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ID PMID Title PublicationDate abstract
1342004 Increased production of interleukin-6 and autoantibodies in patients with Sjögren's syndr 1992 Aug The occurrence of autoantibodies including antinuclear antibody, anti-nDNA, anti-Sm, anti-RNP, anti-SSA, anti-SSB, anticardiolipin (aCL) antibody, M-Proteins, and interleukin-6 (IL-6) and circulating immune complex (CIC) were studied in 18 patients with primary Sjögren's syndrome (SS) and 20 patients with secondary SS. Another 15 healthy individuals were served as a control group. The differences between primary and secondary SS in these autoantibodies, IL-6 and M-protein were also compared. The result showed a high incidence of autoantibodies and CIC in patients with SS. Higher frequencies of anti-nDNA and anti-Sm antibodies were noted in patients with secondary SS. There were also elevated levels of IL-6, much higher in primary than in secondary SS. In addition, higher frequencies of M-protein were detected in patients with primary SS. In conclusion, through immune dysregulations, higher levels of IL-6 were found in patients with SS. Autoantibodies produced in these patients might be derived from IL-6 stimulated B cells.
1283245 Extranodal lymphomas: the MALT concept. 1992 Extranodal lymphomas account for as many as 40% of non-Hodgkin's lymphomas and most arise in the gastro-intestinal tract which is a major lymphoid organ in its own right. Gastrointestinal (gut) associated lymphoid tissue (GALT) and that of other mucosae (MALT), differs both structurally and functionally from nodal lymphoid tissue and low grade B cell lymphomas arising in the gastrointestinal tract and other mucosae have been found to recapitulate the structure and cytological features of MALT. Moreover, these lymphomas are clinically indolent which could be explained by the restricted homing patterns of MALT. Curiously, however, most MALT lymphomas arise in sites, such as the stomach, where MALT is not normally present. Several chronic inflammatory conditions, most of which have an autoimmune component, result in the acquisition of MALT-like lymphoid tissue, and have been identified as necessary precursors for the development of MALT lymphoma. These include Helicobacter pylori induced chronic gastritis, Sjögren's syndrome and Hashimoto's thyroiditis. Histologically, low grade MALT lymphomas are characterized by centrocyte-like (CCL) B cells which surround reactive follicles and form characteristic lympho-epithelial lesions with adjacent epithelium; they frequently show plasma cell differentiation. Specific colonization of reactive follicles by CCL cells often occurs and transformation into a high grade lymphoma may occur. The phenotype of MALT lymphoma CCL-cells is similar to that of marginal zone B cells; no characteristic genotypic features have yet been identified. When lymph nodes are involved by MALT lymphoma their appearance may be indistinguishable from those of so-called monocytid B cell lymphoma, a primary lymph node tumour which, unlike MALT lymphoma, shares the clinical features of other low grade nodal B cell lymphomas.
1556696 Sialochemistry in human immunodeficiency virus associated salivary gland disease. 1992 Jan Human immunodeficiency virus (HIV) associated salivary gland disease is defined as the presence of enlargement of one or more major salivary glands and/or diminished salivary function in an HIV infected individual. It has a number of similarities to, as well as differences from, Sjögren's syndrome (SS). We studied the sialochemistry of stimulated parotid saliva of 11 patients with HIV associated salivary gland disease and bilateral parotid gland enlargement, and compared these findings with those of 15 HIV negative controls, 13 HIV positive individuals with no salivary gland involvement and 18 individuals with SS. The patients with HIV associated salivary gland disease had a significant decrease in the level of salivary protein, with increases in salivary IgA, lysozyme and albumin compared to the HIV negative controls. There were no changes in concentration of electrolytes. The sialochemistry among the patients with HIV associated salivary gland disease was unrelated to the degree of immune suppression and did not change over a 6 month period. The observed changes were similar to those of SS but less pronounced. The similar clinical, histologic and sialochemical features of HIV associated salivary gland disease and SS suggest that these conditions share common pathogenetic mechanisms, which may be modified in the former by the HIV infection.
8774178 Neutral endopeptidase (EC 3.4.24.11) in labial salivary glands in healthy controls and in 1996 Aug OBJECTIVE: Neuropeptides from nerve fibres can cause neurogenic inflammation. The potency of these peptides in vitro has led to the hypothesis that enzyme degradative systems are operative in vivo to limit their action. To consider this question neutral endopeptidase (NEP) in labial salivary glands in patients with Sjögren's syndrome was studied. METHODS: Synthesis of NEP mRNA in situ in labial salivary glands was studied using the reverse transcriptase polymerase chain reaction (RT-PCR). Immunohistochemical staining was used to localise the NEP enzyme protein and its neuropeptide substrates and fluorophotometry to measure the corresponding enzyme activities in saliva. RESULTS: NEP was found in nerve fibres and in perivascular, periductal, and periacinar axon terminal varicosities. Double labelling of PGP 9.5 and NEP confirmed this neuronal localisation of NEP. Although some fibroblast-like cells and occasional intravascular neutrophils were NEP positive, NEP mRNA was not found in labial salivary glands. Patients with Sjögren's syndrome and healthy controls did not have nerves containing NEP or neuropeptides (vasoactive intestinal peptide, substance P, or calcitonin gene related peptide (CGRP)) in lymphocyte foci. Salivary NEP activity was not decreased in patients compared with controls. CONCLUSION: NEP in labial salivary glands is almost totally of neuronal origin and plays a part in proteolytic modulation of neuropeptides in salivary glands and saliva. These regulatory interactions seem to be altered in focal lymphocyte accumulations in Sjögren's syndrome.
7533494 E-selectin expression in salivary endothelial cells and sera from patients with systemic s 1995 Mar OBJECTIVE: To assess endothelial cell activation in patients with systemic sclerosis (SSc). METHODS: Concomitant study of salivary gland biopsy tissues and sera for expression of E-selectin and its potent activator tumor necrosis factor alpha (TNF alpha), using immunostaining and enzyme-linked immunosorbent essay. RESULTS: E-selectin was overexpressed in SSc patients, but not in controls. TNF alpha was detected in mast cells. CONCLUSION: Mast cell-derived TNF alpha may contribute to endothelial cell activation in SSc.
8141677 Two-dimensional electrophoresis of human salivary proteins from patients with sialoadenopa 1993 Dec Unstimulated saliva was fractionated by micro two-dimensional gel electrophoresis, and the proteins visualized by silver staining and immunostaining. The subjects with Sjögren's syndrome exhibited both quantitative and qualitative alterations in the protein composition of the saliva not only from the parotid gland but also from the submandibular/sublingual glands.
1315723 [Epstein-Barr virus infection--a lympho- and epitheliotropic infection]. 1992 Mar Epstein-Barr virus (EBV) has long been thought to be primarily a B-lymphotropic virus. This tropism becomes obvious in the association of the virus with diseases that become manifest in lymphoproliferative conditions, such as acute infectious mononucleosis or endemic Burkitt's lymphoma. In the course of mononucleosis, however, viraemia cannot be detected and B-lymphocytes infected with EBV in vitro produce only small amounts of the virus. In contrast, recent studies document that EBV replicates in the epithelial cells in the mouth, and pronounced secretion of virus can also be detected. Cells of the basal layer of the epithelium can be infected via the EBV-specific CR2 receptor. Upon mitosis of the cells of the basal layer, EBV genome in episomal form is partitioned to the daughter cell. On the other hand, differentiation and maturation of the epithelial cells is paralleled by active virus production. Thus, there is evidence that the epithelial EBV infection is the main factor in the persistence and production of EBV. Accordingly, the EBV infection of epithelial cells which can result in diseases, seems to be the primary process, leading to the infection of B-lymphocytes and then to other diseases. Diseases associated with infection of epithelial cells by EBV and diseases involving B-lymphocytes are discussed with reference to this idea.
8869909 Late development of anti-La/SS-B antibodies in a patient with Sjogren's syndrome and high 1996 Aug The frequent coexistence of anti-Ro and anti-La autoantibodies is well described, however, there is little evidence of sequential development of these two autoantibodies. We report a case of typical Sjogren's syndrome with high titer anti-Ro antibodies, who subsequently developed anti-La antibodies later in the course. This case suggests that the anti-La antibodies may actually follow the anti-Ro antibodies in some cases as hypothesized in the concept of linked set of autoantibodies, analogous to development of anti-Sm in certain anti-nRNP antibody positive SLE patients and animal models.
7621590 Diverse T cell receptor beta gene usage by infiltrating T cells in the lacrimal glands of 1995 Jul Sjögren's syndrome (SS) is an autoimmune disease characterized by T cell infiltration into the salivary and lacrimal glands (LG). Previous studies on T cell receptor (TCR) usage in the minor salivary glands (SG) have yielded controversial results. We studied TCR beta gene usage of the T cells infiltrating to LG, which is the other major target organ of SS. Total RNA was extracted from fresh LG and SG biopsy samples, and peripheral blood mononuclear cells from five SS patients, and converted to cDNA. TCR V beta gene repertoire was then assessed with quantitative polymerase chain reaction (PCR) assay. Oligoclonality was studied by sequencing V-D-J junctional regions of the PCR products. The TCR V beta gene usage in LG was diverse in every patient irrespective of disease duration, and similar to that of peripheral lymphocytes from a corresponding patient. The junctional region sequences of over-expressed V beta families in LG T cells were heterogeneous. We did not find any identical clones shared by LG, SG and peripheral blood. These results showed that the infiltrating T cells in LG of SS patients are polyclonal, and LG and SG do not share the same dominant T cell clonotypes. These suggest that TCR-targeted disease manipulation may have a limited effect on SS.
8398610 Antiphospholipid antibodies in systemic lupus erythematosus and Sjögren's syndrome. 1993 Sep The spectrum of clinical descriptions and clinicopathologic studies on patients with primary and secondary forms of antiphospholipid antibody syndrome continues to widen. Some differences exist for patients with lupus compared with those with Sjogren's syndrome. Some new thoughts regarding pathogenetic mechanisms and the cofactor beta 2 glycoprotein I have been generated. Last year marked the first time the International Symposium on Anti-Phospholipid Antibodies was held in the United States; new data regarding the heterogeneity of antiphospholipid antibodies and lupus anticoagulant were highlighted, as well as the growing concept that assay modifications should not only include attention to the cofactor but also to prothrombin and other phospholipids such as phosphatidylserine and phosphatidylethanolamine. Prognostic and predictive factors of both a clinical and serologic nature of antiphospholipid antibodies are the focus of much recent work, as is the controversial role of steroid therapy for specific patients. Murine models of antiphospholipid antibody syndrome have opened new avenues to explore pathogenesis and therapeutic efficacy.
8083850 [Role of radiology in the diagnosis of joint chondrocalcinosis. The so-called atypical sym 1994 Jun In a preceding article, we described "pseudogout" which is the expression of an episode of acute synovitis related to microcrystals of dehydrated calcium pyrophosphate invading the joint. This brutal episode of inflammation, predominantly occurring in the knee joint, is the most spectacular, most frequent and most characteristic manifestation of articular chondrocalcinosis. We attempted to demonstrate the important role of radiographs in the diagnosis, discovering in many cases the microcrystal impregnation of cartilage and fibrocartilage. But articular chondrocalcinosis, as has been shown by a large number of clinical and radiological surveys, may present a wide range of atypical or misleading forms, much different from the classic pseudogout. Among the different clinical presentations, some have no particularly special radiographic expression, showing only the common chondrocalcinosis lesions seen during the acute episodes of microcrystal related synovitis. This is the case in different situations of inflammation, notably subacute arthritis, purely algic forms and exsudative forms (chronic hydarthrosis, haemarthrosis). Complete clinical latency is also observed in certain cases. But many cases of articular chondrocalcinosis involve manifest radiological lesions which often appear to be secondary. This may occur in chronic inflammatory forms of chondrocalcinosis which can simulate rheumatoid polyarthritis. Careful analysis of the symptomatology should help to avoid confusion, especially when the radiograph reveals only degenerative lesions which often cause destructive damages. In other cases, a perfectly characteristic articular chondrocalcinosis is associated with typical polyarticular lesions of osteoarthritis. These cases often have the particularity of involving joints usually spared by the common arthrosic disease, especially in the upper limbs. They are also remarkable due to the amount of lytic damage. The deep destructive damage to joints during chondrocalcinosis may produced a particularly striking picture. Such damage is seen in approximately one-third of the cases. The onset is marked by sudden renewal of former arthrosic-type pain and by the development of major functional incapacity. Often, the radiograph is the only examination capable of revealing the diagnosis. The extent of bone destruction varies greatly. Sometimes it is limited to subchondral bone but in other cases underlying bony structures are also involved leading to extensive damage to the epiphysis. The distribution of lytic lesions varies. Damage may occur in the knee, the coxofemoral and the shoulder joints. Surgery is often absolutely indicated. In a number of cases of chondrocalcinosis, especially those involving the knee and the shoulder, true intraarticular foreign bodies may be encountered, opaque calcified or ossified formations simulating osteochondromatosis, existing along with destructive damages.(ABSTRACT TRUNCATED AT 400 WORDS)
8040300 Studies of thrombin-induced proteoglycan release in the degradation of human and bovine ca 1994 Aug Because fibrin is commonly observed within arthritic joints, studies were undertaken to determine whether purified coagulation and fibrinolytic proteases degrade cartilage in vitro and to seek evidence for the activation of coagulation in arthritic joints through measurements of the levels of inhibitor-enzyme complexes and several other proteins associated with coagulation and fibrinolysis. The concentrations of 13 plasma proteins and complexes of thrombin and Factor Xa with antithrombin III were measured in synovial fluids recovered at the time of knee replacement surgery. All zymogens necessary to constitute the coagulation cascade were present. Thrombin and the combination of prothrombin plus prothrombinase induced proteoglycan release from both normal and arthritic cartilages. Factor Xa and plasmin induced release from diseased cartilage only, and urokinase, tissue plasminogen activator, and activated protein C were without effect at the levels used. At saturating levels of thrombin (> or = 2.0 microM) 80% of the proteoglycan content of normal cartilage was released within 24 h. Thrombin, which is cationic, reversibly binds cartilage with Kd = 7.0 +/- 1.0 microM and Bmax = 820 +/- 70 ng/mg of human cartilage. Levels of thrombin-antithrombin III complexes in synovial fluids and arthritis were 4-fold higher in osteo (OA) and 43-fold higher in rheumatoid (RA) than in controls (0.98 nM). Factor Xa-antithrombin III complex levels were threefold lower in OA and fivefold higher in RA than in controls (0.24 nM). These elevated levels of enzyme-inhibitor complexes imply a history of activation of coagulation within the joint, especially in RA. Since thrombin degrades cartilage in vitro and had been generated in vivo, as inferred by the existence of thrombin-antithrombin III complexes, intraarticular activation of coagulation may both contribute to the pathology of arthritis and comprise a target for therapy and diagnosis.
7801138 Epidemiology of silicone-related disease. 1994 Aug The epidemiology of silicone-related disease (SRD) is complicated by the variety of disease endpoints that have been associated with silicone exposure and the atypical nature of these diseases in silicone-exposed women. Current research reviewed here suggests that SRD may constitute a new disease entity, thus complicating disease definition and rendering studies of classic disease unlikely to detect risks of silicone exposure. This report addresses the most important study design issues (disease and exposure definitions, bias, confounding, and power) in the context of studies of SRD. The variety of silicones used complicates the definition of exposure for all studies, and for some populations simply determining who was implanted will be difficult. For any of these studies, inadequate patient follow-up is likely to underestimate disease risk. Studies of SRD are also complicated by confounding. That is, whether or not a woman chooses to receive an implant is related to her age, race, and other variables also related to rheumatoid and autoimmune disease. The absence of an appropriate control group also plaques published studies of silicone-related disease. Finally, inadequate sample size, resulting in studies of low statistical power, is a critical problem for rare diseases such as SRD. These points are illustrated using two published studies and five studies in progress.
8036522 Localized scleroderma in childhood: a report of 30 cases. 1994 Apr Localized scleroderma (LS), a rare disease that occurs primarily in the pediatric age group, differs from systemic sclerosis (SSc) in that it is usually limited to the skin and subcutaneous tissue and is only rarely associated with systemic manifestations. The authors' experience with pediatric LS seen in 30 patients at a tertiary care center was reviewed: 26 had linear scleroderma, 19 on an extremity and 7 on the face; 3 had morphea; and 1 had generalized morphea. Antinuclear antibodies were present in 76% and rheumatoid factor in 39%. Five of 19 patients with linear scleroderma that involved an extremity had growth failure in that limb, and 1 required surgery. Sclerodermatous involvement over a joint resulted in limited range of movement in 6 patients, and 1 required surgery. One of the 30 patients developed SSc and polymyositis. There was difficulty in evaluating disease activity and hence in evaluating treatment. This experience with a large patient population suggests that LS, although usually a self-limiting disease, can result in significant morbidity.
8768479 [Significance of intestinal inflammation in the pathogenesis of spondylarthropathies]. 1996 The concept of spondylarthropathy (SpA) gathers together a group of chronic diseases with common clinical, biological, genetic and therapeutic characteristics. The concept forms a distinct entity, different from other rheumatic diseases. The target organs are not only the joint, but also the axial skeleton, the enthesis, the eye, the gut, the urogenital tract, the skin and sometimes the heart. The prevalence of this entity in the general population is estimated 1%, equal to the prevalence of rheumatoid arthritis. Genetical predisposition (HLA-B27) is one of the clues to the pathogenesis of the disease. Since reactive arthritis is induced by specific urogenital or enterogenic bacteria, and since the gut is implied in different forms of spondylarthropathies, especially in IBD, it was clear that the gut could play an important role by permitting exogenous factors to enter the body. This hypothesis was the rationale for investigating the gut in the spondylarthropathies by performing ileo-colonoscopies. In the first ileo-colonoscopic studies of SpA patients, histological signs of gut inflammation were found in a relatively great number of patients, mostly not presenting any clinical intestinal manifestations. These lesions were not seen in other inflammatory joint diseases. Further ileo-colonoscopic studies confirmed the strong relationship between gut and joint inflammation. In patients in whom a second ileo-colonoscopy was performed, remission of the joint inflammation was always connected with a disappearance of the gut inflammation, whereas persistence of locomotor inflammation was mostly associated to the persistence of gut inflammation. The hypothesis was proposed that some patients with a spondylarthropathy had a form of subclinical Crohn's disease in which the locomotor inflammation was the only clinical expression. This hypothesis was confirmed in prospective long-term studies in which the ileo-colonoscopied patients were reviewed 2 to 9 years later:about 6% of SpA patients not presenting any sign of Crohn's disease at first investigation but demonstrating gut inflammation on biopsy, developed full-blown Crohn's disease. By performing electronmicroscopy it was described that in patients with SpA the number of membranous (M) cells, which are scarce in normal ileum, is increased in number in inflamed mucosa. They showed a thin rim of cytoplasm covering groups of lymphocytes. In chronic inflammatory lesions necrotic M-cells, rupture of M-cells and lymphocytes entering the gut lumen was observed. The bursting of M-cells at the top of the lymphoid follicles leads to interruption of the gut epithelial lining and gives the luminal content access to the lymphoid tissue. This can be responsible for an exponential increase of local antigen stimulation. Accelerated luminal antigen presentation through a break in the epithelial layer, together with cytokines released from activated monocytes, might induce a second line of defense aiming at elimination of the massive antigen penetration into the mucosa. The postulated switch from secretory local immunity to a systemic type of local immune reaction could have different consequences:the local down-regulation of J chain in the IgA immunocytes could shift the production of polymeric IgA to monomers, jeopardizing secretory immunity; the disproportionate increase of IgG-producing cells could favor further inflammation and tissue damage through complement activation and arming of the killer cells, and cause autoimmune responses locally and in target organs at a distance (e.g. joint organs). The discovery of subclinical gut inflammation in the SpA had therapeutic consequences. Sulphasalazine (SASP) has been proven to be an active drug in the treatment of IBD. Since the gut could play a crucial role in SpA, it was logic to use this drug in the treatment of this disease. Multiple open and double-blind studies have proven the effectiveness of this drug in SpA.
7662029 The antiinflammatory effects of an adenosine kinase inhibitor are mediated by adenosine. 1995 Aug OBJECTIVE: The acute antiinflammatory effects of methotrexate are mediated, at least in part, by increased extracellular adenosine concentrations at inflamed sites. This observation suggests that other agents that increase extracellular adenosine concentrations might also reduce inflammation. Since adenosine can be rapidly taken up by cells, phosphorylated by adenosine kinase, and maintained intracellularly as adenine nucleotides, we investigated whether a potent inhibitor of adenosine kinase, GP-1-515, could increase exudate adenosine concentration and thereby diminish inflammation in the murine air pouch model of inflammation. METHODS: We studied the effect of various oral doses of GP-1-515 on carrageenan-induced inflammation in air pouches induced on BALB/c mice. Adenosine concentration in pouch exudates was determined by high performance liquid chromatography, and intensity of inflammation was determined by leukocyte counts in the exudate fluid. RESULTS: There was a greater concentration of adenosine in the pouch exudates of animals treated with GP-1-515 than of those treated with saline (P < 0.002). GP-1-515 inhibited, in a dose-dependent manner (P < 0.01), leukocyte accumulation in the murine air pouch in response to carrageenan. Inhibition of inflammation by GP-1-515 in this model depended upon increased adenosine concentration in the inflamed pouch since injection of adenosine deaminase into the air pouch with the carrageenan completely reversed the antiinflammatory effects of GP-1-515 at all doses of GP-1-515 tested. Moreover, as previously demonstrated, the antiinflammatory effects of adenosine were mediated via occupancy of adenosine A2 receptors, since the specific adenosine A2 receptor antagonist 3,7-dimethyl-1-propargylxanthine, but not the A1 receptor antagonist 8-cyclopentyl-dipropylxanthine, completely reversed the antiinflammatory effects of GP-1-515. GP-1-515 also decreased tumor necrosis factor alpha levels in the air pouch exudates by 51%, most likely as a result of the direct action of adenosine on macrophages. CONCLUSION: These results indicate that the antiinflammatory actions of GP-1-515 are mediated by adenosine. The development of agents that promote adenosine release at sites of inflammation is a novel strategy for the treatment of inflammatory diseases such as rheumatoid arthritis.
8558449 The Chinese herbal remedy, T2, inhibits mitogen-induced cytokine gene transcription by T c 1996 Jan T2, an extract of Tripterygium wilfordii Hook F, has been reported to be effective in the treatment of a variety of autoimmune diseases, including rheumatoid arthritis. Previous studies have shown that T2 inhibited mitogen- or antigen-induced proliferation of human peripheral blood T cells and B cells, IL-2 production by T cells and Ig production by B cells. In contrast, T2 did not affect monocyte functions, such as IL-1 production and antigen presentation. The current studies sought to localize the immunosuppressive action of T2 more precisely. Results show that T2 prevented [3H]-uridine uptake by mitogen-stimulated T cells and arrested them in the early GI phase of the cell cycle. The inhibitory effects of T2 could be partially overcome by costimulating PHA activated T cells with PMA and completely nullified by costimulation with PMA plus a monoclonal antibody to CD28. Moreover, T2 had no effect on expression of IL-2R or the transferrin receptor (CD71), but inhibited production of a number of cytokines, including IL-2 and IFN-gamma by activated T cells. T2 suppressed IL-2 mRNA levels, but not IL-2R mRNA levels, in activated T cells. T2-mediated inhibition reflected suppression of IL-2 gene transcription as indicated by suppression of the expression of a reporter gene driven by the IL-2 promoter. T2 had little inhibitory effect on either IL-2 gene expression or cell cycle progression when added after initial mitogenic stimulation, indicating that an early step in the cascade of activation events was inhibited. However, initial activation events including protein tyrosine phosphorylation, the generation of diacylglycerol, IP3, and the translocation of protein kinase C were not inhibited by T2. Moreover, T2 did not inhibit the phosphatase activity of calcineurin. These results have localized the effect of T2 to a step in the T cell activation cascade after initial second messenger generation, tyrosine phosphorylation and protein kinase activation, but before IL-2 gene transcription.
1351061 Immunomodulatory effects of therapeutic gold compounds. Gold sodium thiomalate inhibits th 1992 Jun Previous studies have shown that the gold compounds, gold sodium thiomalate (GST) and auranofin (AUR), which are effective in the treatment of rheumatoid arthritis, inhibit functional activities of a variety of cells, but the biochemical basis of their effect is unknown. In the current studies, human T cell proliferation and interleukin 2 production by Jurkat cells were inhibited by GST or AUR at pharmacologically relevant concentrations. Because it has been documented that protein kinase C (PKC) is involved in T cell activation, the capacity of gold compounds to inhibit PKC partially purified from Jurkat cells was assayed in vitro. GST was found to inhibit PKC in a dose-dependent manner, but AUR caused no significant inhibition of PKC at pharmacologically relevant concentrations. The inhibitory effect of GST on PKC was abolished by 2-mercaptoethanol. To investigate the effect of GST on the regulation of PKC in vivo, the levels of PKC activity in Jurkat cells were examined. Cytosolic PKC activity decreased slowly in a concentration- and time-dependent manner as a result of incubation of Jurkat cells with GST. To ascertain whether GST inhibited PKC translocation and down-regulation, PKC activities associated with the membrane and cystosolic fractions were evaluated after phorbol myristate acetate (PMA) stimulation of GST incubated Jurkat cells. Translocation of PKC was markedly inhibited by pretreatment of Jurkat cells with GST for 3 d, but the capacity of PMA to down-regulate PKC activity in Jurkat cells was not altered by GST preincubation. The functional impact of GST-mediated downregulation of PKC in Jurkat cells was examined by analyzing PMA-stimulated phosphorylation of CD3. Although GST preincubated Jurkat cells exhibited an increased density of CD3, PMA-stimulated phosphorylation of the gamma chain of CD3 was markedly inhibited. Specificity for the inhibitory effect of GST on PKC was suggested by the finding that GST did not alter the mitogen-induced increases in inositol trisphosphate levels in Jurkat cells. Finally, the mechanism of the GST-induced inhibition of PKC was examined in detail, using purified PKC subspecies from rat brain. GST inhibited type II PKC more effectively than type III PKC, and also inhibited the enzymatic activity of the isolated catalytic fragment of PKC. The inhibitory effect of GST on PKC activity could not be explained by competition with phospholipid or nonspecific interference with the substrate. These data suggest that the immunomodulatory effects of GST may result from its capacity to inhibit PKC activity.
8730496 Cryoglobulinemia in transfusion-dependent thalassemia major. 1995 Nov OBJECTIVE: The aim of this study was to determine the frequency of cryoglobulinemia and associated symptoms in transfusion-dependent thalassemia patients at high risk for HCV infection. METHODS: A controlled epidemiological study was used to evaluate the prevalence of clinical, biochemical and immunological abnormalities in a group of 264 HCV-positive and 106 HCV-negative transfusion-dependent thalassemia patients. Haematologic and hepatic function tests were performed according to standard methods. HCV-RNA was detected by PCR analysis. RESULTS: The significant presence of cryoglobulinemia and associated symptoms (purpura, vasculitis, arthritis, asthenia, proteinuria), serum autoantibodies (SMA, anti-GOR, ANA, LKM), low complement and rheumatoid factor were found in HCV-positive compared with HCV-negative patients. CONCLUSIONS: This study demonstrates the role of HCV in inducing cryoglobulinemia and immunological disorders in transfusion-dependent thalassemia patients. HCV infection and associated immune abnormalities are a new clinical aspect of, and deserve particular attention due to their high frequency in, transfusion-dependent thalassemia patients.
8588121 Autoreactivity to mouse C1q in a murine model of SLE. 1995 A large proportion of systemic lupus erythematosus (SLE) patients develop glomerulonephritis, coincident with the appearance of autoantibodies to C1q, the Fc-recognizing collagen-like subcomponent of the first component of complement, C1. The MRL/lpr/lpr mouse is an established model for SLE, developing both antinuclear and anti-type II collagen autoantibodies, and rheumatoid factors(s), exhibiting reduced complement levels and later on developing glomerulonephritis and often arthritis. We report here an age-dependent decrease in serum C1q levels coincident with the development of IgG2b autoantibodies reactive with mouse C1q in MRL/lpr/lpr mice. Unlike IgG2b, although high levels of IgM, IgG1 and IgG2a are present in these mice, few, if any, antibodies of these subclasses reactive with mouse C1q were observed in this study. This is the first report of autoantibodies against autologous C1q in an animal model, and the results should facilitate in clarification of the roles of C1q and autoantibodies reactive with C1q in SLE, as well as their potential connection with glomerulonephritis.