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)

IgA protease, a proteolytic enzyme found in human saliva and colonic fluid, hydrolyzes human serum IgA immunoglobulins to yield Fab(alpha) and Fc(alpha) fragments. The enzyme is produced by organisms in the normal human microflora and can be purified from culture filtrates of the common human oral organism Streptococcus sanguis (American Type Culture Collection no. 10556). IgA protease is inactive against all other protein substrates examined including the other classes of human immunoglobulins. The role of this enzyme in affecting the function of the secretory IgA immune system is unknown. To further characterize and explain this unusual substrate specificity, the susceptibility of 31 human IgA myeloma proteins of both subclasses was investigated. 16 IgA1 and 15 IgA2 myeloma paraproteins were treated with enzyme and the extent of proteolysis was determined by cellulose actate electrophoresis, immunoelectrophoresis, polyacrylamide gel electrophoresis, and column chromatography. All IgA1 proteins were enzymatically cleaved to Fab(alpha) and Fc(alpha) fragments, but all IgA2 proteins were resistant, yielding no fragments after prolonged enzymatic treatment. N-terminal amino acid sequence analysis of the purified Fc(alpha) fragment of a single IgA1 paraprotein was as follows: Thr-Pro-Ser-Pro-?-Thr-Pro-Pro-Thr-Pro-Ser-Pro-Ser. Comparison of this sequence to that reported for the IgA1 heavy chain shows that the enzyme-susceptible peptide bond is a Pro-Thr in the IgA1 hinge region. The most likely explanation of the resistance of the IgA2 subclass to IgA protease is a deletion in the heavy chain which commences with the critical threonine of the susceptible Pro-Thr bond.
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PMID:Differential susceptibility of human IgA immunoglobulins to streptococcal IgA protease. 443 34

The ability of human myeloma proteins of different classes and subclasses and of macroglobulins (all aggregated with bis-diazotized benzidine or heat) to aggregate washed human platelets and release [(3)H]-serotonin from the platelets was investigated and compared with the activity of normal IgG and tetanus-antitetanus IgG antigen-antibody complexes. Aggregated IgG1, IgG2, IgG3, IgG4, and normal IgG complexes all aggregated platelets and caused release of serotonin to similar extents. In contrast, IgA1, IgA2, IgD, and IgE myeloma proteins as well as IgM macroglobulins were completely inactive in this respect. Approximately 50% of the actvity remained in aggregated, mildly reduced and alkylated IgG myeloma proteins and their Fc fragments, whereas aggregated F(ab')(2) fragments were completely inactive. Addition of fresh serum inhibited the release of serotonin caused by aggregated IgG1 and IgG3 proteins and normal IgG antigen-antibody complexes by about 50% but had no effect upon the release of serotonin obtained with IgG2 and IgG4 proteins. This inhibition appeared to be mediated by complement. The release of serotonin was not accompanied by liberation of the cytoplasmic enzyme lactic dehydrogenase, indicating that no significant lysis of the platelets occurred. Addition of neutrophils did not enhance the serotonin release.
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PMID:Release of serotonin from human platelets induced by aggregated immunoglobulins of different classes and subclasses. 470 Apr 96

Sheep erythrocytes (E) coated with either human IgG1, IgG2, IgG3 or IgG4 myeloma proteins formed rosettes with human neutrophils and eosinophils. Prior incubation with the chemotactic agents f-met-leu-phe or leukotriene B4 enhanced neutrophil and eosinophil E-IgG1 rosettes in a time- and dose-dependent fashion. There were comparable increases in neutrophil and eosinophil f-met-leu-phe-induced rosettes with either E-IgG1, E-IgG2, E-IgG3 or E-IgG4 whereas this agent did not appear to influence E-IgA1, E-IgD, E-IgM or E-IgE binding to these granulocytes. These studies indicate that human neutrophil and eosinophil IgG (Fc) receptors are enhanced by chemotactic agents in a similar way to that previously described for complement receptors.
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PMID:Chemotactic factor-induced enhancement of the binding of human immunoglobulin classes and subclasses to neutrophils and eosinophils. 608 41

Protein A-binding fractions of two IgA1 myeloma proteins failed to produce Fc fragments on digestion with IgA1 protease from Streptococcus sanguis. A polymeric protein A-binding IgA1 fraction yielded a protein A-non-binding monomer, which was further cleaved into Fab fragments but it did not yield Fc fragments. The protein A-binding fraction of a monomeric IgA1 yielded an IgA molecule lacking one Fab fragment. Subsequently, the remaining part of its cleaved alpha chain was degraded. Further digestion yielded Fab but not Fc fragments. Similarly, F(abc)2 and Fabc fragments, which lack the CH3 domain (8), yielded Fab fragments but not CH2 domains. Thus, the enzyme in addition to cleaving IgA in the hinge region, under certain conditions, also degrades its Fc fragments.
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PMID:Cleavage of protein A-binding IgA1 with IgA1 protease from Streptococcus sanguis. 635

Microbial IgA proteases cleave human serum IgA1 immunoglobulin, but human secretory IgA is resistant to hydrolysis. We have found this resistance to be due to an inhibition of protease activity that is mediated by the Fab region of secretory IgA. The IgA proteases of the genus Neisseria are more sensitive to inhibition than is the protease of Streptococcus sanguis. There is also a serum inhibitor of Neisseria proteases that co-chromatographs with IgG. Monoclonal (myeloma) human IgG proteins and plasma protease inhibitors such as alpha-1-antitrypsin and alpha-2-macroglobulin do not inhibit. Human sera do not contain inhibitor to S. sanguis protease activity. We conclude that microbial IgA proteases are subject to inhibition by IgA in secretions and IgG in serum, and this activity is most consistent with being an anti-enzyme antibody. The insensitivity of S. sanguis IgA protease to inhibition is unexplained but provides further evidence that the IgA proteases are structurally diverse.
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PMID:Inhibition of microbial IgA proteases by human secretory IgA and serum. 641 73

IgA subclass distribution in the serum of 40 patients with IgA multiple myeloma and 10 patients with benign monoclonal gammopathy of the IgA class was determined. All were found to be of the IgA 1 subclass. A review of the literature shows a marked predominance (93%) of IgA 1 paraproteins, suggesting an under-representation of IgA2 myelomas. The subclass pattern in 11 double paraproteinemias studied and those previously reported in the literature suggest a pattern of IgG1 - IgA1, IgA1 - IgG4 and possibly also IgG2 - IgA2 switches in malignant cells.
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PMID:IgA subclass distribution in paraproteinemias: suggestion of an IgG-IgA subclass switch pattern. 650 6

In the previous communication (Mellis, S. J., and Baenziger, J. U. (1983) J. Biol. Chem. 258, 11546-11556), the structures of the oligosaccharides present at the 3 asparagine glycosylation sites of a human IgD myeloma protein were defined. In this communication, we present the structures of the O-glycosidically linked oligosaccharides located in the hinge region of IgD:WAH. Three or four threonine residues and one serine residue in the region bear O-glycosidically linked oligosaccharides. Approximately 50% of these molecules have the structure Gal beta 1 leads to 3 GalNAc which is identical with the structure of the predominant oligosaccharide in the hinge region of human IgA1 myeloma proteins (Baenziger, J. U., and Kornfeld, S. (1974) J. Biol. Chem. 249, 7270-7281). The remainder of the oligosaccharides contain 1 or 2 residues of N-acetylneuraminic acid and have the structures NeuAc alpha 2 leads to 3Gal beta 1 leads to 3GalNAc (30%), Gal beta 1 leads to (NeuAc alpha 2 leads to 6)GalNAc (12%), and NeuAc alpha 2 leads to 3Gal beta 1 leads to 3(NeuAc alpha 2 leads to 6)GalNAc (8%). The sialylated molecules have not been encountered previously on other human immunoglobulin heavy chains. These structures, however, have been described on a number of secreted and membrane glycoproteins. Examination of oligosaccharides isolated from different subregions of the IgD hinge indicated that a specific distribution of the sialylated structures among the glycosylated amino acids of the hinge region is not likely.
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PMID:Structures of the O-glycosidically linked oligosaccharides of human IgD. 661 28

Abnormal IgA1 half-molecules consisting of one heavy and one light chain were found in a patient (NN) with typical multiple myeloma. Serum total protein was 9.4 g/dl, and the serum protein electrophoresis showed a monoclonal gamma-1 fraction amounting to 43.1%. The patient's serum and urine showed immunoelectrophoretically double arcs against anti-alpha antiserum having the same mobility. No double precipitin ring was demonstrated on single radial immunodiffusion analysis of the serum. The serum and the urine of this patient contained both 7.0S and 3.9S IgA-lambda type myeloma proteins. The IgA half-molecules (3.9S) were found to have a molecular weight of 59,000 daltons and were composed of one alpha-1 chain of about 40,000 daltons and one light chain of 22,000 daltons. Furthermore, enzymatic degradation suggested that the alpha chain of the half-molecules had a large deletion in its Fc portion. We suggest that its heavy and light chains were probably bound noncovalently, since the interchains connecting the heavy and light chains of these IgA half-molecules were easily dissociated with 1% SDS and 8M urea. The similar half-molecules of IgG type were also found in another patient of multiple myeloma.
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PMID:Identification and quantification of half-molecule immunoglobulins. 677 64

This paper describes an IgA related protein Vla which occurred in the serum and urine of a patient with multiple myeloma. The protein was isolated from urine; it had a molecular mass of 70,000 daltons. It was shown to be a two chain IgA half molecule, consisting of a deleted alpha heavy chain, with a molecular mass of 42,000 daltons, which was disulphide linked to a normal kappa type light chain. Fabc fragments were produced from an unrelated myeloma IgA. These had the same biochemical properties as protein V1a, except for the absence of the disulphide linkage between the deleted heavy chains and the light chains. Protein Vla and the Fabc fragments could both be cleaved by IgA1 protease from Streptococcus sanguis, which indicates the presence of the alpha 1 hinge region. An inventory of its antigenic determinants and their similarity to those of previously characterized F(abc)2 fragments, indicates that protein Vla, like the Fabc fragments, contains the CH1 and CH2 domains, but lacks most of the CH3 domain. The fact that cleavage by IgA1 protease from S. sanguis yields a Fab fragment but fails to yield a CH2 domain demonstrates that cleavage by the enzyme is not only restricted to the Pro227-Thr228 bond in the IgA1 hinge region.
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PMID:IgA1 half molecules in human multiple myeloma and the in vitro production of similar fragments from intact IgA1 molecules. 683 48

Monoclonal hybridoma antibodies to the human IgA subclasses were produced by immunizing mice with purified myeloma proteins. These antibodies were shown to be specific for the appropriate IgA subclass by enzyme-linked immunoabsorbant assay (ELISA) and by immunofluorescent staining of myeloma plasma cells and B cells from normal individuals. These antibodies were used to demonstrate age-related shifts in the proportions of IgA1- and IgA2-bearing B cells that could be correlated with 3 distinct staining patterns. In the newborn equal numbers of IgA1 and IgA2, B cells were found. These cells had only small amounts of surface IgA in a patchy distribution. They also expressed surface IgM. In the infant, large lymphoblastoid cells were observed that bore more IgA in a homogeneous pattern but did not express IgM. Of these cells, 98% were positive for IgA1. In the adult, 80% of the IgA B cells were positive for surface IgA1, and 20% were positive for IgA2. These were small lymphocytes brightly stained for IgA and negative for IgM. In culture, the adult B cells responding to pokeweed gave rise to roughly equal numbers of IgA1 and IgA2 plasma cells. These results suggest that there are equal numbers of precursor cells for IgA1 and IgA2 whose expansion, further differentiation, and migration are selectively affected by immunoregulatory controls.
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PMID:Differentiation of human B cells expressing the IgA subclasses as demonstrated by monoclonal hybridoma antibodies. 696 79


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