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)

An electron microscopy study of human myeloma IgG3 Kuc has shown that the hinge region in an intact molecule is in a compact state. The subunits are not fixed rigidly and are very mobile. These data are supported by results of ultracentrifugation and microcalorimetry. Non-extremal denaturating effects (pH 4.0, 20 degrees C or pH 7.8, 65 degrees C) lead to 'unfolding' of the hinge region which has a rod-like shape in electron micrographs.
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PMID:Structure of human myeloma IgG3 Kuc. 169 64

The human myeloma protein WIE is a lambda-type immunoglobulin D; the amino-acid sequence of its Fc part and aminoethylated heavy chain was completely determined. The VH-part (subgroup III) begins N-terminally with 5-oxoproline, and it contains a long, unique CDR3 region. Since the constant part differs from known delta chains by one amino-acid substitution in the hinge region, IgD WIE probably represents an allotypic variant. As in other protein delta chains, O-glycosylations are confined to the hinge region. Furthermore, the ratios of N-glycosylations at the three positions are identical in IgD WAH [Takahashi, N. et al. (1984) J. Chromatogr. 317, 11-26.] and IgD WIE (100%, 50%, 100%). From the most conserved constant domain, C delta 3, a three-dimensional model was constructed to clarify the role of its delta-specific substitutions and glycosylation.
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PMID:The complete amino-acid sequence of the heavy chain of the human myeloma protein WIE, an immunoglobulin D. 177 93

An expression vector (pIL-2/IgG1) was constructed with the coding sequence of human IL-2 inserted upstream of the four exons (CH1, hinge, CH2, and CH3) that encode the human IgG1 H chain constant region. Introduction of this vector into a nonsecreting murine myeloma cell line resulted in the production of a chimeric molecule (IL-2/IgG1) consisting of IL-2 attached to the three Ig constant region domains. This molecule was secreted by the transfectant as a homodimer. Functional characterization revealed that the IL-2/IgG1 chimeric molecule exhibited the binding and proliferation-mediating activities of IL-2. On a per molecule basis, IL-2/IgG1 was indistinguishable from human rIL-2 in the ability to induce the proliferation of an IL-2-dependent T cell line. This chimeric molecule also possesses Ig effector function, in that it can mediate the specific lysis of IL-2R-positive cells in the presence of complement. These results demonstrate that it is possible to maintain Ig effector function in molecules ("immunoligands") in which the binding specificity is conferred not by Ig variable regions, but rather, by a ligand of choice.
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PMID:A chimeric IL-2/Ig molecule possesses the functional activity of both proteins. 198 2

Human monoclonal IgG1 and IgG3 antibodies specific for the Rh antigen D (anti-D) were tested for their ability to promote the binding of D-positive red cells to peripheral blood monocytes and Fc receptor (FcR)-bearing cell lines (U937, K562 and Daudi). Monocyte-mediated antibody-dependent cell-mediated cytotoxicity and metabolic (chemiluminescent) responses were also determined. By comparing the activity of different cell lines in rosette assays, and by using murine myeloma IgG2a and IgG1 to block FcRI and FcRII respectively, these functional interactions of sensitized red cells (E-IgG1 and E-IgG3) with monocytes or cell lines were shown to be mediated predominantly and perhaps solely by FcRI. E-IgG3 bound to human monocytes and cell lines to a greater extent than E-IgG1. Rosette formation by E-IgG3 was relatively less susceptible to inhibition by fluid-phase murine IgG2a than was rosette formation by E-IgG1. These findings may be due to the long hinge region of IgG3 which enables it to bridge the gap between two negatively charged cells more efficiently than IgG1. Consistent with this hypothesis was the greatly increased rosette formation achieved by treating monocytes or U937 cells with neuraminidase or bromelain, procedures shown to reduce the zeta potential of these cells. The lytic and metabolic activities of untreated human monocytes were also greater towards E-IgG3 than E-IgG1, red cell binding being a prerequisite for these responses. However, after pretreatment of monocytes with neuraminidase, these responses were greater with E-IgG1 than with E-IgG3. Further, the addition of polybrene to non-specifically enhance cell to cell binding also resulted in greater lysis and chemiluminescence with E-IgG1 than with E-IgG3. These results indicate that, although E-IgG3 are more effective than E-IgG1 in promoting red cell binding to monocytes, E-IgG1 are more efficient at activating the lytic and metabolic processes providing the steric disadvantages of the shorter hinge region of cell-bound IgG1 are circumvented.
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PMID:Functional interactions of red cells sensitized by IgG1 and IgG3 human monoclonal anti-D with enzyme-modified human monocytes and FcR-bearing cell lines. 211 55

Immunoglobulin- or multiple myeloma-associated amyloidosis has been distinguished by the tissue deposition of Congophilic, fibrillar protein consisting of light chains or light-chain fragments (AL amyloidosis). We now report the isolation and characterization of another form of immunoglobulin-associated amyloid obtained from a patient who had extensive systemic amyloidosis and in whom the amyloid deposits consisted not of light chains but rather of an unusual form of heavy chain. This component, isolated from splenic amyloid extracts, represented an internally deleted IgG1 heavy chain as evidenced by immunochemical, electrophoretic, and amino acid sequence analyses. A comparable immunoglobulin-related monoclonal protein, consisting only of IgG heavy chains, was present in the patient's urine. Based on serologic reactivity with a battery of anti-immunoglobulin antisera, these two immunoglobulin-related components were antigenically identical; however, when compared to normal IgG, both were deficient in Fc-associated gamma-chain determinants. The structural abnormality of the amyloid gamma-chain protein was further evidenced by SDS/PAGE and immuno-blotting analyses: An unusually low molecular mass of approximately 22 kDa was found for this material vs. the expected value of approximately 55 kDa for a normal gamma heavy chain. Despite the lack of certain Fc determinants, the amyloid and urinary heavy-chain proteins expressed the IgG1 subclass allotype marker G1m(a) located on the third constant region (CH3) domain of the internally deleted IgG1 heavy chains. That the amyloid protein contained an intact CH3 domain was established through amino acid sequence analyses of cyanogen bromide fragments and peptides generated by a lysine-specific protease. These studies also revealed that the gamma-chain amyloid protein contained the complete heavy-chain variable (VH) domain [including the diversity (DH) and joining (JH) segments] that was contiguous with the CH3 domain. The low molecular mass of the protein resulted from the total absence of the first (CH1), hinge, and second (CH2) heavy-chain constant regions. Such extensive CH deletions and the presence of a complete VH distinguish this amyloid-associated heavy chain from all other heretofore characterized gamma-heavy-chain disease proteins. This heavy-chain-related form of immunoglobulin-associated amyloidosis is tentatively designated AH amyloidosis.
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PMID:Immunoglobulin heavy-chain-associated amyloidosis. 211 50

Five different monoclonal IgE proteins, papain and pepsin fragments of myeloma protein IgE(DES) and particle-counting immunoassay were used to study in detail the epitope(s) of IgE(DES) involved in the agglutination with IgM anti-IgE(DES) antibodies. The specificity of these autoantibodies was restricted to IgE(DES) as they did not react with latex particles coated with four other IgE myeloma proteins. Antibodies reactive with latex-IgE other than latex-IgE(DES), when present, were also of restricted specificity as shown by criss-cross absorption experiments. These differences between IgE myeloma proteins could not be attributed to the light chain type nor to the Em(1)-allotype. The epitope(s) of IgE(DES) participating in the reaction was heat-resistant (56 degrees C, 2 h) and localized in the pepsin F(ab')2 epsilon fragment, but was absent in the papain Fc epsilon and Fab epsilon fragments. Further degradation by pepsin of the F(ab')2 epsilon fragment (molecular weight 145,000 daltons) to 5S epsilon (90,000 daltons) and Fc" epsilon fragments (30,000 daltons) destroyed the reacting epitope. These results indicate that the IgM antibodies were not directed against kappa chain or idiotypic determinants of IgE(DES), but to some epitope(s) in the undegraded hinge region. Therefore, it seems that some kind of antigenic heterogeneity, perhaps related to the carbohydrate moieties, is present in IgE myeloma proteins besides the known idiotypic, allotypic and isotypic ones.
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PMID:Autoantibodies of the IgM class against a human myeloma protein IgE(DES). II. Specificity. 241 59

T cell clones specific for IgG2a of the alpha allotype have been isolated from C57BL/6J mice. Antigenic determinants recognized by these clones were localized by using a panel of hybrid IgG2b-IgG2a myeloma proteins. These experiments provide evidence for two distinct antigenic sites, one located in a segment encompassing the hinge region and most of the CH2 domain, and the other in a segment spanning the CH3 domain and the C-terminal eight residues of the CH2 domain. As judged by their failure to respond in the presence of B6.C-H-2bm12 spleen cells, all the clones recognize determinants created, in part, by the I-A beta chain. A strong proliferative response was observed in the presence of spleen cells from several H-2b strains, including C3H.SW, A.BY, D1.LP, and BALB.B. Experiments testing reactivity directed toward spleen cells from appropriate allotype-congenic mouse strains demonstrated that this response was controlled by Igh-linked genes. These results clearly indicated 1) that Igh-1a-specific T cell clones are stimulated by endogenously synthesized IgG2a, and 2) these T cells recognize shared determinants expressed on IgG2a molecules of various strains. These experiments thus provide strong evidence for presentation of self antigens under normal physiological conditions.
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PMID:T cell clones specific for IgG2a of the a allotype: direct evidence for presentation of endogenous antigen. 242 5

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

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 Kva IgG2(k) myeloma protein showed a complete resistance to papain in the presence of cysteine at neutral pH, and a higher resistance to trypsin and alpha-chymotrypsin digestion than other IgG2 proteins. On the other hand, the Kva molecule was cleaved by pepsin at low pH to give the expected F(ab')2 fragment. When the cleavage conditions were altered, it was possible to obtain Fab, Fc, and Fc' fragments from this molecule as well. The Fab/c fragment and FacbFc' complex were also obtained, which have not previously been reported from human IgG2 molecules. Incubation at elevated temperatures (45-50 degrees C) and/or lower pH resulted mainly in enzymatic attack on the C terminal side of the hinge. It was necessary to destroy the hinge by reduction or to expose the Kva molecule at 70 degrees C or at lower pH (2.5) prior to digestion to facilitate enzyme digestion on the NH2 terminal side of the hinge. These results indicate that the hinge region of the Kva molecule has an unusually compact structure, which makes it extremely resistant to proteolysis.
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PMID:Enzymatic fragmentation of an unusual human IgG2 (Kva) myeloma protein. 311 30


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