Biological functioning of human IgG Fc receptors.
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Biomedical subjects
Publications and source records attributed to C L Anderson.
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In 1979, the State of Illinois legislated regionalization of perinatal care. Analysis of perinatal statistics from the Loyola University Perinatal Center from 1979 to 1986 supports: (1) increasing numbers of maternal and neonatal transports, with the number of maternal transports exceeding the number of neonatal transports since 1982; (2) increasing proportion of low birthweight and very low birthweight infants delivered at the perinatal center; (3) a decrease in the number of infants less than 1500 gm sent as neonatal transports; and (4) increasing proportion of neonatal transports with a birthweight greater than 2500 gm. With the change in utilization by local physicians, the perinatal center has expanded its obstetric and neonatal service areas and hired additional staff to meet the increased demand for its services. The perinatal mortality rate for the region has decreased from 1981 to 1986.
A survey of drownings in hot tubs, spas, and whirlpools in California 1960-85 suggests a person- and site-specific profile. The identified 74 deaths occurred mostly in White children, under two years of age, in Southern California, during the late afternoons, from May through August. From 1967 to 1985, the drowning rate increased tenfold. The deaths were associated with access to the water, lack of supervision, neuromotor handicaps, and entrapment by suction. Educational and environmental control efforts are required to reduce the incidence.
Fatal and severe injury crashes for scooters and mopeds in California for 1985 were compared with those for motorcycles during the same year. Scooters had more than twice the injury crash rate of mopeds but one-half the rate of motorcycles. Age of injured drivers and crash patterns for scooters, mopeds, and motorcycles varied significantly.
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To test the hypothesis that chloral hydrate can cause direct hyperbilirubinemia (DHB) in the newborn, two retrospective analyses of the medical records of patients admitted to a neonatal intensive care unit during an 18-month period were conducted. In one analysis of 14 newborns who had nonhemolytic DHB, 10 did not have an identified cause of DHB, and all 10 had received chloral hydrate. In the second retrospective study, all newborns who received chloral hydrate were divided into groups according to whether or not DHB had developed. The newborns with DHB, compared with those without DHB, had received a higher total accumulative dose of chloral hydrate (1035 +/- 286 vs 183 +/- 33 mg/kg [+/- 1 SEM], respectively). In the patients with DHB, the direct serum bilirubin levels increased 6.8 +/- 0.8 days after the chloral hydrate administration began and resolved after the chloral hydrate was discontinued or markedly decreased. These data support the hypothesis that prolonged use of chloral hydrate in newborns can be associated with DHB.
A 670 g premature infant is described in whom an intracardiac thrombus was documented. This thrombus formation probably resulted as a complication of an indwelling right atrial catheter. Thrombolytic therapy with urokinase was instituted, resulting in total and rapid dissolution. No hemorrhagic complications resulted. We believe that this particular thrombolytic therapy is safe and effective and should be considered when facing this particular complication.
Microscopic techniques have been employed to study the cell surface distributions of the immunoglobulin Fc receptors (FcR) II and III on living human neutrophils. Fluorescein-or rhodamine-conjugated monoclonal IgG or Fab fragments directed against FcRII (CDw32) and FcRIII (CD16) were employed to label receptors. FcRII and III were found to be uniformly distributed at neutrophil surfaces during resting conditions. During neutrophil polarization and migration FcRII but not FcRIII preferentially accumulated at the uropod. Sheep erythrocytes (SRBCs) were opsonized with IgG and then incubated with neutrophils. When neutrophils were labeled prior to target addition, FcRII but not FcRIII were found to cluster at the target-effector interface. Little or no clustering of FcRs was observed if labeling was performed after target binding. SRBC oxidation was observed using Soret band illumination during transmitted light microscopy. Time-lapse studies of FcRII distribution and target oxidation were performed. FcRII formed clusters at target effector interfaces prior to target oxidation. Three lines of evidence suggest that clustering is not a general plasma membrane response. Firstly, FcRIII do not cluster lannic acid-modified erythrocytes avidly bound to neutrophils but did not trigger clustering of FcRII. Furthermore, irrelevant neutrophil membrane labels were unaffected by the presence of IgG-opsonized erythrocytes. We suggest that FcRII clustering is one important component leading to the oxidative destruction of target cells.
The fusion protein of an avian paramyxovirus-3 from turkeys was detected as a poorly-labelled 56K 3H-glucosamine band. After immunopurification by a monoclonal antibody it elicited antisera which inhibited haemolysis but not haemagglutination.
Considerable recent progress has been made in our understanding of how IgG immune complexes interact with plasma membrane Fc receptors (FcR) to mediate a diversity of biological responses in man. These responses include endocytosis of antibody complexes; stimulation of the secretion of various inflammatory mediators such as enzymes, oxygen products, and arachidonic acid derivatives; antibody-mediated cell killing by FcR-bearing cells; immune complex-mediated stimulation of the platelet release reaction; modulation of the immune response; and others. The Fc receptors responsible for transducing these responses have largely been characterized. They fall into three distinct classes (FcRI, FcRII, FcRIII) based upon a number of criteria including molecular size, affinity, and specificity for ligand, cell-specific display, and epitope expression; but with a few possible exceptions these three classes do not seem to correlate with the multiple functional properties of the receptors. Recently the primary structures of these molecules have been inferred from cDNA sequences. As members of the Ig gene superfamily, they all have extracellular portions consisting of two or three truncated disulfide-looped Ig-like domains. As a rule, these are rather conventional integral membrane glycoproteins bearing a short lipid-spanning polypeptide and a cytoplasmic tail of varying length, although one appears to be linked to the plasma membrane by a glycosyl phosphatidylinositol moiety and thus bears no cytoplasmic domain. Remarkably, within each class of FcR there appears to be considerable polymorphism, especially within the cytoplasmic portions. How these various structures dictate specific biological consequences is currently under study.
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Trapped occluded fourth ventricle has been considered a rare occurrence. Intraventricular hemorrhage followed by repeated shunt revisions may increase the risk (8/47 cases). Because premature infants with intraventricular hemorrhage and shunted hydrocephalus often have preexisting neurologic abnormalities, dilation may produce clinically undetected further neurologic damage. Shunting improved function in both currently treated as well as 13 of 14 previously treated patients. In light of this observation, the importance of recognition is stressed.
A variable T lymphocyte proliferative response to murine IgG1 anti-T3 monoclonal antibodies, in which most North American Caucasians respond whereas a minority do not, is well established. This is most likely the result of a genetic polymorphism manifested by 1) the inability of the monocyte 40-kDa IgG FcR of some individuals to bind murine IgG1, and 2) a distinctive trimorphic pattern on IEF of the monocyte 40-kDa FcR, one form being seen in all individuals who do not respond and another form (or a combination of both forms) being seen in those who do respond. We have evaluated the IEF patterns of the platelet 40-kDa FcR and find that in every individual tested the pattern for platelet FcR correlates with that seen for the monocyte 40-kDa FcR pattern. Furthermore, the platelets of those individuals whose "nonresponder" monocyte 40-kDa FcR did not mediate a murine IgG1 anti-T3 response did not respond with an aggregation reaction to murine IgG1 immune complexes (opsonized E). In contrast, platelets from donors possessing "responder" monocytes displayed positive "aggregation" responses to E coated with murine IgG1 antibody. However, the platelet FcR structural polymorphism described earlier did not correlate with the donor-specific variability in capacity of platelets to respond functionally to aggregated human IgG described in an earlier paper. Rather, the variation in capacity of platelets from individual donors to respond functionally to aggregated human IgG was related to the quantitative expression of platelet FcR. These data indicate that the molecular mechanisms responsible for the platelet 40-kDa FcR structural polymorphism are quite different from the mechanisms governing the variation in quantitative expression of the receptor.
Sixteen monoclonal antibodies (Mabs) which immunoprecipitated the haemagglutinin neuraminidase (HN) of chorio-allantoic membrane-grown avian paramyxovirus-3 (PMV-3) of British turkeys were produced. Thirteen were PMV-3 specific. Three were nonspecific because they also bound to other viral proteins and to bovine kidney cells treated with neuraminidase enzyme or infected with influenza virus. The thirteen specific Mab defined four antigenic regions A-D by competition and variant selection assays. Region A was subdivided into five epitopes and region B into two epitopes. The thirteen Mab neutralized and were active in haemagglutination inhibition (HI) and twelve were active in haemolysis inhibition (HLI) tests. Neuraminidase inhibition (NI) was epitope-dependent. Mabs to five of the epitopes A1, A2, A3, A5, and C bound to the 1981 British turkey isolates but not the 1968 American turkey isolate. The Mab to epitope A4 bound to both viruses. The Mabs to epitopes B1, B2, and D also bound to a parakeet isolate of PMV-3 which was the third PMV-3 tested. The Mab to B2 gave identical titres to all three viruses and had HI, HLI, and NI activities. This made it a potential diagnostic reagent for avian PMV-3 viruses. One of the nonspecific Mabs bound to lactose-like moieties as reported on influenza virus and one to maltose-like moieties as on retroviruses. Immunoglobulin from all three nonspecific Mab had some HI activity.
The high affinity Fc receptor (FcRI) of a human monocytic cell line, U937, was further characterized using a previously described murine monoclonal antibody, FcRmAb32. This antibody immunoprecipitated a 70 K cell surface glycoprotein. A solid phase ligand binding assay and a solid phase immunoprecipitation assay were combined to confirm that the 70 K cell surface glycoprotein immunoprecipitated by FcRmAb32 is an IgG binding protein. N-glycanase digestion shows that at least 20% of the relative mobility of the 70 K FcRI glycoprotein is due to N-linked carbohydrate. FcRmAb32 immunoprecipitated a 70 K glycoprotein from biosynthetically labelled U937 cells that co-migrated with the surface iodinated glycoprotein on 2-dimensional gel electrophoresis. A 50 K protein, that is biosynthetically labelled but not accessible to surface iodination, which, bound to control antibodies was also present in FcRmAb32 immunoprecipitates. FcRmAb32 only bound the mature fully glycosylated form of FcRI. The 70 K FcRI was not phosphorylated constitutively nor when U937 cells were stimulated by PMA.
Three different receptors for the Fc portion of IgG (FcR) have been characterized on human leukocytes. We have identified four healthy members of one family, whose blood phagocytic cells lack functional 72 kD high-affinity FcRI. Their monocytes were unable to bind the Fc portion of mouse (m)-IgG2a and of monomeric human IgG, and they were unreactive with two anti-FcRI monoclonal antibodies. Thus, FcRI is either absent, expressed at very low density, or is so structurally altered as to be unable to bind both its ligand and the anti-FcRI antibodies. The failure to bind the Fc portion of mIgG2a underlies the previously reported inability of these monocytes to support T cell mitogenesis on OKT3 stimulation. FcRI was not inducible upon incubation of their monocytes or neutrophils in gamma interferon. However, their monocytes were able to bind aggregated human IgG, and to phagocytose IgG-coated particles in vitro. Both functions could be blocked with a monoclonal antibody to the 40-kD low-affinity FcRII and therefore apparently were mediated exclusively through FcRII. This also demonstrates that FcRII can mediate phagocytosis independently. Despite the FcRI defect, these subjects had no circulating immune complexes, no evidence of autoimmune pathology and no increased susceptibility to infections.
Evidence has recently been presented that a 40,000 dalton membrane sialoglycoprotein (p40) shared by monocytes and granulocytes serves as the human platelet receptor for aggregated IgG. We now report that the platelets of normal donors exhibit stable quantitative differences in the expression of this receptor molecule, as determined by flow cytometry using fluorescent staining with murine monoclonal antibody to p40 (mab IV.3). These inter-donor differences were reproducible on repeated testing over at least 4 mo. In concurrent assays, the binding of mab IV.3 to each donor's platelets was highly correlated with the binding of heat-aggregated human IgG, also assayed by flow cytometry. The biological relevance of this quantitative variation in IV.3 binding is suggested by its reproducible correlation with platelet responsiveness to aggregated IgG measured by aggregometry. Such stable quantitative variation in platelet Fc receptor expression among individual humans could contribute to differences in severity of certain pathologic processes initiated by IgG-containing immune complexes.