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Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The specificity of 14 monoclonal antibodies has been determined by immunoblotting (IB) and haemagglutination-inhibition (HAI) analysis using IgA1 and IgA2 myeloma proteins and eight different IgA1 fragments. Two antibodies probably recognized epitopes on the CH1 domain of IgA. They reacted with all Fab-containing fragments irrespective of whether these originated from the same or different IgA proteins. Seven antibodies were directed against epitopes on the CH2 domain. These antibodies were reactive with F(abc)2 fragments. They failed to react with Fab, Fab' and F(ab')2 fragments. Two out of these seven antibodies did not react with two-chain IgA half-molecules and Fabc fragments containing a single heavy and a single light chain. This suggests that these two antibodies recognized an epitope whose structure is dependent on disulfide linked heavy chains. Five other antibodies showed specificity for the CH3 domain. They were reactive with all CH3-containing molecules, irrespective of whether they comprised one or two alpha chains. Our study demonstrates that IB is an appropriate technique to determine domain specificity of monoclonal anti-immunoglobulin reagents. Although the IB tests were performed on denatured proteins the results agreed surprisingly well with those of the HAI analyses. Moreover, the IB technique could be used on fragments which could not be purified well enough for HAI analyses.
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PMID:Monoclonal antibodies against different domains of human IgA: specificities determined by immunoblotting and haemagglutination-inhibition. 243 12

We used an immunofluorescent sequential-saturation-of-antibody assay and an interactive computer program for Scatchard analysis to determine association constants (Ka) of 33 murine monoclonal antibodies (Mabs) specific for human IgA epitopes. Ka ranged from 0.37 to 690 x 10(7) liters per mole (an approximate 1900-fold difference). Specificity was validated with a panel of 18 highly purified IgA1 and IgA2 myeloma proteins and secretory IgA using an immunofluorometric assay. Western blots of bacterial IgA protease digests were used to locate the epitopes of IgA specific Mabs in either the Fab, Fc, or hinge region. Mabs specific for unique epitopes on secretory IgA or free secretory component (FSC) were produced and evaluated.
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PMID:Specificity and association constants of 33 monoclonal antibodies to human IgA epitopes. 247 39

The interaction of human IgA antibodies with the classical pathway of complement activation was investigated in a homologous human system, by means of two IgA1 and three IgG1 myeloma proteins having antibody activity against a defined antigen, staphylococcal alpha-toxin. In a solid-phase antigen-dependent C3b-binding ELISA system, the monoclonal IgG antibodies were previously shown to activate the classical complement pathway synergistically, resembling polyclonal IgG antibodies, whereas IgA antibodies were unable to activate complement by either pathway. In the present study, IgA antibodies were found to inhibit significantly the activation of complement initiated by antigen-bound polyclonal or mixed monoclonal IgG antibodies, in relation to the amount of IgA antibodies applied and bound to antigen. IgA1 myeloma proteins devoid of antigen-binding activity were without effect. Inhibition was independent of the ability of the IgA antibodies to compete against the IgG antibodies in binding to antigen, and was demonstrable with physiological concentrations of antibodies. Similar results were obtained with polyclonal serum IgA having antigen-binding activity. However, the binding of C1q to antigen-complexed IgG was inhibited only by a monoclonal IgA antibody that could compete against one of the three monoclonal IgG antibodies that bound C1q synergistically. This observation implied that at least two mechanisms were involved in the inhibition of C3b fixation. Fab alpha fragments of monoclonal IgA antibodies, obtained by cleavage with IgA1 protease from Haemophilus influenzae type b, were found to have a similar inhibitory effect on C3b fixation to the intact IgA1 antibodies. This observation supports the hypothesis that IgA1 proteases contribute to the invasive pathogenicity of certain mucosal bacteria, by cleaving secretory IgA1 antibodies to antigen-binding Fab alpha fragments, which are not only defective in mucosal defense properties, but which also protect the organisms from other immune effector systems, such as complement activation.
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PMID:Anti-inflammatory activity of human IgA antibodies and their Fab alpha fragments: inhibition of IgG-mediated complement activation. 260 39

The liver plays a key role in the translocation of IgA into the upper gastrointestinal tract. The amount of IgA transported and the mechanisms involved, however, vary widely among species. In some, best defined in the rat, large amounts of polymeric IgA (pIgA) are cleared from the plasma by hepatocytes, which synthesize the polymeric immunoglobulin receptor, secretory component (SC), and express it on their sinusoidal plasma membranes. Circulating pIgA binds to SC, is internalized into endocytic vesicles and transported across the hepatocyte to the bile canalicular membrane, where the pIgA is released into bile in complex with a portion of the SC, i.e., secretory sIgA (sIgA). In some other species, including man, there is much less hepatic transport of circulating IgA, at least in part because SC is present only in biliary epithelium, and there is relatively more local synthesis of IgA within hepatobiliary tissues. On the other hand, certain IgA1 myeloma proteins appear to bind to and enter human hepatocytes via an asialoglycoprotein receptor. These species differences have implications for the biological significance of the biliary secretion of IgA, including the disposal of circulating IgA-antigen complexes into bile.
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PMID:The role of the liver in translocation of IgA into the gastrointestinal tract. 265 12

Patients with IgA nephropathy have circulating immune complexes containing IgA, IgG, and C3. We have mixed human IgG and IgA1 and heated them to form mixed aggregate. On sucrose density gradients IgG aggregates were 11 to 19S whereas IgA aggregates were either 11S or greater than 19S. Mixed aggregates had both an 19 and 11 S peak. The isoelectric point of aggregates with only IgG was 7 to 9 and of only IgA 4.5 to 5.5. The isoelectric point of mixed aggregates decreased as the percent IgA increased. IgG aggregates mixed with normal human serum caused 30% C3 activation (20 min, 37 degrees C) whereas IgA aggregates causes no activation. There was a linear decrease in C3 activation as the percent IgA increased. Mixed aggregates that contained either radiolabeled IgG or IgA were mixed with normal human serum (1 h, 37 degrees C) and then solubilized, reduced, and separated by 10% SDS-PAGE. Heavy m.w. bands, consistent with covalent bonding of C3b and C3bi to Ig H chain were only seen in lanes with labeled IgG. This was confirmed by Western blot analysis. A human dimeric IgA1 myeloma protein with rheumatoid factor activity was also studied. It caused 15% alternative pathway C3 activation but did not fix C3 to its H chain. Binding of aggregates (+/- C3) to E was tested. Aggregates with IgG C3 bound but IgA (+/- C3) did not. Addition of greater than 10% IgA to an IgG-C3 aggregate inhibited E binding. We conclude that IgG in mixed aggregates is the site of C3 fixation. In contrast, IgA does not fix C3 but instead lowers the isoelectric point, increases the size and inhibits binding to E. These properties would inhibit clearance and promote mesangial deposition and local C activation.
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PMID:Mixed IgA-IgG aggregates as a model of immune complexes in IgA nephropathy. 271 39

Expression of receptors for IgA (Fc alpha Rs) was investigated on a panel of 35 human B cell lines by labelling with human secretory IgA (0.5 mg/ml) and flow cytometry analysis after staining with fluoresceinated goat anti-human secretory component and/or anti-alpha chain F(ab')2 fragments. Receptors for IgA could be demonstrated on one out of nine Burkitt's lymphoma cell lines, three out of five myeloma cell lines and five out of 21 lymphoblastoid cell lines. The percentage of Fc alpha R-positive cells within the same B cell line varied upon repeated examination. Human dimeric IgA1 lambda myeloma protein revealed the same number of IgA receptor positive cells as did secretory IgA, whereas monomeric IgA did not bind to Fc alpha R. Detection of Fc alpha R was not inhibited when the tests were carried out in the presence of human dimeric IgG, IgM, asialo-orosomucoid, and secretory component but it was abrogated by pre-treatment of the cells with trypsin. The binding characteristics of Fc alpha Rs were studied on the myeloma cell line Esteve, using 125I-labelled human dimeric IgA and secretory IgA. The binding was dose-dependent with rapid kinetics and specific inhibition by unlabelled secretory IgA. Scatchard plot analysis resulted in an equilibrium constant K ranging from 3.2 to 4.7 x 10(6) M/l. No correlation was observed between Fc alpha R expression and differentiation stage, monoclonality, polyclonality of the cell lines, or Ig class produced by the B cells.
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PMID:Spontaneous expression of a low affinity Fc receptor for IgA (Fc alpha R) on human B cell lines. 278 48

A patient affected with multiple myeloma displayed in the serum, urine, and cerebrospinal fluid a paraprotein with identical electrophoretic mobility. The paraprotein, which was polymeric, appeared in the serum and cerebrospinal fluid mainly as the dimer and tetramer, whereas in the urine the tetramer was predominant. The myeloma protein, identified as an IgA1 kappa, was isolated from the serum and urine and submitted to structural analysis. For reasons of scarcity of material, it was decided to approach the structure of the cerebrospinal fluid paraprotein by means of antiidiotypic antiserum. Complete idiotypic identity between, on the one hand, cerebrospinal fluid and, on the other hand, IgA1 isolated from serum and urine and F(ab)2 alpha derived from serum IgA1 was observed. Adsorption experiments confirmed the idiotypic identity among the three biological fluids. Although the blood-brain barrier of the patient was only slightly disturbed, IgA polymers of MW varying from approximately 280,000 to approximately 840,000 appeared in the cerebrospinal fluid. Consequently the results are good evidence for synthesis within the central nervous system by subsequent generations of a malignant B-cell line which invaded the central nervous system.
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PMID:A paraprotein IgA1 occurring in serum, urine, and cerebrospinal fluid (CSF): immunochemical and idiotypic evidence of synthesis in situ by the central nervous system (CNS). 309 30

Eight human IgA1 myeloma proteins were analysed by SDS-PAGE. These experiments showed that purified IgA1 proteins comprise both fully S-S bonded and partly S-S bonded molecules. Pepsin digestion of the IgA1 proteins yielded three four-chain and two two-chain fragments. The four-chain fragments are likely to be derived from intact IgA through cleavage of its alpha chains at different sites: between the CH2 and CH3 domains or in the hinge region. The occurrence of F(abc) (ab') fragments, with alpha chains of different lengths, showed that the alpha chains of IgA can be cleaved independently at the hinge region site. The two-chain pepsin fragments must originate from IgA molecules, which lack inter-assay-chain disulphide linkages. The fragments F(abc)2 and Fabc tended to form dimers, probably through non-covalent interactions of their CH2 domains. An immunoblotting method was used to identify Fd-, CH2- and CH3-specific anti-IgA antibodies. The CH2-specific antibodies could be subdivided into antibodies recognizing an isotype present on both four-chain and two-chain molecules or on two-chain molecules only.
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PMID:Production and characterization of pepsin fragments of human IgA1 to determine domain-specificity of monoclonal anti-IgA antibodies. 309 70

The concentration of IgA in a serum was 5.99 g/L as assayed nephelometrically with reagent from one company, but varied between 5 and 3 g/L (for sixfold and 36-fold dilutions, respectively) without giving a definitive answer when assayed with reagent from another source. Immunofixation electrophoresis indicated an IgA lambda monoclonal protein of 45 g/L. Radial immunodiffusion showed two components, having a total concentration of 41 g/L. By fluorometry the IgA was 3.1 g/L. Increasing the dilution caused the (dilution-corrected) lower values to increase. Although the most frequent cause of such discrepant findings is an IgA2 myeloma, which occurs in about one of every 100 myeloma cases, Ouchterlony double diffusion indicated the major component to be IgA1. A polymer, Mr 670,000, was identified by column chromatography. Contrary to the usual behavior of polymers assayed with radial immunodiffusion, which underestimates their concentration, this polymer reached equivalency in agreement with its true concentration as assayed by the Mancini-Heremans technique.
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PMID:Inaccurate measurement of a polymeric IgA myeloma protein by nephelometric and fluorometric instrumentation. 309 5

In the present study the in vitro binding, internalization and degradation of IgA immune complexes (IC) by phagocytes was studied. As a model for IgA IC, heat-aggregated human secretory IgA (AsIgA) was prepared and resident rat peritoneal macrophages (PM phi) were used as a source of phagocytes. First, binding of 125I-AsIgA to rat PM phi was investigated. Binding of 125I-AsIgA to PM phi at 4 degrees was saturable and reached plateau values after 2 hr. At 37 degrees, degradation of membrane-bound 125I-AsIgA into trichloroacetic acid (TCA)-soluble fragments occurred. Parallel experiments with unlabelled AsIgA and 125I-labelled anti-human IgA revealed that degradation of AsIgA was preceded by internalization of AsIgA. The specificity of binding of 125I-AsIgA to PM phi was investigated using human IgG, human serum IgA, human myeloma IgA1, human sIgA and the glycoproteins asialofetuin and ovalbumin. The binding of 125I-AsIgA to rat PM phi was inhibited in the presence of sIgA and asialofetuin. In contrast IgG and ovalbumin had no effect. These results suggest that receptors with a specificity for galactose on the rat PM phi are involved in the binding of AsIgA.
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PMID:Binding, internalization and degradation of soluble aggregates of human secretory IgA by resident rat peritoneal macrophages. 316 44


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