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)

It is well known that there are many independent and inter-related clinical and pathologic factors which influence the prognosis of patients with benign and malignant conditions. Lymphocyte level is an index of cell-mediated immunity which is important in host defense against cancer. But it is surprising that a simple test such as peripheral lymphocyte count could be correlated with clinical stages and survival results in patients with Hodgkin's disease, non-Hodgkin's lymphoma and non-lymphomatous solid tumors. Regarding the latter, lymphocyte count had prognostic values in patients with cancer of the bone, Ewing's sarcoma; breast; colon; kidney, neuroblastoma; uterine cervix, and other sites. In general, higher lymphocyte counts before therapy correlated with longer survival. Using newer immunologic techniques, T and B lymphocytes can be identified and the different subtypes of leukemia, immunodeficiency and lymphoproliferative diseases have been studied intensively. Chronic lymphocytic leukemia represents a proliferation of B cells, while the Sezary syndrome represents that of T lymphocytes. There is a qualitative and quantitative disturbance of Blymphocytes in patients with multiple myeloma. In Hodgkin's disease, there is hyperactivity of the B cells and functional defect of the T cells. Finally, the nodular non-Hodgkin's lymphoma resulted from neoplastic transformation of the B lymphocytes. In several nonmalignant autoimmune conditions, abnormality of T-cell or B-cell counts has been reported. For example, T cells were reported to be decreased in patients with ulcerative or granulomatous colitis and in patients with rheumatoid arthritis, However, it needs to be pointed out that, in 1973, Farid and associates (44) reported a significant increase in T and a proportionate reduction of B rosette in 17 patients with untreated Grave's disease and 16 with Hashimoto's thyroiditis as compared with 24 normal and eight goiter controls. In 1975, six publications later, they (143) had to announce a retraction because further studies by them and by other investigators could not repeat the earlier results. Despite variations and lack of standardization of the test systems, some consistent deviations of T-lymphocyte and B-lymphocyte counts have been reported. T lymphocytes were quantitatively decreased in patients with carcinoma of the brain, breast, head and neck, liver, lung and urologic organs and with malignant melanoma. In general, there is a marked decrease of T cells with increasing stage of disease and a return of T cells to normal level after successful therapy. Cellular immunity is depressed, often lasting for years after localized radiation therapy, whether or not the thymus is included in the treatment field...
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PMID:Peripheral lymphocyte count and suppopulations of T and B lymphocytes in benign and malignant diseases. 30 Jan 79

Sera from patients with Graves' disease and Hashimoto's thyroiditis have been shown to react with the Forssman glycolipid antigen (Gb5) using the techniques of high performance thin-layer chromatography (HPTLC) immunostaining and ELISA. Human monoclonal antibodies (MoAbs) have been prepared by fusion of human myeloma with peripheral lymphocytes from patients with Graves' disease. A MoAb, TRMo-4, reacted strongly and specifically with Gb5. These results suggest that anti-Forssman antibody may be involved in the pathogenesis of these autoimmune diseases. The detection of anti-Forssman glycolipid antibody may provide a useful means for clinical diagnosis and therapy.
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PMID:Autoantibodies against Forssman glycolipids in Graves' disease and Hashimoto's thyroiditis. 174 56

Four monoclonal antibodies to the thyrotropin (TSH) receptor were established by fusing human peripheral lymphocytes of patients from Graves' disease with a human myeloma cell line. Of two antibodies with TSH-binding inhibitory immunoglobulin activity (TBII), one inhibited TSH stimulation of adenylate cyclase and another stimulated adenylate cyclase. These antibodies showed competitive and noncompetitive modes of binding inhibition, respectively. Of the other two antibodies without TBII activity, one stimulated adenylate cyclase and the other inhibited TSH stimulation of adenylate cyclase. Of the two antibodies, which inhibited TSH stimulation of adenylate cyclase, one with TBII activity inhibited stimulation of adenylate cyclase by stimulating antibody with TBII activity, but another without TBII activity inhibited stimulation by both stimulating antibodies with or without TBII activity. These inhibitory antibodies did not influence the stimulation of adenylate cyclase by Forskolin and guanosine 5'-(beta,gamma-imido)triphosphate compounds which are known to affect other parts of the receptor-adenylate cyclase system than the receptor unit. Four antibodies with heterogeneous potencies to the TSH receptor reacted with glycoproteins extracted from thyroid membranes. One stimulating antibody without TBII activity also interacted with the glycolipid fraction of the membrane preparation, and the binding decreased after desialylation or deglycosylation of the membrane components. In order to identify the binding sites of these monoclonal antibodies, receptor proteins interacting with antibodies were visualized by Western blot analysis and by the label transfer cross-linking method. All of these antibodies with different characteristics reacted with a 56-kDa molecule.
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PMID:Monoclonal antibodies to the thyrotropin receptor bind to a 56-kDa subunit of the thyrotropin receptor and show heterogeneous bioactivities. 246 Apr 48

Human-human B-cell hybridomas were established using peripheral blood lymphocytes from patients with autoimmune thyroiditis and Graves' disease. Peripheral mononuclear cells (PMC), with or without mitogen prestimulation, were fused with HGPRT-negative human myeloma cell lines (Gm4672 and GM0462) using 44% polyethylene glycol. Developing hybridomas were screened by enzyme-linked immunosorbent assays (ELISAs) for human IgG and IgM and antibodies to human thyroglobulin (hTg) and microsomal antigen (M-Ag). A 125I-TSH binding inhibition assay was utilized for detecting antibodies to TSH receptor (TSH-R) protein. Hybridoma formation was observed only after prior mitogen stimulation of PMC. The amount of antibody secreted by the human-human hybridomas was highly variable (10 ng-100 micrograms/ml IgG/IgM). Nine and six-tenths percent of the hybrids secreted anti-hTg and 8.4% secreted anti-M-Ag. A 5% cloning efficiency was achieved, with detection of specific thyroid autoantibody secretion in one-third of the clones derived from positive hybridomas. Immunoglobulin secretion decreased with time and long-term stable clones were not achieved. Thyroid monoclonal autoantibodies to hTg, M-Ag, and TSH-R (IgG and IgM) detected during these studies were of a low affinity. In addition, antibodies were identified which exhibited marked specificity crossover between hTg, M-Ag, and nonthyroid antigens, suggesting the presence of recurrent epitopes. Such observations may help explain the multiplicity of thyroid autoantibodies in human thyroid disease and indicate a common defect in immunoregulation. We suggest that cross-reacting epitopes may be important in the derivation of thyroid-specific B-cell clones.
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PMID:A study of human-human hybridomas from patients with autoimmune thyroid disease. 355 36

Recent studies revealed that anti-TSH receptor autoantibodies are involved in the pathogenesis of both Graves' disease and a part of hypothyroidism, but precise mechanism of action of these antibodies remained to be studied. In order to delineate the heterogeneity of these antibodies and their pathophysiological significance, we produced monoclonal antibodies to TSH receptor and studied their characteristics. Mouse monoclonal antibodies to TSH receptor were derived from spleen cells of mice immunized with partially purified human TSH receptor, which was prepared by TSH-coupled affinity chromatography of thyroid membrane solubilized with Triton X-100. By fusing spleen cells and mouse myeloma cells in the presence of polyethylene glycol and selecting with limiting dilution method, 5 hybridomas were obtained. Among 3 antibodies, which inhibited TSH binding to thyroid membrane (TSH displacing activity, TDA), 2 inhibited TSH stimulation of thyroid adenylate cyclase (AC) (human thyroid adenylate cyclase inhibitor activity, HTACI), and one showed no bioactivity. Among other 2 antibodies without TDA, 1 stimulated AC (human thyroid adenylate cyclase stimulator activity, HTACS) and the other inhibited TSH stimulation (HTACI). All activities of these antibodies were dependent on IgG concentration and disappeared by treatment of anti-mouse IgG antibodies. In addition, 4 human-human hybridomas were established by fusing human peripheral lymphocytes of patients with Graves' disease and nongoitrous hypothyroidism with human lymphoblastoid cell line. Among 2 antibodies with TDA, one antibody inhibited TSH stimulation of AC, inhibiting TSH binding competitively and another antibody stimulated AC, inhibiting TSH binding noncompetitively. Among the other 2 antibodies, which did not inhibit TSH binding but were shown to bind to TSH receptor by immunoprecipitation, one stimulated AC and the other inhibited TSH stimulation of AC. Among 2 antibodies with HTACI, one antibody with positive TDA inhibited stimulation of AC by stimulative antibodies with positive TDA, but the other without TDA inhibited stimulation of AC by both antibodies with or without positive TDA. These inhibitory antibodies did not inhibit stimulation of AC by Forskolin and Gpp(NH)p, which are known to affect other parts of receptor-AC system than receptor unit. These data suggest that anti-TSH receptor antibodies are heterogenous in the mode of binding to the receptor and in their bioactivities, and may be involved in the pathogenesis of both Graves' disease and a part of idiopathic hypothyroidism.
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PMID:[Studies on monoclonal antibodies to TSH receptors--heterogeneity and pathophysiological significance of antibodies to TSH receptor]. 381 31

We have used an automatic cell harvester and micro culture techniques to examine the accumulation of [35S]methimazole by monocytes, macrophages and lymphocytes. Significant temperature-dependent accumulation of the drug was found in resting monocytes and macrophages; this was increased up to 4-fold by phagocytosis. Lymphocytes accumulated little or no drug and myeloma and leukaemic cell lines accumulated none. These results show that two interrelated cells with endogenous peroxidatic activity take up the antithyroid drug methimazole providing further support for the concept that immunosuppression by this drug in Graves' disease is mediated via an action on antigen-presenting cells.
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PMID:The accumulation of [35S]methimazole by monocytes and macrophages. 620 6

Hybridoma cells have been obtained by fusing P3-NS1/1-Ag4-1 mouse myeloma cells with spleen cells from mice immunized with solubilized preparations of the thyrotropin receptor. Five clones were produced that secrete a monoclonal antibody whose binding to thyroid membranes is specifically inhibited by unlabeled thyrotropin. The antibody interacts with functioning thyroid cells in culture but not with nonfunctioning cells; this interaction is prevented by thyrotropin. The antibodies are capable of competitively blocking thyrotropin binding to bovine thyroid membrane preparations; they prevent 125I-labeled thyrotropin binding to a solubilized preparation of the glycoprotein component of the bovine thyrotropin receptor but are unable to inhibit 125I-labeled thyrotropin binding to liposomes containing gangliosides at comparable concentrations. They prevent 125I-labeled thyrotropin binding to rat, bovine, or human (Graves disease) thyroid membrane preparations. They do not stimulate adenylate cyclase activity in thyroid membrane preparations but can inhibit thyrotropin-stimulated iodide uptake by functioning thyroid cells in culture.
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PMID:Monoclonal antibodies to the thyrotropin receptor: implications for receptor structure and the action of autoantibodies in Graves disease. 626 39

Human monoclonal antibodies have been generated from heterohybridomas obtained by fusing mouse myeloma cells with peripheral lymphocytes from patients with active Graves disease. This report characterizes four antibodies as presumptive thyrotropin receptor antibodies because they specifically inhibit thyrotropin binding and competitively inhibit thyrotropin-induced cAMP levels in human thyroid cells. Two of these antibodies, 208F7 and 206H3, are representative of autoimmune stimulators in Graves disease sera because they stimulate thyroid function in all assays, including the mouse bioassay; their ability to inhibit thyrotropin-induced cAMP increases in thyroid cells competitively is complemented by more than additive agonism at low (10 pM) thyrotropin concentrations. These stimulating antibodies interact more potently with human thyroid ganglioside preparations than with bovine thyroid or brain gangliosides; in contrast, they are poor inhibitors of 125I-labeled thyrotropin binding to liposomes containing the glycoprotein component of the human thyrotropin receptor. Antibodies 129H8 and 122G3 appear to be representative of inhibiting or "blocking" antibodies in Graves disease sera. Thus they have no intrinsic stimulatory action in assays of thyroid function but rather inhibit thyrotropin activity in the assays tested. These two antibodies do not react with human thyroid gangliosides but are strong inhibitors of thyrotropin binding to liposomes containing the high-affinity glycoprotein component from human, bovine, and rat thyroid membranes. The data unequivocally establish the pluritopic nature of the immunoglobulins in Graves disease and relate individual components or determinants of the thyrotropin receptor structure with specific autoimmune immunoglobulins.
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PMID:Monoclonal antibodies to the thyrotropin receptor: stimulating and blocking antibodies derived from the lymphocytes of patients with Graves disease. 629 12

Immune responsiveness was investigated in a family comprising 12 first- and second-degree relatives, one of whom had kappa-myelomatosis, one IgA-lambda paraproteinaemia, two Graves' disease and a further two thyroid antibodies without disease. Relatives by marriage served as controls. Parameters of immune capacity studied were the humoral and cellular immune response to haemocyanin of Helix pomatia (HPH), dinitrochlorobenzene (DNCB) skin reactivity and in vitro lymphocyte proliferation capacity to phytohaemagglutinin (PHA). Mean antibody titres to HPH were higher in the family than in the control group in all main Ig classes and IgG subclasses after primary and secondary immunization, and the difference was statistically significant for IgG, IgG2 and IgG4 titres. This could not have been predicted from the (normal) serum Ig levels in this family. In vitro lymphocyte proliferation capacity to HPH after primary and secondary immunization was also significantly increased. DNCB skin reactivity also tended to be high in the family, whereas PHA-induced lymphocyte proliferation was normal. These findings support the idea that myelomatosis clusters in families with immune dysregulation.
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PMID:High immune responsiveness in a family with multiple paraproteinaemia and autoimmune thyroid disease. 743 57

Anti-thyrotropin (TSH) receptor autoantibodies (TRAbs) have been known to be involved in Graves' disease. To understand the molecular mechanism for pathogenesis of TSAbs in Graves' disease, we isolated and reconstituted the Ig genes of EBV-transformed B cell clones producing monoclonal thyroid stimulating Ab (TSAb) obtained from patients with Graves' disease. The V region genes of Ig heavy (H) and light (L) chains of two TSAb clones, IgG clone B6B7 and IgM clone 101-2, were isolated by the PCR. Nucleotide sequencing analysis revealed that germ-line VH and VK segments widely used for autoantibodies including the previously isolated TRAbs were utilized in the two clones. A significant number of somatic mutations were found in V regions of both clones, indicating the involvement of somatic mutations for the TSAb specificity. Reconstituted Ig H and L chain genes of the two clones were stably introduced into myeloma cells for IgG1 production. IgGs purified from cultured supernatants of both transfectants exhibited significant TSAb activities, while they did not inhibit TSH binding to the receptor. The successful expression of recombinant TSAbs in eukaryotic cells will provide opportunities to apply them to various pathophysiologic, diagnostic and therapeutic investigations in autoimmune thyroid diseases.
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PMID:Molecular analysis of stimulatory anti-thyrotropin receptor antibodies (TSAbs) involved in Graves' disease. Isolation and reconstruction of antibody genes, and production of monoclonal TSAbs. 881 26


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