Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The arrangement of disulfide bonds joining secretory component (SC) to the alpha chains in secretory IgA was studied by determining the molecular size of the principal fragments resulting from CNBr digestion of secretory dimeric Fc fragments from IgA (Fc)2alpha fragments). In vitro complexes formed by incubating 125I-free SC and myeloma 131I-(Fc)2alpha fragments were isolated by gel filtration and subsequently digested with cyanogen bromide. The CNBr digests of SC-(Fc)2alpha fragments were analyzed by gel filtration in 5 M guanidine. Two principal fragments were obtained, one containing a monomeric Fc fragment from IgA (Fcalpha) associated with SC (m.w. congruent to 110,000) and a second containing the second Fcalpha monomer (m.w. congruent to 50,000) from the dimeric SC-(Fc)2alpha. Similar results were obtained when secretory (Fc)2alpha fragments isolated from native secretory IgA dimer were subjected to CNBr digestion. The data indicate that SC is disulfide bonded to a single monomer subunit in secretory IgA dimer.
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PMID:Disulfide bonding of secretory component to a single monomer subunit in human secretory IgA. 40 58

Urinary proteins from 50 patients with multiple myeloma (37 Ig G, 6 Ig A, 7 Bence Jones) were investigated by discelectrophoresis in polyacrylamidgels containing sodium dodecylsulfat. All samples were also characterized by immunelectrophoresis. Quantitatively and qualitatively normal proteinuria was found in 13 patients (26%). 22 patients (44%) had monoclonal free light chains in the urine, kappachains were eliminated mainly in the monomeric form, lambdachains in all samples in the dimeric form. In 2 patients were found to exist light chains as monomers and dimers. 11 other patients (22%) had peaks of monoclonal Ig G or Ig A in the urine, always associated with the elimination of other nonmonoclonal proteins. Non-specific proteinuria was found in the remaining 4 patients. The clinical validity of the findings is discussed.
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PMID:[Analysis of urinary proteins from 50 patients with multiple myeloma by discelectrophoresis (author's transl)]. 43 51

Three efficient mouse interferon gamma (MoIFN gamma) inhibitors were constructed, which consist of the MoIFN gamma receptor (MoIFN gamma R) extracellular portion and constant domains of immunoglobulin (Ig) molecules. These are: 1) the constant domain of the mouse kappa chain, 2) the hinge region and the constant domains 2 and 3 of the mouse gamma 2a chain, and 3) the hinge region and the constant domains 2 and 3 of the human gamma 3 chain. The hybrid molecules were expressed in the mouse myeloma cell line J558L and recovered from the supernatants of cell cultures in one purification step. The proteins MoIFN gamma R-M gamma 2a and MoIFN gamma R-H gamma 3 form homodimers, whereas MoIFN gamma R-M kappa is a monomer. All three constructs inhibit the binding of radiolabeled MoIFN gamma to its receptor on L1210 cells. They are biologically active in vitro, neutralizing the action of MoIFN gamma in an antiviral activity assay. The fusions of Ig regions to the soluble MoIFN gamma R do not decrease the affinity of the binding site for the ligand. MoIFN gamma R-M kappa has about the same affinity as the soluble MoIFN gamma R and the cell surface receptor of L1210 cells in situ, which are also monomers, whereas the dimers MoIFN gamma R-M gamma 2a and MoIFN gamma R-H gamma 3 display a 5-10-fold higher affinity for MoIFN gamma than the monomeric molecules. This is best documented in the efficacy of the inhibitors to antagonize the antiviral activity of MoIFN gamma, as the dimeric constructs are about 10 times more active than MoIFN gamma R-M kappa and the soluble MoIFN gamma R. The hybrid constructs can be used as high efficiency MoIFN gamma inhibitors in mouse models of several pathological states in humans, where IFN gamma is thought to play a disease-promoting role.
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PMID:Construction, purification, and characterization of new interferon gamma (IFN gamma) inhibitor proteins. Three IFN gamma receptor-immunoglobulin hybrid molecules. 153 30

The in vivo efficacy of human recombinant soluble tumor necrosis factor (TNF) receptor protein to prevent and to treat lipopolysaccharide (LPS)-induced lethal toxicity in D-galactosamine-treated mice was investigated. Chimeric proteins of the receptor extracellular domains fused to the hinge region of human IgG3 were expressed in myeloma cells (rsTNFR-h gamma 3). The fusion proteins had a disulfide-bonded dimeric structure. Upon intravenous injection, their serum concentration decreased relatively slowly after an initial phase of rapid elimination. D-galactosamine-sensitized mice were fully protected from the toxic effects of LPS, if the animal were pretreated with rsTNFR-h gamma 3 at 20 micrograms/animal. Partial protection was seen at significantly lower doses and when rsTNFR-h gamma 3 was given up to 3 h after LPS.
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PMID:Recombinant soluble tumor necrosis factor receptor proteins protect mice from lipopolysaccharide-induced lethality. 165 17

Previous studies have shown that splenic T cells from mice that bear IgA myelomas, as well as certain T cell lines, express receptors for the Fc of IgA, and are termed Fc alpha R. In this study, we have isolated and characterized two CD3+ T cell lines derived by fusion of murine Peyer's patch (PP) CD4+ T cells with the BW 5147 lymphoma cell line. These cell lines, designated PPT4-6 and PPT4-16, were shown to bind monomeric or dimeric IgA, whereas the fusion partner did not bind either form of IgA. However, polymeric IgA (m.w. 600,000) bound equally well to all three cell lines. Similar results were also obtained with two known Fc alpha R+ T cell lines, ThHA1 nos. 9 and 10. Immunoprecipitation studies with IgA on PPT4-16 and ThHA1 no. 9 have shown that IgA binds to a 38-kDa protein. A rabbit antiserum was prepared to a 38-kDa fraction of Fc alpha R+ T cell membranes, and heterophilic antibody was removed from the antiserum by adsorption with mouse thymocytes, BW 5147 and R1.1 lymphoma. The antiserum bound to both PPT4-16 and ThHA1 no. 9 as well as to other Fc alpha R+ T cells, but did not bind to thymocytes or to the T lymphomas R1.1 or BW 5147. The antiserum appeared specific for the Fc alpha R, because it failed to block binding of anti-CD3 (145 2C11) or other surface molecule-specific antibodies. Further, competitive inhibition studies with IgA and anti-Fc alpha R (38 kDa) showed that preincubation of Fc alpha R+ T cells with the anti-38-kDa protein completely eliminated IgA binding, whereas IgA partially blocked the binding of the anti-Fc alpha R antibodies to the cell membrane. Immunoisolation with the anti-Fc alpha R antibody of radioiodinated cell membrane proteins from Fc alpha R+ T cells, but not from Fc alpha R- cells, gave a distinct band at 38 kDa. To further test the specificity of this antiserum, we have isolated T cells from spleens of IgA-myeloma bearing mice, and tested the phenotype and IgA binding. A subset consisting of 15 to 20% of CD3+, CD8+ T cells was found that bound monomeric or dimeric IgA. Further, the anti-Fc alpha R antiserum also recognized this CD8+ T cell subset, and preincubation of the cells with antibody resulted in their failure to bind IgA. Our results indicate that the Fc alpha R on T cell lines derived from PP is a 38-kDa protein.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Mouse IgA Fc receptor on CD3+ T cells. Molecular forms of IgA that bind to a 38-kDa Fc alpha R protein and development of an anti-Fc alpha R antisera. 214 6

alpha 1-Microglobulin (alpha lm), a glycoprotein heterogeneous in charge, was reported to occur both as a 31-kilodalton (kd) monomer [low mol. wt alpha lm (LMW-alpha lm)] and as polymers or complexes formed with other plasma proteins including IgA [high mol. wt alpha lm (HMW-alpha lm)]. The present study was designed to characterize HMW-alpha lm in normal human serum and in myeloma sera. The following sera were selected: five IgG, 16 IgA and four Bence-Jones protein myelomas. alpha lm was identified by specific monoclonal antibodies in competitive radioimmunoassay and solid-phase ELISA. HMW-alpha lm was found to be associated almost exclusively with monomeric IgA and possibly in very small proportion with dimeric IgA. Ever in cases of predominantly dimeric IgA myelomas, alpha lm was associated with the monomeric form of the monoclonal IgA. The molar ratio of HMW-alpha lm to monomeric IgA never exceeded 3.5% and it was estimated to range from 0.5 to 1.4% in normal serum. No association with other proteins than IgA and no alpha lm polymers were found in IgA myeloma. Two types of HMW-alpha lm-IgA complexes were found: (a) those that were dissociable into IgA and LMW-alpha lm after mild reduction, and (b) those which were dissociated only after complete reduction of the complexes into IgA and an 88-90-kd component bearing alpha lm but no IgA epitopes. It was concluded that either of the two molecular species of alpha lm bearing common epitopes, with apparent mol. wts of 31,000 and 88,000-90,000, respectively, could form stable complexes with monomeric IgA. The association is likely to be performed through disulfide bridges. Nearly all the 88-90-kd but only a small proportion of the 31-kd component is associated with IgA.
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PMID:Complexes of alpha 1-microglobulin and monomeric IgA in multiple myeloma and normal human sera. 241 Jul 80

Human basophils release approximately 90 pmol of LTC4/micrograms histamine when challenged with anti-IgE antibody, but donor to donor variation produces a 1000-fold range of response. There is little conversion to LTC4 to LTE4 in purified preparations of basophils, but conversion to LTE4 does occur if cell densities are high during incubation. Like histamine release, leukotriene release is calcium and temperature dependent and is complete in 20 min, with a t1/2 of approximately 8 min. The process of desensitization also ablates leukotriene release, but there is a distinct two phase process where leukotriene release is enhanced after 5 min of desensitization, whereas histamine release is inhibited and total ablation of leukotriene release occurs only after 45 min of desensitization. Human basophils respond well to stimulation with covalently cross-linked trimeric IgE myeloma but respond poorly to dimeric IgE. This differential sensitivity to the two forms of cross-linked IgE is most exaggerated in the context of leukotriene release, where dimer is 30-fold less efficacious and 100- to 1000-fold less potent than trimer on some donors' basophils. This dichotomy of response is also observed in antigen-challenged cells, where the bivalent hapten, BPO2, also poorly induces leukotriene release in accord with the fact that it predominantly induces dimeric cross-links of penicillin-specific IgE. Anti-IgE dose-response curves reveal a region of dimeric cross-link dominance that may explain the peculiar differences observed in pharmacologic studies of basophil release induced with antigen vs anti-IgE. In addition, there is a continuum of "releasability," where some donors' basophils display no response (histamine or leukotriene release) to dimeric IgE, and others' basophils are essentially equally responsive to both dimeric and trimeric IgE. This releasability difference manifests itself by conferring increased sensitivity to antigenic challenge in those donors' basophils capable of responding to dimeric cross-links such that these donors' basophils are capable of releasing histamine upon antigen challenge while possessing only 50 molecules of cell surface antigen-specific IgE; other dimer-insensitive donors' basophils require 6 to 10-fold greater IgE densities for equal histamine release.
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PMID:Characteristics of human basophil sulfidopeptide leukotriene release: releasability defined as the ability of the basophil to respond to dimeric cross-links. 241 27

The tissue sites of monomeric IgA (mIgA) catabolism were determined in a BALB/c mouse model. Mouse mIgA myeloma proteins were labeled either by direct iodination or by coupling the residualizing label, dilactitol-125I-tyramine (125I-DLT) to the proteins; catabolites from protein labeled with 125I-DLT accumulate at the site of protein degradation, allowing identification of the tissue and cellular sites involved in catabolism of the protein. The circulating half-lives of 125I- and 125I-DLT-mIgA were the same. The distribution of radioactivity in tissues was measured at 1, 3, 24, and 96 h after iv. injection of 125I-DLT-labeled mIgA, dimeric IgA (dIgA), IgG, or mouse serum albumin. The greatest uptake of 125I-DLT-mIgA was attributable to the liver. This organ accounted for more internal catabolism of mIgA than all other tissues combined. In contrast, 125I-DLT-IgG was catabolized equally in skin, muscle, and liver. These data indicate that, in mice, the liver is the major site of mIgA catabolism. To determine the cell types involved, collagenase digestion was used to isolate parenchymal and non-parenchymal cells from perfused liver of animals injected with 125-DLT-mIgA. Most of the radioactivity was associated with the hepatocyte fraction, even though both cell types showed uptake of 125I-DLT-mIgA. Inhibition studies, with asialofetuin and mouse IgA demonstrated that the uptake of mIgA by liver cells was mediated primarily by the asialoglycoprotein receptor.
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PMID:The sites of catabolism of murine monomeric IgA. 245 58

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


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