gamma RIIa, and Fc gamma RIIIa on stromal macrophages, and Fc gamma RII on fetal capillary endothelial cells.     

Fc receptors are required in passive and active immunity to melanoma

Effective tumor immunity requires recognition of tumor cells coupled with the activation of host effector responses. Fc receptor (FcR) gamma-/- mice, which lack the activating Fc gamma R types I and III, did not demonstrate protective tumor immunity in models of passive and active immunization against a relevant tumor differentiation antigen, the brown locus protein gp75. In wild-type mice, passive immunization with mAb against gp75 or active immunization against gp75 prevented the development of lung metastases. This protective response was completely abolished in FcR gamma-deficient mice. Immune responses were intact in gamma-/- mice because IgG titers against gp75 develop normally in gamma-/- mice immunized with gp75. However, uncoupling of the Fc gamma R effector pathway from antibody recognition of tumor antigens resulted in a loss of protection against tumor challenge. These data demonstrate an unexpected and critical role for FcRs in mediating tumor cytotoxicity in vivo and suggest that enhancement of Fc gamma R-mediated antibody-dependent cellular cytotoxicity by inflammatory cells is a key step in the development of effective tumor immunotherapeutics.     

Characterization of angiotensin receptors in rabbit isolated atria

Bremsstrahlung x-rays are produced when energetic beta-particles are emitted and absorbed. Measurements of total-body bremsstrahlung efficiencey (x-ray photon output per muCi 90Sr in the body, relative to that in water) have been made in the intact mouse, rat, rabbit, and dog sacrificed 2 weeks after the injection of 90Sr + 85Sr. Efficiencies were determined by a comparison of the bremsstrahlung output from 90Sr + its daughter 90Y and the gamma-ray emission of 85Sr. Results were checked by a beta-assay of the ashed animals. Bremsstrahlung efficiencies averaged 1.10 in a 0.04 kg mouse, 1.14 in a 0.13 kg rat, 1.23 in a 2.6 kg rabbit, and 1.32 in an 8.5 kg beagle. Extrapolating to a 70 kg human, a relative bremsstrahlung efficiency of about 1.4 is predicted. An estimate was made of the 90Sr body content in a former dial painter based on in vivo counting and a bremsstrahlung efficiency of 1.39 predicted for a 55 kg human female by these animal data. Our value of 1.42 +/- 0.08 muCi 90Sr was in good agreement with corresponding results reported for this subject by 8 other laboratories.     

Reciprocal modulation of the binding of angiotensin agonists and antagonists to angiotensin receptors in smooth muscle

1. Direct ligand binding studies have shown that the agonist 125I-[Sar1]Ang II and the antagonist 125I-[Sar1Ile8]Ang II bind to bovine uterus smooth muscle membranes in a time-dependent, reversible and saturable manner; both ligands had the same number of high affinity sites. 2. [Sar1Ile8]Ang II inhibited the binding of 125I-[Sar1]Ang II in a non-competitive manner by decreasing the number of high affinity sites without changing the binding affinity of the radioligand. 3. [Sar1]Ang II also inhibited the binding of 125I-[Sar1Ile8]Ang II in a non-competitive manner. 4. Dissociation of both radioligands from their receptor sites was fast enough that pseudo irreversible occupancy of the binding sites could not account for the observed non-competitive inhibition. 5. Displacement studies using 125I-[Sar1Ile8]Ang II as the radioligand provided evidence for the existence of two binding sites when the displacing ligand was [Sar1]Ang II but not when the displacing ligand was [Sar1Ile8]Ang II. 6. GTPS gamma S had no discernible effect on the binding of either 125I-[Sar1]Ang II or 125I-[Sar1Ile8]Ang II to bovine uterine membranes. 7. The present findings are consistent with an allosteric mechanism of antagonism for [Sar1Ile8]Ang II. The data are also consistent with a mechanism wherein agonist and antagonist ligands occupy different binding modes at the same receptor site and induce long-term conformational changes in the receptor which are idiosyncratic with respect to the nature of the ligand. An emerging relationship between the actions of angiotensin peptides and non-peptide mimetics of angiotensin is presented.     

Distinct deactivation and desensitization kinetics of recombinant GABAA receptors

The functional role of the large heterogeneity in GABAA receptor subunit genes and its role in setting the properties of inhibitory synapses in the CNS is poorly understood. A kinetic comparison between currents elicited by ultra-rapid application with a piezoelectric translator of 1 mM GABA to mammalian cells transfected with cDNAs encoding distinct GABAA receptor subunits revealed that the intrinsic deactivation and desensitization properties depend on subunit combination. In particular, receptors containing alpha 6 with beta 2 gamma 2 subunits were endowed with a significantly slower deactivation as compared to those receptors containing alpha 1 with beta 2 gamma 2 subunits. While desensitization produced by prolonged GABA applications on alpha 1 beta 2 gamma 2 receptors was characterized by a rapid exponential decay followed by a slower decay and a steady state response, alpha 6 beta 2 gamma 2 receptors lacked desensitization. Furthermore, GABAA receptors lacking the gamma 2 subunit were characterized by a much larger non-desensitization component and a very rapid deactivation. Lastly, analysis of GABA-activated currents in cells cotransfected with alpha 1 and alpha 6 together with beta 2 gamma 2 subunit revealed unique kinetic properties. Our results suggest that distinct subunit composition confers specific deactivation and desensitization properties that may profoundly affect synaptic decay kinetics and the capability to sustain high frequency synaptic inputs.     

Identification of metabolic pathways of brain angiotensin II and angiotensin III: predominant role of angiotensin III in the control of vasopressin secretion

A complex seven species model community, including bacteria and fungi, was selected from organisms isolated from the walls of an industrial flowing water system. Growth rates of the species were determined in single and mixed batch culture growth. The rates were found to be significantly higher in mixed culture for Pseudomonas alcaligenes and Flavobacterium indologenes and higher in single culture for Xanthomonas maltophilia, Rhodotorula glutinis and Fusarium solani, whereas no significant difference was recorded for Alcaligenes denitrificans and Fusarium oxysporum. All species attached to PVC in single and mixed culture to form biofilms. Xanthomonas maltophilia, Alc. denitrificans, Ps. alcaligenes and F. solani biofilm cell densities cm-2 were significantly higher than attachment of the component species in mixed culture. Statistical analyses showed a significant difference in rate of colonization between single and mixed cultures for some species. No significant difference was noted between mixed culture cell densities cm-2 at laminar flows of Reynolds number 2.7 and 5.4.     

Type 1 angiotensin II receptors in human endometrium

OBJECTIVE: This paper is the summary of "National Symposium on the Value of Immunodiagnostic Assays in Schistosomiasis by Treatment Effects Assessment" which was directed by the Expert Advisory Committee for Schistosomiasis of the Ministry of Public Health. This symposium was held to evaluate the diagnostic effects of the new system of detection in the sensitivity and specificity by treatment assessment. MATERIALS AND METHODS: Twelve laboratories with 14 assay systems participated in this collaborative study, in which, 450 sera were detected by double blind trial using a classical antibody detection with ELISA as a control. RESULTS: The results showed that 6 test systems were superior or close to the classical antibody detection, especially in evaluating the value of treatment effects. CONCLUSIONS: It is unanimously recognized that much progress has been made in the research of immunodiagnosis of schistosomiasis in China, but many problems remain to be solved and worth further studying.     

Gene-polymorphisms of angiotensin converting enzyme and endothelial nitric oxide synthase in patients with primary glomerulonephritis

The human pre-B acute lymphoblastic leukemia cell line REH6 was utilized for characterization of CD45 glycoprotein by monoclonal antibodies (mAb) recognizing four distinct CD45 antigen specificities, i.e. nonrestricted CD45, restricted CD45RA, CD45RB and CD45R0. Immunoprecipitation revealed two antigen specificities on REH6 cells of m.w. 220 kDa and 190 kDa, both presenting wide range of isoelectric point pI approximately 6.0-7.5. Nonrestricted CD45 epitopes were not affected by the sialyl acid cleavage with sodium metaperiodate or neuraminidase, but were sensitive to both, tunicamycin, the N-glycosylation inhibitor and monensin, an inhibitor of protein transport through the Golgi compartment. O-sialoglycoprotein endopeptidase from Pasteurella haemolytica A1 partially cleaved CD45RA and CD45RB epitopes, while nonrestricted CD45 determinants were not affected by this enzyme. Limited proteolysis of this antigen resulted in the appearance of 160-180 kDa peptide domains which retained CD45 epitopes. Further, the treatment of cells with phorbol myristate acetate (PMA) induced marked down-regulation of 220 and 190 kDa isoforms and the appearance of new 210, 180 and 170 kDa variant glycoprotein forms which were not found on parental cells. This PMA effect was not accompanied by the programmed cell death and was markedly blocked by a nonselective protein kinase (PK) inhibitor isoquinoline sulfonamide H7. Modulation of CD45 by phorbol esters might serve as an in vitro model for an additional insight into the function of CD45 in hematopoietic cells.     

The nature of macrophage functional heterogeneity exemplified by Fc receptors

It is known that functional activity of macrophages (Mph), adhesion and phagocytosis, depends on the local concentration of Fc receptors (Fc gamma R) on the cell surface. Fc gamma R may have a random distribution on cell membrane or form clusters of different sizes. This process depends on the local activity of microfilaments that, in its turn, reflects peculiarities of macrophage microenvironments. One may conceive that the number of opsonized erythrocytes (OE) subject to adhesion (engulfing) to separate Mph depends on the amount of active centres on the cell surface and their activity. The structures, such as Fc gamma R clusters, phagosomes and others, in whose formation numerous components of Mph (cell skeleton, microvesicles, signal receptive system and others) are involved, are arbitrarily called the structural functional units (SFU). Thus, we used two parameters: the average number of SFU per Mph in population, and the average activity of SFU instead of a generally accepted number of OE per Mph. The number of SFU per Mph can be 0, 1, 2 etc., and one SFU may bind (engulf) 0, 1, 2 etc. EA. For the assessment of the parameters, the approximation of experimental histograms by type-A Neyman's distribution was used. To verify the adequacy of the model, observations of OE adhesion and phagocytosis in different conditions were made. The results show that the parameters of the model fit well the biological processes in this system.     

Induction of angiotensin converting enzyme and angiotensin II receptors in the atherosclerotic aorta of high-cholesterol fed Cynomolgus monkeys

Psychometric characteristics of the Social Introversion (Si) scale, the Social Discomfort (SOD) scale, and the Si subscales of the MMPI-2 were examined in clinical samples of 122 psychiatric patients and 399 patients with substance-use disorders. The combined Si1 (Shyness/Self-Consciousness) and Si2 (Social Avoidance) subscales correlated highly with SOD and are apparent measures of the social introversion construct. Si3 (Self/Other Alienation) was found to be a measure of the general maladjustment factor of the MMPI-2. Content not included on the Si subscales was divided into a group of items that measures general maladjustment and 2 other item groups that may assess minor constructs related to social introversion. As in previous research, the 3 Si subscales accounted well for variance in Si scores.