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ID PMID Title PublicationDate abstract
10414851 New concepts for the development of autoimmune exocrinopathy derived from studies with the 1999 May The non-obese diabetic (NOD) mouse is now recognized as an appropriate model to study autoimmune exocrinopathy prevalent in human Sjögren's syndrome patients. With increasing age, NOD mice undergo histopathological changes similar to human Sjögren's syndrome patients, but more importantly, exhibit the same clinical manifestation of declining exocrine tissue secretory function. Studies with the immunodeficient NOD-scid mouse have provided evidence for the temporal loss in the expression of several major salivary proteins and a decreased presence of acinar cells in salivary tissues. The diminished presence of acinar cells is accompanied by an increase in the enzymes associated with apoptosis in the absence of T- and B-lymphocytes. Despite these alterations, NOD-scid mice, unlike NOD mice, do not lose secretory function. Recent analyses of a second congenic NOD strain, the NOD.Igmnull, which lacks B-lymphocytes, indicate the histological presence of a T-cell infiltrate of the exocrine glands, increased caspace activity and induction of the biochemical alterations in protein expression observed in NOD and NOD-scid mice. NOD.Igmnull mice also do not lose secretory function, but can be manipulated to generate a reduced secretory response following the infusion of IgG fractions from autoimmune NOD mice or Sjögren's syndrome patients. These observations, in the absence of components of the adaptive arm of the immune system, have given rise to the concept that autoimmune exocrinopathy develops in two phases. The initial phase is lymphocyte independent and occurs as a consequence of an innate error in exocrine tissue homeostasis or differentiated function. The subsequent tissue specific immunological attack, generated in part by B-cell autoantibodies, is responsible for the loss of secretory function. Our preliminary observations in both NOD mice and Sjögren's syndrome patients is that antibody directed against the cell surface muscarinic/cholinergic receptors appears to play an important part in the onset of clinical disease.
9301502 Induction of intestinal lesions in nu/nu mice induced by transfer of lymphocytes from syng 1997 Aug BACKGROUND: Murine leukemia virus, LP-BM5, induces severe immunodeficiency with abnormal lymphoproliferation in susceptible C57BL/6 mice. In a previous study, it was shown that a Sjögren's syndrome-like systemic exocrinopathy is induced in the virus infected mice. AIMS: To examine lymphocyte functions of the virus infected mice. METHODS: Four-week old mice were inoculated with the virus and their spleen cells were transferred into syngeneic nu/nu mice. Their organs were examined by light and electron microscopy. Phenotypes of the colon infiltrating cells were examined by flow cytometry. RESULTS: All nu/nu recipients had died by six weeks after cell transfer, showing runting disease like cachexia with diarrhoea and anal bleeding. Histopathological examination revealed that systemic exocrinopathy was adoptively transferable and that the colon became thickened due to mononuclear cell infiltration into the mucosal and submucosal layer with hyperplasia of intestinal epithelial cells. No virus particles were found in the colon. Flow cytometric analyses revealed that most of the infiltrating CD4+ T cells showed CD45RBlow. No intestinal lesions were observed in the virus infected mice nor in nu/nu mice inoculated with normal lymphocytes. CONCLUSION: Lymphocytes of the virus infected mice induced colitis and hyperplasia of intestinal epithelial cells as well as systemic exocrinopathy in nu/nu mice. Our experimental system may give some insight into intestinal lesions associated with virus infection.
9872535 Human primary Sjögren's syndrome autoantibodies as mediators of nitric oxide release coup 1998 Dec IgG obtained from sera of primary Sjögren's syndrome (pSS-IgG) patients and its interaction with M3 muscarinic cholinoceptors of rat exorbital lacrimal glands were studied by indirect immunofluorescence (IFI) and binding assay. Primary Sjögren's syndrome IgG stained epithelial cells with a continuous fluorescence pattern. The IFI imagen was attenuated by incubating the pSS-IgG with a synthetic peptide corresponding to the second extracellular loop of M3 muscarinic cholinoceptor. Primary SS-IgG was also able to bound irreversibly to muscarinic acetylcholine receptors (mAChRs) displacing the specific cholinergic antagonist QNB. Moreover, these antibodies triggered intracellular signals coupled to M3 muscaric cholinoceptors such as nitric oxide synthase (NOS) activation and cGMP production. Both primary Sjögren's syndrome IgG effects mimicked carbachol action and were abrogated by specific muscarinic antagonist 4-DAMP. The nitric oxide pathway through muscarinic cholinoceptors activation by pSS-IgG on rat exorbital lacrimal gland is also described. We proposed that chronic interaction of these autoantibodies on lacrimal gland muscarinic acetylcholine receptors could lead to tissue damage through nitric oxide release after immunological stimulation.
9490668 Clonal salivary gland infiltrates associated with myoepithelial sialadenitis (Sjögren's s 1998 Mar 15 Myoepithelial sialadenitis (MESA) is the reactive salivary gland lymphoid infiltrate that occurs in patients with Sjogren's syndrome. Although it is well established that mucosa-associated lymphoid tissue (MALT)-type lymphomas may develop from MESA, the issue of whether monoclonal B-cell populations in early MESA-associated lesions represent MALT lymphomas or more benign types of expansions has been very controversial. In addition, it is unknown whether antigen stimulation plays a role in the development or growth of MESA-associated clones. To investigate these issues, we have analyzed the Ig VH genes used by MESA-associated clones in sequential biopsies obtained from contralateral sites of seven different patients. In three cases, single clones were identified in the follow-up biopsies that were distinct from the single clones identified in the initial specimens, whereas in three other cases, the same clone was identified in both the initial and subsequent specimens. In the remaining case, two clones were identified in the second biopsy specimen, one of which was distinct from the initial clone. Of the 11 distinct clones identified in the 14 specimens that were analyzed, 8 were derived from a V1-69 VH gene segment, whereas the other 3 were derived from a V3-7 VH gene segment. In addition, the MESA clones also showed conserved amino acids sequence motifs in their third complementarity-determining regions (CDR3), some of which were encoded by N nucleotides. The marked VH gene restriction along with the similar CDR3 sequences suggests that MESA-associated clones even from different patients may bind the same or similar antigens and are selected for clonal expansion on that basis. The high rates of ongoing VH gene mutation observed in some of the cases futher suggest that the growth of early MESA clones is still dependent on antigen stimulation. In addition, our finding that different biopsies from the same patient may contain distinct clones indicates that some MESA-associated clones have not yet evolved to malignant lymphomas.
11303309 Cryoglobulinemia in systemic lupus erythematosus: prevalence and clinical characteristics 2001 Apr OBJECTIVES: To determine the prevalence and nature of cryoglobulins in 122 patients with systemic lupus erythematosus (SLE) and identify the clinical and immunologic features related to their presence. METHODS: In a cross-sectional study, we investigated 122 consecutive patients (106 women and 16 men) with SLE who fulfilled the 1982 revised criteria of the American College of Rheumatology for the classification of SLE. All patients had documented medical histories and underwent a medical interview as well as a routine general physical examination by a qualified internist, and their clinical and serologic characteristics were collected on a protocol form. Serum samples were obtained at 37 degrees C, and cryoglobulinemia was estimated by centrifugation at 4 degrees C after incubation for 7 days in all patients. The type of cryoglobulinemia was identified by agarose gel electrophoresis and immunofixation. RESULTS: Cryoglobulins were detected in the sera of 31 SLE patients (25%): 20 patients (65%) had a cryocrit lower than 1%, 8 (26%) had percentages ranging between 1% and 5%, and only 3 patients (9%) had a cryocrit over 5%. Only cutaneous vasculitis (39% v 16%; P = .01) was more prevalent in patients with than in those without cryoglobulins. Rheumatoid factor (RF) (42% v 15%; P = .002) and low CH50 levels (84% v 49%; P <.001) were more prevalent in SLE patients with cryoglobulins. Hepatitis C virus (HCV) infection was investigated in 24 of the 31 cryoglobulinemic SLE patients and was detected in 5 (21%). In comparison, 4 (5%) of the 75 noncryoglobulinemic SLE patients studied were positive (P = 0.035; odds ratio, 4.67). Patients with a cryocrit greater than 1% showed a higher frequency of HCV infection than those with a cryocrit less than or equal to 1% (46% v 0%, P = .01). CONCLUSIONS: Cutaneous vasculitis, RF, hypocomplementemia, and HCV infection were associated with cryoglobulins in SLE patients. Testing for HCV infection is therefore recommended for patients with SLE and cryoglobulinemia to identify this subset of patients for prognostic and therapeutic reasons.
9751095 Spectrum and clinical significance of autoantibodies against transfer RNA. 1998 Sep OBJECTIVE: To characterize the clinical features of patients who have autoantibodies against transfer RNA (tRNA) or tRNA-associated proteins. METHODS: Sera from 1,472 patients with suspected systemic rheumatic disease were screened by RNA immunoprecipitation of HeLa cell extracts. The specificities of the antibodies that precipitated tRNAs were further analyzed by immunoprecipitation using deproteinized RNAs and 35S-methionine-labeled HeLa cell extracts, followed by immunoblotting. RESULTS: Forty-one serum samples (2.8%) were found to immunoprecipitate tRNAs. Thirteen patients were identified as having previously defined anti-aminoacyl-tRNA synthetase antibodies (anti-histidyl-tRNA synthetase in 4 patients, anti-threonyl-tRNA synthetase in 1, anti-alanyl-tRNA synthetase in 3, anti-glycyl-tRNA synthetase in 4, and anti-isoleucyl-tRNA synthetase in 1). All 13 patients had myositis and/or interstitial pneumonitis. Sera from the remaining 28 patients immunoprecipitated previously unidentified tRNAs, including 13 serum samples that bound deproteinized cognate tRNA; 24 of the 28 patients met criteria for either systemic lupus erythematosus (SLE) or Sjögren's syndrome (SS). In addition, nonerosive polyarthritis, leukocytopenia, rheumatoid factor, and characteristic annular or papulosquamous recurrent erythema were noted in these patients; however, renal involvement was rare. Sera from 16 of these 28 patients also contained anti-Ro/SSA and/or anti-La/SSB antibodies. While 189 patient sera precipitated Ro/SSA and/or La/SSB-associated RNAs but not tRNA, only 12 of the patients (6.3%) developed skin lesions (P=0.0009, odds ratio 8.85). CONCLUSION: Novel autoantibodies against tRNAs or tRNA-associated proteins were identified in 28 sera. These autoantibodies appear to be distinct from anti-aminoacyl-tRNA synthetase antibodies and are associated with SLE and SS. The presence of anti-Ro/SSA and/or anti-La/SSB along with anti-tRNA antibodies is more strongly associated with recurrent erythema than is the presence of anti-Ro/SSA or anti-La/SSB alone.
10886142 IgA antineutrophil cytoplasmic antibodies in cutaneous vasculitis. 2000 Jul BACKGROUND: Antineutrophil cytoplasmic antibodies (ANCA) of the IgA isotype have, for the most part, been detected in patients with Henoch-Schönlein purpura (HSP) or inflammatory bowel disease. OBJECTIVES: We have evaluated the prevalence of IgA ANCA in a series of patients with different causes of cutaneous vasculitis. METHODS: Forty consecutive patients with histologically proven leucocytoclastic vasculitis were included in the study: 18 had systemic vasculitis as well as cutaneous lesions, 10 of whom were diagnosed as having HSP, and 22 had only cutaneous vasculitis (with no identified cause in 10 cases). IgA ANCA were sought by indirect immunofluorescence using ethanol-fixed human neutrophil preparations as the substrate. RESULTS: IgA ANCA were detected in six of 40 patients (15%) (one each with HSP, ulcerative colitis, Sjögren's syndrome, hypergammaglobulinaemia associated with Castelman's disease, erythema elevatum diutinum and bacterial endocarditis). Three of these patients also had IgG ANCA whose target antigen remained unidentified. CONCLUSIONS: IgA ANCA are rarely observed in HSP (10%) and can be detected in a wide variety of other cutaneous vasculitides.
10607305 Glycosylation of immunoglobulin A influences its receptor binding. 1999 Dec Immunoglobulin A (IgA), which is heavily glycosylated, interacts with a variety of receptors, e.g. the asialoglycoprotein receptor (ASGP-R), which binds terminal galactose residues, and the Fcalpha receptor (FcalphaRI). It has thus been proposed that elevated serum levels of IgA in primary Sjögren's syndrome (pSS) are caused by its defective clearance. To test this hypothesis, we developed a method (based on sialyl transferases eluted from a hepatoma cell line) to increase the amount of sialic acid (SA) on IgA, and used a battery of IgA1- and IgA2-specific glycosidases to reduce this amount. Binding of IgA1 and IgA2 to ASGP-R and FcalphaRI was found to be sugar dependent because oversialylated IgA bound less than native or desialylated IgA. However, individual sugars did not play a direct role in this binding. Given that IgA are oversialylated in pSS, defective clearance of IgA may indeed be ascribed to an excess of SA in IgA1 and IgA2.
9314950 Role of cytokines in the destruction of acinar structure in Sjögren's syndrome salivary g 1997 Sep Our aim in the present study was to understand the mechanism whereby specific destruction of acinar but not ductal structure occurs in salivary glands in Sjögren's syndrome (SS). Thus, we examined the effects of cytokines including TNF-alpha and IL-1 beta on the proteolytic activity of cultured normal human salivary gland cell clones, because degradation of the basement membrane by proteolytic enzymes leads to the disruption of acinar or ductal structure in salivary glands. Simian virus 40 (SV40)-immortalized normal human salivary gland cell clones with ductal (NS-SV-DC) or acinar (NS-SV-AC) phenotype were treated either with TNF-alpha or IL-1 beta alone or with a combination of both, and then proteolytic activity was examined. Although cytokine-treated NS-SV-AC demonstrated high matrix metalloproteinase-2 (MMP-2) activity at both protein and mRNA levels, no remarkable increase in MMP-2 activity was detected in NS-SV-DC. Expression of tissue inhibitor of metalloproteinase-2 (TIMP-2), a specific inhibitor of MMP-2, was similarly inhibited by cytokines in these cell clones. Thus, the net balance estimated by MMP-2/TIMP-2 suggested enhanced proteolysis in cytokine-treated NS-SV-AC and, to a much lesser extent, in NS-SV-DC. To examine whether enhanced expression of MMP-2 occurred in acinar cells of SS salivary glands, we carried out an immunohistochemical study using SS salivary gland tissues. This study indicated that acinar cells adjacent to the lymphocytic infiltrate exhibited enhanced expression of MMP-2 compared with those distant from infiltrated lymphocytes or with those in normal salivary glands. By Northern blot analysis, NS-SV-DC and NS-SV-AC expressed receptor mRNA for both cytokines. The signal-dependent activation of the transcription factor NF-kappa B was observed only in NS-SV-AC. I kappa B-alpha, a specific inhibitor of NF-kappa B, was down-regulated by treatment with cytokines in NS-SV-AC. However, the expression of I kappa B-alpha protein was not detected in NS-SV-DC at the basal level. Treatment of NS-SV-AC with calpain inhibitor-I restored the expression of I kappa B-alpha protein in cytokine-treated cells, thus leading to the inhibition of NF-kappa B activation. Reverse transcriptase-PCR analysis confirmed that there was a marked reduction in I kappa B-alpha mRNA expression in NS-SV-DC as compared to that in NS-SV-AC. As such, it seems likely that there is a relationship between the activation of MMP-2 and the activity of NF-kappa B, and that the NF-kappa B/I kappa B-alpha complex is not a signal mediator involved in cytokine-induced suppression of TIMP-2. These observations, therefore, indicate that the divergent response to cytokines in each constituent cell of salivary gland may result in the histopathologic manifestation of SS.
10580604 Fetal treatment of congenital heart block ascribed to anti-SSA antibody: case reports with 1999 Oct PROBLEM: Maternal anti-SSA(B) antibody crosses the placenta and causes fetal myocarditis, congenital heart block (CHB), hydrops fetalis, and intrauterine fetal death. The aim of this study was to evaluate corticosteroids' efficacy as a treatment for CHB. METHOD OF STUDY: One fetus with complete CHB and one fetus with incomplete CHB due to anti-SSA(B) antibody received maternal prednisolone (PSL) and dexamethasone (DEXA) treatments. Heart rate, cardiothoracic ratio (CTR), left ventricular fractional shortening (FS), and preload index (PLI) were longitudinally measured by serial fetal echocardiograms. RESULTS: In the former case, after maternal PSL/DEXA administration, improvement of cardiohemodynamics, i.e., the reduction of PLI from 1.7 to 0.4, CTR from 70 to 52%, and FS from 63 to 54% were observed. In the latter case, second degree 2:1 block was converted to 3:2 block/sinus rhythm, resulting in the increase of the fetal heart rate from 65 to 116 beats per minute (bpm). CONCLUSIONS: We disclosed for the first time the beneficial effects of corticosteroids in the fetal cardiohemodynamics and conduction system of affected fetuses with the presence of maternal anti-SSA(B) antibodies.
10905094 [Extrahepatic manifestations of hepatitis C virus infection]. 2000 May 15 HCV virus is associated with various immunological disorders. Some of them like mixed cryoglobulinemia, are proved by molecular biology and virology. Others are presumed auto-immune: auto-antibodies production (antinuclear, anti-smooth muscle, anti-liver-kidney microsomal antibodies...) has generally no pathological significance; however, true auto-immune diseases such as auto-immune hepatitis type 1 or 2, Sjögren's syndrome, lichen planus and auto-immune thyroiditis can be associated with HCV related liver disease. Finally, the association of some extra-hepatic manifestations like porphyria cutanea tarda with hepatitis C virus are only based on epidemiological data. Alpha interferon, the reference treatment of chronic hepatitis C, can be efficient on manifestations such as cryoglobulinemia which are directly linked to the virus. However, because of its immunological effect, the same treatment can severely worsen auto-immunological diseases associated with hepatitis C virus (autoimmune hepatitis, thyroiditis...). In practice, it's of great importance to identify and classify these extra-hepatic manifestations to optimize the treatment of chronic hepatitis C.
11427527 A novel approach to the design of inhibitors of human secreted phospholipase A2 based on n 2001 Aug 31 Human Type IIA secreted phospholipase A(2) (sPLA(2)-IIA) is an important modulator of cytokine-dependent inflammatory responses and a member of a growing superfamily of structurally related phospholipases. We have previously shown that sPLA(2)-IIA is inhibited by a pentapeptide sequence comprising residues 70-74 of the native sPLA(2)-IIA protein and that peptides derived from the equivalent region of different sPLA(2)-IIA species specifically inhibit the enzyme from which they are derived. We have now used an analogue screen of the human pentapeptide (70)FLSYK(74) in which side-chain residues were substituted, together with molecular docking approaches that modeled low-energy conformations of (70)FLSYK(74) bound to human sPLA(2)-IIA, to generate inhibitors with improved potency. Importantly, the modeling studies showed a close association between the NH(2) and COOH termini of the peptide, predicting significant enhancement of the potency of inhibition by cyclization. Cyclic compounds were synthesized and indeed showed 5-50-fold increased potency over the linear peptide in an Escherichia coli membrane assay. Furthermore, the potency of inhibition correlated with steady-state binding of the cyclic peptides to sPLA(2)-IIA as determined by surface plasmon resonance studies. Two potential peptide interaction sites were identified on sPLA(2)-IIA from the modeling studies, one in the NH(2)-terminal helix and the other in the beta-wing region, and in vitro association assays support the potential for interaction of the peptides with these sites. The inhibitors were effective at nanomolar concentrations in blocking sPLA(2)-IIA-mediated amplification of cytokine-induced prostaglandin synthesis in human rheumatoid synoviocytes in culture. These studies provide an example where native peptide sequences can be used for the development of potent and selective inhibitors of enzyme function.
10643704 Oligoclonal non-neoplastic B cell expansion is the key feature of type II mixed cryoglobul 2000 Jan OBJECTIVE: Type II mixed cryoglobulinemia (type II MC) is often characterized by features of indolent B cell lymphoma (IBCL) found on pathologic examination of bone marrow, whereas the clinical evidence does not indicate a neoplastic disorder. To better address the issue of indolent malignant versus nonmalignant bone marrow lymphoproliferation underlying type II MC, molecular analyses of B cell clonality were performed in the present study, in conjunction with clinical and pathologic characterization. METHODS: Polymerase chain reaction DNA amplification of immunoglobulin heavy chain genes was performed in bone marrow biopsy specimens obtained from 15 selected patients with type II MC, all infected with hepatitis C virus. Five of them had also developed overt B cell lymphoma (OBCL) during followup. Bone marrow features were consistent with IBCL in 9 of the 15 patients (group 1) and with reactive lymphoplasmacytosis in 6 of the 15 (group 2). RESULTS: An oligoclonal B cell expansion was detected in 6 of 9 baseline bone marrow lesions from group 1 patients (biclonal or monoclonal expansion in the remaining 3 cases), and in 6 of 6 from group 2 patients. OBCL was always monoclonal. Selected lesions were analyzed by clonospecific hybridization and by cloning and sequence analysis in patients who had developed OBCL at followup. In 4 of 5 cases, OBCL did not originate from the dominant B cell clones that were overexpanded in the putative neoplastic baseline bone marrow lesions. OBCL clones showed significant homology with rheumatoid factor database sequences. CONCLUSION: Based on the present results, as well as on evidence from previous studies of liver lesions, oligoclonal non-neoplastic B cell proliferation in the course of chronic infection-related inflammation appears to be the key feature of type II MC. Of note, molecular evidence from target tissues supports the clinical findings both at the time of type II MC diagnosis and in cases of OBCL complication. Bone marrow pathologic findings resembling those of IBCL should thus be considered in the light of clinical and molecular evidence.
9312179 Outside-in signaling in the chondrocyte. Nitric oxide disrupts fibronectin-induced assembl 1997 Oct 1 Elevated levels of fibronectin (Fn) in articular cartilage have been linked to the progression of both rheumatoid and osteoarthritis. In this study, we examined intracellular events which follow ligation of Fn to its receptor, the integrin alpha5beta1. In addition, we examined the regulatory influence of nitric oxide on these events, since this free radical has been implicated in cartilage degradation. Exposure of chondrocytes to Fn-coated beads resulted in the circumferential clustering of the alpha5beta1 integrin receptor, which was accompanied by the subplasmalemmal assembly of a focal activation complex comprised of F-actin, the tyrosine kinase, focal adhesion kinase (FAK), the ras related G protein rho A, as well as tyrosine-phosphorylated proteins. Treatment with exogenous nitric oxide (NO) or catabolic cytokines which induce nitric oxide synthase blocked the assembly of F-actin, FAK, rho A and tyrosine-phosphorylated proteins while not affecting the total number of beads bound per cell nor the clustering of alpha5beta1 integrin. Use of a cGMP antagonist (Rp-8-Br cGMPS) or cGMP agonist (Sp-cGMPS) either abolished or mimicked the NO effect, respectively. Adherence of chondrocytes to fibronectin enhanced proteoglycan synthesis by twofold (vs. albumin). In addition, basic fibroblast growth factor (FGF) and insulin growth factor (IGF-1) induced proteoglycan synthesis in chondrocytes adherent to Fn but not albumin suggesting a costimulatory signal transduced by alpha5betal and the FGF receptor. Both constitutive and FGF stimulated proteoglycan synthesis were completely inhibited by nitric oxide. These data indicate that the ligation of alpha5beta1 in the chondrocyte induced the intracellular assembly of an activation complex comprised of the cytoplasmic tail of alpha5beta1 integrin, actin, and the signaling molecules rho A and FAK. We show that NO inhibits the assembly of the intracellular activation complex and the synthesis of proteoglycans, but has no effect on the extracellular aggregation of alpha5beta1 integrin. These observations provide a basis by which nitric oxide can interfere with chondrocyte functions by affecting chondrocyte-matrix interactions.
9480718 Combined analysis of GAD65 and ICA512(IA-2) autoantibodies in organ and non-organ-specific 1998 Feb There is evidence that insulin-dependent diabetes mellitus (IDDM) may develop in association with other non-beta-cell-specific autoimmune diseases. We aimed to assess whether autoantibodies to the islet cell antigens glutamic acid decarboxylase (Mr 65,000 isoform) (GAD65) and ICA512(IA-2), present alone or in combination, are limited to IDDM or also occur in other organ- or non-organ-specific autoimmune disorders. We determined the frequency of these autoantibodies by radioimmunoassay in 199 sera from patients with autoimmune thyroid diseases (AITD), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and primary biliary cirrhosis (PBC), and compared the results with those from 507 newly diagnosed patients with IDDM and 280 healthy controls. ICA512(IA-2) autoantibodies were detected exclusively in AITD with concurrent IDDM, but not in other autoimmune diseases without IDDM, whereas GAD65 autoantibodies exceeded the limit of normal in 67.7% (21 of 31) of patients with AITD who also had IDDM and in 5.5% (three of 55) of patients with PBC. The frequency of either GAD65 and/or ICA512(IA-2) autoantibodies was significantly higher in patients with AITD who also had IDDM (27 of 31, 87.1%) than in those with AITD alone (one of 53, 1.9%; P<10(-6)), but was not significantly different from those patients with newly diagnosed IDDM (418 of 507, 82.4%). Neither patients with organ- or non-organ-specific autoimmune diseases without IDDM nor healthy controls had autoantibodies against both GAD65 and ICA512(IA-2). Despite the fact that one of the two autoantibodies was occasionally detected in patients with non-beta-cell-specific autoimmune diseases without IDDM, combined determination of GAD65 and ICA512(IA-2) autoantibodies specifically identified IDDM in the majority of patients with AITD. In conclusion, because of the strong association of IDDM with AITD, testing for multiple islet autoanti-bodies could be useful as a predictive marker for risk of progression to IDDM onset amongst patients with autoimmune thyroid disorders.
11207308 Oncostatin M-induced matrix metalloproteinase and tissue inhibitor of metalloproteinase-3 2001 Mar 1 Oncostatin M (OSM), a member of the IL-6 superfamily of cytokines, is elevated in patients with rheumatoid arthritis and, in synergy with IL-1, promotes cartilage degeneration by matrix metalloproteinases (MMPs). We have previously shown that OSM induces MMP and tissue inhibitor of metalloproteinase-3 (TIMP-3) gene expression in chondrocytes by protein tyrosine kinase-dependent mechanisms. In the present study, we investigated signaling pathways regulating the induction of MMP and TIMP-3 genes by OSM. We demonstrate that OSM rapidly stimulated phosphorylation of Janus kinase (JAK) 1, JAK2, JAK3, and STAT1 as well as extracellular signal-regulated kinase (ERK) 1/2, p38, and c-Jun N-terminal kinase 1/2 mitogen-activated protein kinases in primary bovine and human chondrocytes. A JAK3-specific inhibitor blocked OSM-stimulated STAT1 tyrosine phosphorylation, DNA-binding activity of STAT1 as well as collagenase-1 (MMP-1), stromelysin-1 (MMP-3), collagenase-3 (MMP-13), and TIMP-3 RNA expression. In contrast, a JAK2-specific inhibitor, AG490, had no impact on these events. OSM-induced ERK1/2 activation was also not affected by these inhibitors. Similarly, curcumin (diferuloylmethane), an anti-inflammatory agent, suppressed OSM-stimulated STAT1 phosphorylation, DNA-binding activity of STAT1, and c-Jun N-terminal kinase activation without affecting JAK1, JAK2, JAK3, ERK1/2, and p38 phosphorylation. Curcumin also inhibited OSM-induced MMP-1, MMP-3, MMP-13, and TIMP-3 gene expression. Thus, OSM induces MMP and TIMP-3 genes in chondrocytes by activating JAK/STAT and mitogen-activated protein kinase signaling cascades, and interference with these pathways may be a useful approach to block the catabolic actions of OSM.
11464655 [Distal renal tubular acidosis with rhabdomyolysis as the presenting form in 4 pregnant wo 2001 Mar We describe four pregnant patients with distal renal tubular acidosis (type I) (DRTA) whose initial presentation was rhabdomyolysis (RML) secondary to severe hypokalemia. We draw attention to the unusual presentation of DRTA during pregnancy, the low frequency of DRTA in adult patients and RML as initial manifestation. In one case the DRTA was secondary to Sjögren Syndrome and the etiology was unknown in the rest of the cases. We discuss the potential pathogenic mechanisms to explain hypokalemic RML and the various causes of DRTA in adult patients.
10895371 Detection of the tax gene of HTLV-I in labial salivary glands from patients with Sjögren' 2000 May OBJECTIVE: To confirm a possible association between Sjögren's syndrome (SS) and the tax gene of human T lymphotropic virus type I (HTLV-I). METHODS: We studied by PCR labial salivary glands (LSG) from 50 patients with definite SS and from 58 controls including 32 patients with LSG involved by other inflammatory processes and 26 normal LSG. Antibodies to HTLV-I and antibodies to the Tax protein were searched for in serum. RESULTS: We detected the tax gene of HTLV-I in LSG from 15/50 (30%) of patients with SS but also in specimens from 9/32 (28%) patients with LSG involved by other inflammatory processes (3/9 graft-versus-host disease, 5/19 extra-vasated cysts, 1/4 sarcoidosis) and from only 1/26 (4%) normal LSG. A 652 bp region, sequenced in 2 SS patients, was 98-98.5% homologous to the canonic sequence of tax HTLV-I. The HTLV-I gag, pol and env genes were never detected. The serum of the SS patients did not contain antibodies to HTLV-I. However, anti-Tax antibodies were detected in the serum of 18/25 (72%) SS patients, 10/10 (100%) patients positive for tax DNA in their LSG and 8/15 (53%) patients negative for tax DNA in their LSG. CONCLUSION: Our observations raise the possibility that a very low number of copies of the tax gene may be harbored innocuously in cells within the oral cavity in some healthy individuals, but that this gene may play a role as a co-factor in the development of SS or other diseases of oral cavity.
10812497 Aberrant proteolytic digestion of biglycan and decorin by saliva and exocrine gland lysate 2000 Mar OBJECTIVE: The protein components of the extracellular matrix (ECM) are responsible for driving tissue morphogenesis, the development of differentiated function, and the sequestration of biologically active molecules such as growth factors in close proximity to tissue and organ cells. Recent reports indicate that saliva and exocrine tissue lysates from Sjögren's syndrome patients and the non-obese diabetic (NOD) mouse model for autoimmune exocrinopathy demonstrate elevated levels of specific enzymes that degrade the ECM, especially the matrix metalloproteinases (MMPs). To determine if elevated levels of MMPs could be important in exocrine tissue destruction, we examined proteolytic activity against two ECM proteoglycans, decorin and biglycan. METHODS: Purified recombinant human core protein for decorin or biglycan was incubated with saliva or gland lysates from either control BALB/c or NOD mice. Degraded proteoglycan products were estimated by Western blotting analysis using anti-decorin or anti-biglycan monospecific polyclonal antibodies. The levels of TGF beta protein were measured by ELISA. RESULTS: Proteolytic activity for decorin and biglycan was not observed in the saliva and salivary gland lysates collected from C57BL/6 or BALB/c mice used as normal controls. In contrast, both proteoglycans were degraded by saliva and exocrine gland lysates from NOD mice and the congenic partner strains NOD-scid and NOD.B10.H2b. This proteolytic activity for proteoglycans was inhibited by the MMP inhibitors, EDTA, GM6001 and 1,10-phenanthroline. Protein steady state levels for TGF beta were increased in the saliva and gland lysates from 20-week old NOD strains, as compared to BALB/c mice and NOD treated with the MMP inhibitor GM6001. With the inhibition of MMP activity, TGF beta levels declined in saliva and gland lysates. CONCLUSION: Proteolytic degradation of the ECM molecules decorin and biglycan is elevated in the exocrine tissues of the NOD mouse model for Sjögren's syndrome. Furthermore, the proteolysis of small leucine-rich proteoglycans correlates with the presence of elevated levels of TGF beta in gland lysates and saliva.
9775165 [Gougerot-Sjögren syndrome and malignant lymphoproliferative syndromes]. 1998 May INTRODUCTION: This review is aimed at defining the frequency, anatomical and clinical presentation, pathogenesis, predictive factors and treatment of malignant lymphoproliferative diseases occurring in the course of Sjögren's syndrome. CURRENT KNOWLEDGE AND KEY POINTS: The frequency of non-Hodgkin's lymphoma (NHL) is estimated to be about 7%. Other malignant lymphoproliferative diseases (Waldenstrom's macroglobulinemia, multiple myeloma, Hodgkin's disease) are rarely observed. NHL is most frequently extranodal (affecting the salivary glands, stomach, lung, etc) in low grade malignancy (MALT lymphoma [mucosa associated lymphoid tissue]). The pathogenesis of NHL in Sjögren's syndrome is a multi-step process, including B cell monoclonal proliferation, oncogenic and/or infectious agents, and/or cytokines. Various predictive factors such as persistent enlargment of parotid glands, adenopathy, splenomegaly, mixed cryoglobulinemia, monoclonal gammopathy, suggest potential lymphoma evolution. The treatment of Sjögren's syndrome-associated NHL depends on the type of lymphoma. Moreover, in patients with low-grade lymphoma therapeutical strategies varies according to the stage and evolution of the disease. FUTURE PROSPECTS AND PROJECTS: Future prospective longitudinal studies should permit to define the best criteria for malignant transformation and to improve therapeutical strategies.