[Four patients with thrombocytopenia associated with Sjögren's syndrome].
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Biomedical subjects
Publications and source records attributed to S Konda.
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A T lymphoma cell line (KT-3) established from a patient with Lennert's lymphoma showed macrophage-dependent growth. Macrophage-derived factors were able to replace the macrophage functions. Experiments using a variety of cytokines demonstrated that KT-3 proliferated in response to recombinant interleukin-2 (rIL-2), rIL-4, or rIL-6 but did not proliferate in response to rIL-1 alpha, rIL-1 beta, rIL-3, recombinant granulocyte colony-stimulating factor (rG-CSF), rGM-CSF, recombinant interferon-alpha (rIFN-alpha), rIFN-gamma, recombinant tumor necrosis factor (rTNF-alpha), or native IFN-beta. Polyclonal rabbit anti-IL-6 antibody almost completely neutralized the activities of macrophage-derived factors or IL-6 but not IL-2 or IL-4. Scatchard plot analysis demonstrated that KT-3 cells indeed express IL-6 receptors. The results indicate that the macrophage-derived factor that supports the growth of KT-3 is IL-6 and suggest that macrophage-derived IL-6 may play an important role in the histopathogenesis of Lennert's lymphoma.
A T lymphoma cell line, KT-3, was established from the peripheral blood of a patient with so-called Lennert's lymphoma when the patient developed leukemic lymphoma. The KT-3 cells stain positively for alpha-naphthyl acetate esterase, PAS, and acid phosphatase. The surface phenotype is E rosette-positive, CD1-, CD2+, CD3-, CD4+, CD5+, CD8-, CD11-, CD20-, CD25 (anti-Tac)+, OKla-1+, HNK-1-, J-5-, and My9-, and the surface membrane immunoglobulin is negative, which is almost the same phenotype as the leukemic cells studied when the culture was started. Southern blot analysis showed rearrangement in both beta and gamma T cell receptor genes. Although KT-3 cells proliferate spontaneously and form clusters, they cease proliferating when they are cultured at low cell densities. They proliferate vigorously in response to macrophages, macrophage-derived factor, or recombinant interleukin 2 (rIL-2) added to the culture. Furthermore, they secrete interferon-gamma (IFN-gamma) spontaneously, and the secretion is augmented when they are stimulated with macrophage-derived factor. The macrophage-derived factor enhancing KT-3 cell growth is different from IL-1 alpha, IL-1 beta, IL-2, or IFN-gamma. To our knowledge, this is the first tumor cell line established from a patient with Lennert's lymphoma. The results conclusively confirmed that, at the least, Lennert's lymphoma included CD4+ T lymphoma and also suggested that cytokines or factors secreted by T lymphoma cells and epithelioid histiocytes play an important role in the histopathogenesis of Lennert's lymphoma.
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Eighty-two adult patients with advanced B-lymphoma, treated between 1981 and 1983 with VEPA (vincristine, cyclophosphamide, prednisolone and doxorubicin) or VEPA-M (VEPA plus methotrexate) in a prospective randomized fashion, were evaluated for pretreatment characteristics. The overall complete response (CR) and the 4-year survival rates were 74% and 45%, respectively. The relapse rate was 51%. Stage of disease only was negatively associated with the CR rate in a multivariate analysis. The primary extranodal tumor site other than upper gastrointestinal (GI) tract and high grade pathology were found to affect disease-free survival adversely in a Cox proportional hazards model. Poor performance status, advanced stage, primary extranodal tumor site other than upper GI tract, advanced age, high grade pathology and prior therapy by either surgery or radiation, were significantly associated with shortened survival in a Cox proportional hazards model. These results indicate advanced B-lymphoma in Japan to be generally similar to advanced non-Hodgkin's lymphoma in the West in terms of prognostic factor characteristics, but the importance of the primary site in predicting survival has not been reported in the West. Also, the lack of a survival plateau in patients with diffuse large cell lymphoma indicates more intensive chemotherapy regimens than VEPA or VEPA-M to be needed. It was also found that the significant prognostic factors in patients with advanced B-lymphoma were very different from those with T-lymphoma. The five factors: pathology, stage, primary site, age, prior therapy by surgery or radiation, for which the risk ratio was more than 2.3, were used to construct a model containing 23 categories of patients running an increasing risk of shortened survival; this divided patients into three groups. The CR and 4-year survival rates of low-, moderate- and high-risk groups were 90% and 74%, 74% and 58%, and 50% and 5%, respectively. The risk-grouping provides indications for determining optimal therapy for individual patients and the need for new therapeutic trials in patients at high risk.
We studied 17 short prepubertal children, aged 7.5 to 17.0 years (mean +/- SD: 11.7 +/- 2.4) more than 2.0 SD below the mean height for their age and of delayed bone age (M +/- SD: 8.1 +/- 2.3), to clarify their physiological GH secretory status. The mean concentration of GH (MCGH) was calculated and was compared with the subjects' GH responses to insulin and arginine tolerance tests (IATT) and plasma somatomedin-C (SM-C). The mean 24-h MCGH value was 3.2 +/- 1.3 ng/ml (range 1.6-5.5). The mean peak GH response to the IATT was 13.0 +/- 7.5 ng/ml (range 2.4-33.9). In addition to the two patients with abnormally low GH responses to the IATT, seven with normal responses showed low 24-h MCGH values, a small number of GH pulses and low mean GH amplitude. The mean plasma SM-C in all patients was 0.60 +/- 0.20 U/ml. This was significantly lower than that of age-matched children of normal height (p less than 0.001). The 24-h MCGH was significantly correlated with plasma SM-C levels (r = 0.51, p less than 0.05) and with that of the first three hours of sleep at night (r = 0.84, p less than 0.01). These results indicate that: 1) some short children with normal GH response to pharmacological tests secrete a low amount of GH physiologically and 2) blood sampling during the first three hours of sleep as well as 24-hour sampling is suitable in evaluating the physiological secretion of GH.
Six patients with malignant lymphomas in autoimmune diseases are described. Four patients who had Sjögren's syndrome (SS) alone or with progressive systemic sclerosis (PSS) or rheumatoid arthritis (RA) developed non-Hodgkin's lymphomas of the B cell type. One patient who had systemic lupus erythematosus (SLE) developed a B cell lymphoma. Another patient with chronic thyroiditis (ChTD) and idiopathic thrombocytopenic purpura (ITP) had a T cell (OKT3/T4) lymphoma. In 5 patients, the autoimmune diseases (2SS, SS/PSS, SS/RA and SLE) preceded B cell lymphomas by one to 11 years. In the patient with ChTD/ITP, ChTD and a malignant lymphoma were found simultaneously. A review of Japanese reports on lymphoproliferative disorders associated with these autoimmune diseases is given. This report offers the suggestion that disorders in the immunoregulatory system caused by autoimmune diseases may predispose lymphoproliferative disorders.
A 53-year-old male with Bence Jones lambda myeloma developed hypercalcemia and acute renal failure (calcium 14.4 mg/dl, BUN 40 mg/dl, creatinine 3.0 mg/dl) after initial response to chemotherapy. A 99mTc-MDP bone scan revealed unusual isotope accumulation in the left hypochondrium. Extensive calcium deposition was confirmed in the gastric mucosa in the postmortem examination. Detection of gastric calcification by a bone scan is very rare. Only two cases of gastric calcification visualized on bone scans can be found in the literature, one with multiple myeloma) and one in Hodgkin's disease).
A patient with B-cell leukemic lymphosarcoma, whose lymphocytes had a monoclonal (IgM/D-L) surface immunoglobulin (SmIg) and formed rosettes with ox red blood cells (ORBC), is described. The leukemic cells were documented to have a monoclonal SmIg and cytoplasmic Ig (CIg) and secreted a monoclonal immunoglobulin (MIg) whose antibody activity was directed to the surface antigen of ORBC. Pretreatment of the leukemic cells with anti-mu, anti-delta, or anti-lambda inhibited E(ox) rosette formation specifically. Pretreatment of the leukemic cells with pronase removed the SmIg and abolished E(ox) rosette formation simultaneously, and regeneration of the SmIg was parallel with recovery of the rosette formation. A small amount of serum MIg could be detected by agarose gel electrophoresis and antiidiotypic antibody against the 19 S component of the serum revealed that the monoclonal SmIg, CIg, and serum MIg shared the same idiotope. This case suggests that lymphocytes of some B-cell malignancies may bind to ORBC through SmIg.
A small amount of monoclonal IgM was demonstrated in the serum of four B cell malignant lymphoma patients in whom electrophoretically homogeneous protein bands were not detected by either cellulose acetate membrane electrophoresis or immunoelectrophoresis. By using anti-idiotypic (Id) antisera prepared against serum IgM, the M proteins were detected and identified as the products of malignant cells. These findings suggest that the use of more sensitive technics than the usual serum electrophoresis shows that the incidence of M proteins in B cell malignant lymphomas is higher than has been previously reported.
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Fourteen Sjögren's syndrome (SS) patients with monoclonal gammopathy (MG), 4 SS patients with malignant lymphoma (ML) and one with pseudolymphoma (PL) were described. Among the 14 MG patients, the IgG class was found in 3, IgA in 6, IgM in 3, and 2 M proteins (IgM/IgG and IgA/IgG) were found in 2 patients. The monoclonal rheumatoid factor (RF) was found in 4 patients (3 IgA and one IgM). Idiotypes (Id) of M proteins were studied in 11 out of 14 patients. The histology of ML showed the diffuse, large cell, medium-sized cell and follicular, mixed cell type. The monoclonal surface membrane Ig (SmIg) and/or cytoplasmic Ig (CIg) were identified (3 IgM and one IgG). A review of the Japanese literature on lymphoproliferative disorders (LPD) in SS patients disclosed additional 15 MG patients (3 IgG, 5 IgA, 6 IgM and one Bence Jones protein) and 22 LPD patients (14 non-Hodgkin's ML, 4 PL, 2 plasmacytomas and 2 thymomas). The literature was also reviewed on LPD in non-Japanese SS patients; 26 patients with MG (4 IgG, 2 IgA, 19 IgM and one Bence Jones protein) and 104 patients with LPD (59 non-Hodgkin's ML, 4 Hodgkin's lymphomas, 23 PL, 5 thymomas, 4 immunoblastic lymphadenopathies (IBL), 2 Lennert's lymphomas and 7 others) were found. These results indicate that non-IgM class MG was more dominant in Japanese than in non-Japanese SS patients and that there was a higher incidence of MG in primary than in secondary SS patients, and also that B cell lymphomas (9 in Japanese and 11 in non-Japanese) were more common in SS patients.
Monoclonal anti-idiotypic antibodies (mA-IDs) were produced against IgM-K, IgA-L and IgA-K monoclonal rheumatoid factors (mRFs), respectively, derived from patients with Sjögren's syndrome (SS). Each mA-ID inhibited the RF activity of the autologous M-protein, but did not inhibit the activity of the other mRFs. As for the specificity of mA-IDs, it was confirmed to bind only to the mRF used for immunization. A cross-reactive idiotype (CRI) was detected in 3 out of 106 polyclonal RFs (pRFs) using AW5/3 mA-ID by double immunodiffusion or ELISA inhibition assay on pRF activity. However, no CRI was detected on AMB1/5 or SF18/2 mA-ID. One of the mA-IDs, AW5/3, cross-reacted with nuclei of proliferating lymphocytes, such as PHA-stimulated lymphocytes, interleukin 2 dependent T cell lines, B-lymphoblastoid cell lines or cultured lymphoma cell lines, but barely reacted with nuclei of normal resting lymphocytes.
We report 10 Japanese patients with Sjögren's syndrome (SS) who developed monoclonal gammopathies (MG). One was of the IgG class, five of IgA, three of IgM, and one of IgG/IgM. The monoclonality of 7 of 10 M proteins was studied using antiidiotypic (Id) antibodies against M proteins. Four (three IgA and one IgM) of 10 M proteins had rheumatoid factor (RF) activity. Hemagglutination inhibition tests and enzyme-linked immunosorbent assays (ELISA) showed that the RF activity was inhibited by anti-Id antibodies in all four monoclonal RFs. In two patients examined, many cells infiltrating into the salivary glands were stained with anti-Id antibodies. Our review of 19 Japanese SS patients with MG revealed that the non-IgM class predominated (13/19). This contrasts with 19 reported non-Japanese SS patients, among whom 14 were IgM. In both Japanese and non-Japanese patients there was a higher incidence of MG in primary than in secondary SS. The difference in the dominant heavy-chain class may reflect a difference in the genetic factors affecting B cell differentiation in immunologically disordered states.
We report a patient with progressive systemic sclerosis (PSS) and Sjogren's syndrome (SS) who developed B cell malignant lymphoma 11 and 10 years after the onset of signs of PSS and SS, respectively. As her lymphoma developed, autoantibodies such as rheumatoid factor and antinuclear antibody disappeared from the serum, the lupus erythematosus test yielded negative results and her immunoglobulin levels declined. A good response to chemotherapy was obtained but she died of acute interstitial pneumonitis. Postmortem examination revealed marked diffuse interstitial fibrosis of the lungs.
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