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  • 1
    ISSN: 1432-1203
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary Three probands heterozygous for a mutant of apolipoprotein AI (apo AIMarburg, Utermann et al. 1982a) were detected by screening of 2282 unrelated individuals resulting an a frequency estimate of about 1/750 in the German population. All three probands with apo AIMarburg had hypertriglyceridemia (triglyceride above 250 mg/dl) and subnormal HDL-cholesterol (below 30 mg/dl), but no other lipoprotein abnormalities. The kindreds of two probands with AIMarburg were studied. The family data are consistent with an autosomal codominant inheritance of the trait. A total of 16 heterozygous blood relatives with the mutant AIMarburg were detected in these kindreds. Analysis of the plasma lipid and lipoprotein levels in relation to the apo AI phenotype was complicated by the high prevalence of diabetes mellitus and thyroid disease in one kindred and of hyperlipidemia in both kindreds. No consistent relationship between plasma lipid and lipoprotein levels, and the mutant apo AI could be demonstrated. Instead the mutant apo AI and the dyslipoproteinemia seem to co-exist independently in these kindreds. Three sibs with the homozygous apo E-2/2 phenotype were detected in one kindred, and all three sibs had subnormal LDL-cholesterol and beta-VLDL, e.g., the lipoprotein abnormality characterizing primary dysbetalipoproteinemia. Genetic apo E phenotypes and the apo AI mutant segregated independently, indicating that the structural gene loci for apo E and apo AI are not closely linked.
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  • 2
    Publication Date: 1982-01-01
    Print ISSN: 0340-6717
    Electronic ISSN: 1432-1203
    Topics: Biology , Medicine
    Published by Springer
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  • 3
    Publication Date: 1989-06-01
    Description: Anti-Bra was first identified in four cases of neonatal alloimmune thrombocytopenia (NAIT). The antigen Bra is localized on the glycoprotein Ia/IIa complex of platelets. Anti-Bra can best be detected by a glycoprotein-specific immunoassay using monoclonal antibodies for antigen immobilization (MAIPA assay) and radioimmunoprecipitation (RIP). Recently, we have identified sera from two polytransfused patients that contain an antibody that recognizes Brb, the allele of Bra. Family studies show that both antigens are inherited as autosomal codominant characters. The gene frequency of the new allele Brb is 0.888. Approximately 2,000 anti-Bra binding sites are present on homozygous platelets and 1,000 on heterozygous platelets. Our findings provide evidence for the first polymorphism observed on the glycoprotein Ia/IIa complex. Immunization against these alloantigens is implicated in NAIT and poly-transfused patients.
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
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  • 4
    Publication Date: 1987-12-01
    Description: The analysis of sera containing different platelet-reactive antibodies, eg, autoantibodies, platelet-specific alloantibodies like anti-PIA1, - PIA2, -Baka, and HLA antibodies, is still difficult. Recently, monoclonal antibodies against major platelet membrane constituents (glycoproteins IIb/IIIa and Ib and HLA class I molecule) have become available. In this report we describe a new assay that takes advantage of these highly specific reagents to investigate selectively platelet reactive antibodies against epitopes on different glycoproteins. The reliability and specificity of this assay is demonstrated with known platelet-reactive autoantibodies and alloantibodies (anti-PIA1, -Baka, - Pen). The discovery of a PIA2 antibody in a serum of a polytransfused patient underscores the efficiency of this technique. Possible applications of this assay are discussed in detail.
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
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  • 5
    Publication Date: 1986-02-01
    Description: Redistribution of glycoproteins (GP) Ib, glycocalicin, IIb, and IIIa on the surface of human platelets in response to stimulation with corresponding monoclonal antibodies (MoAb) and a polyclonal antiglycocalicin antibody was studied by immunofluorescence, immunoelectron microscopy, and a quantitative radioimmune assay. Immobilization of the antigens by prefixation with formaldehyde showed a uniform distribution over the surface of the platelet. Incubation of unfixed platelets with specific MoAb against various epitopes on GPIIb and/or IIIa resulted in a time-dependent patching, subsequent capping, and after prolonged exposure to the antibody/label complex, internalization of the complex, possibly by endocytosis. In contrast, GPIb could not be shown to cap. From these results we conclude that platelet GPIIb and/or IIIa undergo spatial rearrangement in a manner analogous to that observed in lymphocytes, whereas GPIb does not. Since both GPIb and GPIIb and/or IIIa seem to be transmembraneous GP associated with the cytoskeleton, a special, though unidentified, role of GPIIb/IIIa in the induction of lateral membrane mobility is postulated.
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    Electronic ISSN: 1528-0020
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  • 6
    Publication Date: 1986-08-01
    Description: An otherwise healthy woman developed a hemorrhagic diathesis with fluctuating clinical symptoms and laboratory findings, but without thrombocytopenia, over 8 years. In periods of bad clinical condition, a platelet defect, characteristic of thrombasthenia, was found. In contrast to classic thrombasthenia, electrophoresis of the patient's platelet membranes revealed normal amounts of glycoproteins IIb alpha, IIb beta, and IIIa in the normal positions. Monoclonal antibodies, specific for GPIIIa and GPIIb/IIIa, respectively, bound normally to the P1A1-positive platelets from the patient. Although no antibody and no platelet function inhibitor were evident in the autologous plasma, an IgG1 antibody that was bound to the patient's platelets and was directed against GPIIb/IIIa could be demonstrated. After elution from the patient's platelets, this antibody immunoprecipitated GPIIb (both subunits), IIIa, and a 200-kilodalton (kd) band (probably undissociated GPIIb/IIIa complex) from solubilized normal platelets, but did not react with thrombasthenic platelets. Adding the eluate from the patient's platelets to normal platelet-rich plasma immediately caused concentration-dependent inhibition of adenosine diphosphate (ADP)- induced and collagen-induced aggregation and also strong inhibition of ADP-stimulated fibrinogen binding. Because it was very unlikely from the patient's medical history that the antibody was caused by alloimmunization, the hemorrhagic diathesis must be interpreted as acquired thrombasthenia due to an anti-GPIIb/IIIa autoantibody.
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    Electronic ISSN: 1528-0020
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  • 7
    Publication Date: 1986-12-01
    Description: Nomifensine (Merital, Alival; Hoechst, Frankfurt, FRG), an antidepressant drug, may cause immune hemolytic anemia (IHA) of the so- called immune complex type that is believed to occur by means of an innocent-bystander mechanism. In this report we describe findings that are not consistent with this mechanism in a patient with nomifensine- induced intravascular IHA associated with renal failure. In vitro studies showed a transitory positive direct antiglobulin test (DAT) due to IgG, IgM, and C3 fixation. The causative antibodies were found to be a drug-independent IgM antibody in the serum and eluate that reacted only with E-positive RBC, although the patient's RBC were E-negative; an IgG antibody in the serum and initial eluates that showed a stronger reaction with e-positive than with e-negative or Rhnull RBC, but only in the presence of ex vivo antigen (ie, urine containing the drug and all its metabolites); and an IgM antibody in the serum and initially also on the patient's RBC that, in the presence of ex vivo antigen as well as in the presence of known metabolites of the drug, agglutinated all RBC equally strongly, but was hemolytically more active against E- positive than E-negative cells. Within a few days of stopping the drug the hemolysis rapidly resolved without administration of prednisone, the DAT became negative with anti-IgG and anti-IgM, and the drug- independent anti-E disappeared, but both metabolite-dependent antibodies remained detectable in the patient's serum. We conclude that the production and specificity of the causative antibodies in this case were controlled by a larger antigenic site, presumably consisting of the drug and/or its metabolites plus RBC antigens, rather than by epitopes of the drug or metabolites alone.
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
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  • 8
    Publication Date: 1986-12-01
    Description: Nomifensine (Merital, Alival; Hoechst, Frankfurt, FRG), an antidepressant drug, may cause immune hemolytic anemia (IHA) of the so- called immune complex type that is believed to occur by means of an innocent-bystander mechanism. In this report we describe findings that are not consistent with this mechanism in a patient with nomifensine- induced intravascular IHA associated with renal failure. In vitro studies showed a transitory positive direct antiglobulin test (DAT) due to IgG, IgM, and C3 fixation. The causative antibodies were found to be a drug-independent IgM antibody in the serum and eluate that reacted only with E-positive RBC, although the patient's RBC were E-negative; an IgG antibody in the serum and initial eluates that showed a stronger reaction with e-positive than with e-negative or Rhnull RBC, but only in the presence of ex vivo antigen (ie, urine containing the drug and all its metabolites); and an IgM antibody in the serum and initially also on the patient's RBC that, in the presence of ex vivo antigen as well as in the presence of known metabolites of the drug, agglutinated all RBC equally strongly, but was hemolytically more active against E- positive than E-negative cells. Within a few days of stopping the drug the hemolysis rapidly resolved without administration of prednisone, the DAT became negative with anti-IgG and anti-IgM, and the drug- independent anti-E disappeared, but both metabolite-dependent antibodies remained detectable in the patient's serum. We conclude that the production and specificity of the causative antibodies in this case were controlled by a larger antigenic site, presumably consisting of the drug and/or its metabolites plus RBC antigens, rather than by epitopes of the drug or metabolites alone.
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
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  • 9
    Publication Date: 1987-04-01
    Description: The mechanisms of sensitization and attachment of drug-dependent antibodies to RBC in drug-induced immune hemolytic anemias are largely speculative. Nomifensine has been incriminated in causing immune hemolysis in a large number of patients. The hemolysis was usually of the so-called immune complex type, less commonly of the autoimmune type, and more surprisingly, few patients had developed both types of hemolysis. To determine whether nomifensine (metabolite)-dependent antibodies (ndab) exhibit specificity for antigenic structures of RBC membranes, 30 ndab were tested against large panels of RBC with common and rare antigens. We found that only 14 out of 30 ndab were invariably reactive with all cells tested. Nine antibodies were, similar to the majority of idiopathic or drug-induced autoantibodies, not or only weakly reactive with Rhnull RBC. Three antibodies did not react with cord RBC and could be inhibited by soluble I antigen. The remaining four antibodies gave inhomogeneous reaction patterns or were even negative with selected RBC; their specificity could not be identified. On a Scatchard plot analysis of one ndab, a maximum of 173,000 drug- dependent antibodies of the IgG class can specifically bind per RBC in the presence of the drug. Although nomifensine and its metabolites do not attach tightly onto RBC, our results clearly indicate that RBC do not act as “innocent bystanders,” but rather serve as a surface for a loose attachment of drugs that possibly cause a subtle structural change in the cell antigens and, by this means, allow in vivo sensitization; and a specific binding of the resultant antibodies. This concept would explain why these antibodies can be directed against drug- cell complexes, against cell antigens alone (autoantibodies), or against both in the same patient.
    Print ISSN: 0006-4971
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  • 10
    Publication Date: 1989-06-01
    Description: Anti-Bra was first identified in four cases of neonatal alloimmune thrombocytopenia (NAIT). The antigen Bra is localized on the glycoprotein Ia/IIa complex of platelets. Anti-Bra can best be detected by a glycoprotein-specific immunoassay using monoclonal antibodies for antigen immobilization (MAIPA assay) and radioimmunoprecipitation (RIP). Recently, we have identified sera from two polytransfused patients that contain an antibody that recognizes Brb, the allele of Bra. Family studies show that both antigens are inherited as autosomal codominant characters. The gene frequency of the new allele Brb is 0.888. Approximately 2,000 anti-Bra binding sites are present on homozygous platelets and 1,000 on heterozygous platelets. Our findings provide evidence for the first polymorphism observed on the glycoprotein Ia/IIa complex. Immunization against these alloantigens is implicated in NAIT and poly-transfused patients.
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
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