Sjogren's syndrome and the danger model.
Explore the source record for details and available documents.
Acetylcholine↗
Biomedical subjects
A Bredberg
Publications and source records attributed to A Bredberg.
Immunohistochemistry of the B-cell component in lower lip salivary glands of Sjögren's syndrome and healthy subjects.
Serial sections of lower lip salivary gland (LSG) biopsies were examined by immunohistochemistry, using a battery of B- and partly T-related antibodies (CD5, CD20, CD21, CD27, CD38, CD45RO, CD79a, Bcl-2 and Bcl-6) in different groups of subjects: healthy controls and clinically verified smoking or nonsmoking cases of primary Sjögren's syndrome (SS). The purpose was to characterize the B-cell pattern of the lymphocytic foci and of the tiny perivascular infiltrates preceding the development of foci. Hyperplastic tonsil was used as stain control. In normal LSG, widely dispersed CD38+ and CD79a+ as well as some CD5+ cells are a normal constituent, with lack of staining with the other antibodies. In SS/LSG, the lymphocytic foci showed staining with all the antibodies, with variable degrees of overlapping or nonoverlapping. In SS/LSG of nonsmokers, CD20+ B cells make up a prominent part of the fully developed periductal lymphocytic foci, not overlapping with CD45RO. Also, CD20+ B cells did not overlap in the infiltrates with colocalized CD27+/CD38+ cells. CD20+ B cells and CD45RO+ T cells also occur as minute infiltrates perivascularly in areas of no foci in SS/LSG as well as in SS smokers lacking the typical foci. Smokers lack foci, but tiny infiltrates express CD20 as well CD45R0. Our findings suggest that CD20+ B cells and CD45RO+ T cells are early immigrants in the LSG of SS of smokers as well as nonsmokers and that another subgroup of CD27+/CD38+ B cells gradually mix with the first two to form the characteristic foci in SS/LSG. The simultaneous demonstration of CD20+ and CD27+ B cells in SS/LSG may constitute a significant diagnostic tool. Further, the findings suggest that the early immigrating lymphocytes may have been primed at a site remote from the glands before arriving via the blood to the gland tissue.
ADP-ribosyl Cyclase↗
Enhanced DNA-dependent protein kinase activity in Sjögren's syndrome B cells.
OBJECTIVE: To examine the stress response, including the role of DNA-dependent protein kinase (DNA-PK), in B cells from Sjögren's syndrome (SS) patients. METHODS: B-cell lines were exposed to gamma radiation and then postincubated to allow inducible stress functions to develop. The magnitude of the DNA damage response was monitored with respect to DNA-PK phosphorylation of a p53 peptide, defence protein levels (Ku, DNA-PK catalytic subunit, ATM, p21 and p53) and flow cytometric determination of cell cycle phases and apoptosis. RESULTS: B cells from SS patients, compared with healthy controls, displayed enhancement of two stress functions in undamaged cells: DNA-PK kinase activity and apoptosis. In addition, SS showed enhanced cell cycle arrest in gamma-irradiated cells. CONCLUSIONS: Strong kinase activity of DNA-PK, functioning not only in a DNA damage response but also in immunoglobulin gene rearrangement, may be an important component of the heightened stress response displayed by SS cells. In combination with recent reports, our data indicate that constitutional hyper-reactivity to danger signals is a basic pathogenetic factor in SS.
Antigens, Nuclear↗
A role of the macrophage in Sjögen's syndrome?
Explore the source record for details and available documents.
Animals↗
Enhanced DNA damage-induced p53 peptide phosphorylation and cell-cycle arrest in Sjögren's syndrome cells.
BACKGROUND: Cells from primary Sjögren's syndrome (SS) patients have been reported to show alterations in DNA repair and p53 expression. The DNA-dependent protein kinase (DNA-PK) autoantigen may be involved in both of these alterations in relation to cellular DNA damage responses. We conducted this study of cell-cycle kinetics and p53 to find additional evidence for an abnormal stress response role in the pathogenesis of SS. DESIGN: DNA-dependent protein kinase activity, p53 peptide phosphorylation and p53 protein levels were determined in gamma-irradiated long-term T lymphocyte cultures. Cell-cycle progression of peripheral blood mononuclear cells was analysed with flow cytometry. RESULTS: No significant differences in the DNA-PK activities or p53 protein levels appeared between the SS patients and the healthy individuals. However, patients with the SS hallmark Ro/SS-A and La/SS-B autoantibodies showed enhancement of both p53 peptide phosphorylation (P = 0.036) and G1 cell-cycle arrest (P = 0.015) in response to gamma radiation. CONCLUSIONS: Sjögren's syndrome cells express an enhanced G1 checkpoint function which may be mediated partly by p53 phosphorylation, suggesting that an abnormal stress response in SS is of relevance for the development of this autoimmune disease.
Adult↗
A longitudinal cohort study on the prevalence of Helicobacter pylori antibodies in Swedish children and adolescents.
UNLABELLED: The aim of this study was to monitor the Helicobacter pylori antibody seroprevalence of an asymptomatic cohort between the ages of 4 and 18 y. The H. pylori antibody titres in a longitudinally followed cohort of 168 native Swedish children (born between 1972 and 1974) were established at 4, 8, 12, 16, and 18 y of age. Seventeen children (10.1%) were found positive on at least one occasion when a paediatric cut-off was applied. Five children (3.0%) reached levels considered positive in adults. The seroprevalence at 4 y of age was 4.0%, at 8 y 2.5%, at 12 y 4.9%, at 16 y 5.3%, and at 18 y 6.3%. The difference in serological titres between the age groups was not significant. A change from negative to positive after the age of 4 took place in 5 of the cases. Spontaneous seroreversion appeared in 5 cases. CONCLUSION: Our findings showed no significant differences among the various age groups. Seventeen of the 168 children (10.1%) had been infected at some time, the prevalence ranging from 2.5% to 6.3%. Seroconversion and seroreversion occurred infrequently between the ages of 4 and 18 y.
Adolescent↗
Ku protein in human T and B lymphocytes: full length functional form and signs of degradation.
DNA-dependent protein kinase (DNA-PK) has been shown to take part in cell cycle regulatory signal transduction and in the repair of X-ray-induced DNA double-strand breaks. Functional DNA-PK is furthermore needed for the generation of antigen specificity during lymphocyte maturation. The Ku86 subunit of DNA-PK has been reported to exist in human B lymphocytes in a truncated form capable of binding to broken DNA but lacking the ability to activate the kinase function of DNA-PK. In the present work the Ku70 and Ku86 dimer proteins in T and B lymphocytes from human blood donors were analysed by immunoblotting and were observed apparently to be of full length. Also, nuclear protein extracted from B and non-B lymphocytes displayed DNA-dependent kinase activity. However, a minor fraction of Ku86 in lymphocytes was observed to be truncated with a molecular mass of approx. 70 kDa.
Antigens, Nuclear↗
Ku protein and DNA strand breaks in lip glands of normal and primary Sjögren's syndrome subjects: lack of correlation with apoptosis.
UNLABELLED: The aim was to examine tissue expression of Ku protein in lower lip salivary gland (LSG) biopsies from cases of primary Sjögren's syndrome (SS) and from normal subjects. METHODS: immunohistochemistry was used with antibodies to Ku70/86 and also Ki67, PCNA and p53. In addition, the Klenow method was applied in order to detect evidence of apoptosis. Sections of hyperplastic tonsil served as additional controls. RESULTS: in normal controls, LSG acinar cells stained negatively whereas LSG excretory duct cell nuclei stained positively with Ku and Klenow and occasionally with PCNA but negatively with Ki67 and p53. In LSG focal sialadenitis of SS cases, some lymphocytic cells showed staining with Ku, Ki67, PCNA, Klenow and p53. In addition to duct cell Ku and Klenow as well as PCNA staining which was not much different from normals, a few ductal epithelial and also mononuclear cells stained with p53. In focal sialadenitis, some acinar cells showed staining with PCNA as well as with Klenow. CONCLUSIONS: our findings in LSG biopsies of SS cases added little to an increased understanding about the pathogenetic mechanisms in the development of focal sialadenitis in SS. However, in normal LSG, ductal epithelial but not acinar cells seem to express a constitutively specific Ku protein and Klenow profile, suggestive of DNA strand breaks but not clearly associated with ongoing apoptotic events. It may reflect an enhanced stress response, which may be pathogenetically important in the early events of focal sialadenitis development in primary Sjögren's syndrome.
Antibody Specificity↗
Antibodies to CD4 in primary Sjögren's syndrome.
OBJECTIVE: The purpose of this study was to examine whether antibodies against CD4 are present in patients with primary Sjögren's syndrome, and to explore the possible correlation between these antibodies and the CD4+ T lymphocyte depletion that is seen in some Sjögren patients. METHODS: Sera from 214 patients with primary Sjögren's syndrome, 154 healthy blood donors, 38 age- and sex-matched controls without autoimmune disease, and 77 HIV-1-seropositive individuals were analysed by an enzyme-linked immunosorbent assay (ELISA) using recombinant soluble CD4 as the antigen. RESULTS: Anti-CD4 antibodies were observed more frequently in patients with Sjögren's syndrome (12.6%) as compared with the control groups (0.6%) (P < 0.001), and at a level similar to that seen among the HIV-1 patients (13.0%). However, no correlation was found between the presence of anti-CD4 antibodies and CD4+ T lymphocytopenia in the Sjögren patients. CONCLUSION: This is the first study that shows anti-CD4 antibodies in patients with primary Sjögren's syndrome. The significance of these antibodies in the immunopathogenesis of Sjögren's syndrome remains to be determined.
Adolescent↗
Sjögren's syndrome: lymphoma predisposition coupled with a reduced frequency of t(14;18) translocations in blood lymphocytes.
Sjögren's syndrome (SS) is a systemic autoimmune disorder with a strong tumor predisposition (a 44-fold elevated incidence of non-Hodgkin's lymphoma has been reported). By polymerase chain reaction analysis of t(14;18), a key lymphomagenic event in peripheral blood lymphocytes, we found a lower frequency in a subset of 12 SS patients positive for SS-A/SS-B autoantibodies than in 21 healthy subjects and 20 SS patients lacking these SS marker autoantibodies (P < 0.001). All 14 mutants sequenced displayed signs typical of V(D)J recombinase activity. This perplexing result of a low rate of t(14;18) in a population strongly predisposed to t(14;18)-associated tumor development may be explained by a constitutive deficiency in V(D)J recombinase leading to autoimmunity and increased lymphoproliferation.
Antibodies, Antinuclear↗
Streptokinase antibodies inhibit reperfusion during thrombolytic therapy with streptokinase in acute myocardial infarction.
OBJECTIVES: To evaluate the influence of pretreatment IgG against streptokinase on the outcome of streptokinase treatment in acute myocardial infarction. SETTING: Coronary care unit. DESIGN: From 88 patients admitted to the coronary care unit due to chest pain, blood samples were taken for determination of the pre-existing titre of antibodies against streptokinase. The patients were treated and monitored according to standard protocols. Fifty of the patients received thrombolytic therapy with streptokinase due to acute myocardial infarction and were monitored with continuous dynamic vectorcardiography, making possible the continuous analysis of ST- and QRS-vector changes and determination of the event of reperfusion. None of these 50 patients had been given streptokinase therapy previously. RESULTS: According to the vectorcardiographic criteria 21(42%) patients had signs of early (within 2 h) reperfusion after streptokinase therapy. These patients had lower pre-existing antibody titres than patients without signs of reperfusion (mean values 0.20 and 0.45 arbitrary units, P = 0.01). None of the patients with a titre higher than 0.50 arbitrary units (nine patients) had signs of early reperfusion. Of the 41 patients with a titre lower than 0.50 arbitrary units 52.5% had signs of early reperfusion. CONCLUSION: The present investigation indicates that pre-existing streptokinase antibodies play an important role in reperfusion failure during thrombolytic therapy with streptokinase in acute myocardial infarction. Therefore, the determination of streptokinase antibodies may differentiate between those patients who may benefit from streptokinase treatment and those who should be treated with some other regime.
Enzyme-Linked Immunosorbent Assay↗
Prevalence of coeliac disease in Turner syndrome.
This study was undertaken to investigate the prevalence of coeliac disease in children and adolescents with Turner syndrome. Eighty-seven children and adolescents with Turner syndrome were screened for IgA-antiendomysium antibodies (EMA) and IgA-antigliadin antibodies (AGA), 5% (4/87) being found to be EMA-positive, and 15% (13/87) to have AGA levels above normal. Of the 10 patients who were either AGA- or EMA-positive and further investigated with intestinal biopsy, four manifested villous atrophy (i.e. all three of the EMA-positive patients, but only one of the seven AGA-positive patients). The results suggest EMA-positivity to be a good immunological marker for use in screening for coeliac disease, and such screening to be justified in patients with Turner syndrome.
Adolescent↗
Abnormal DNA damage-inducible protein in cells from Sjögren's syndrome patients.
Antinuclear antibodies are commonly found in patients with Sjögren's syndrome. It has been suggested that the development of antinuclear antibodies depends on the activation of the spliceosome and other transcription-related subcellular particles, some of which have recently been shown also to function in DNA-modifying processes, such as DNA repair and V(D)J recombination. These observations add weight to a previously proposed model for the aetiology of Sjögren's syndrome. This includes the abnormal processing of the T-cell receptor and immunoglobulin genes. To test this hypothesis further, the present study on DNA-modifying proteins in Sjögren's syndrome was initiated. Gel-shift experiments using protein extracted from UV-treated Sjögren cells provided evidence of high molecular weight DNA-binding protein in six out of 12 Sjögren patients studied (but not among seven healthy controls). Some Sjögren sera displayed antibodies to protein extracts from cells treated with psoralen plus UVA radiation. These results indicate an abnormal DNA damage-inducible response in Sjögren's syndrome. It may therefore be concluded that alterations in nuclear protein may play a role in the aetiology of Sjögren's syndrome.
Antibodies, Antinuclear↗
Screening for coeliac disease in adult insulin-dependent diabetes mellitus.
OBJECTIVES: To study, by sequential screening for gliadin antibodies (GA) and endomysial antibodies (EMA), the prevalence and clinical characteristics of coeliac disease (CD) in adult IDDM patients. SUBJECTS AND MEASUREMENTS: A series comprising 1664 diabetes patients [848 with IDDM, 745 with non-insulin-dependent diabetes (NIDDM) and 71 with secondary diabetes] were screened for GA. IgA- or IgG-GA positive sera were analysed for EMA. RESULTS: IgA-GA were more frequent in all the diabetes subgroups (13.7% in IDDM,12.3% in NIDDM and 23.9% in secondary diabetes, P < 0.001 in all three cases) than among healthy blood donors (4.7%). Two patients with NIDDM had CD. Of the IDDM group (n = 848), 8 had previously diagnosed CD and 14 more (of whom 7 could be biopsied) were EMA positive. All had villous atrophy. The minimum prevalence of CD (including probable cases) in IDDM was 2.6% (22/848). Patients with previously known CD had more symptoms (P < 0.001), more deficiency states (P < 0.001) and more autoimmune diseases (P < 0.04) than those identified by screening. IDDM patients with a diabetes duration of 31-40 years were characterised by a higher prevalence of CD than patients with a duration of less than 30 years (6.7% vs. 1.7%; P < 0.02). CONCLUSIONS: Serial analysis of GA and EMA confirmed a high prevalence of CD in adult IDDM (2.6%). False-positive IgA-GA test results are frequent in patients with diabetes, irrespective of type. EMA analysis is the preferable screening tool for CD in diabetes.
Adult↗
Ciprofloxacin induces an immunomodulatory stress response in human T lymphocytes.
Exposure of cells to adverse environmental conditions invokes a genetically programmed series of events resulting in the induction of specific genes. The fluoroquinolone antibiotic ciprofloxacin has recently been reported to upregulate interleukin-2 (IL-2) gene induction. In the present investigation, the effect of ciprofloxacin at supratherapeutic concentrations on immediate-early (<2 h) gene expression in primary human peripheral blood lymphocytes was studied with Northern blots. In addition, transcriptional activity of IL-2 and metallothionein enhancer and promoter regions and transcription factors AP-1, NF-kappaB, and NF-AT were analyzed by chloramphenicol acetyltransferase (CAT) and electrophoretic mobility shift assays, respectively. The concentration of c-fos, c-jun, c-myc, junB, and fra-1 mRNAs was increased in activated peripheral blood lymphocytes incubated with ciprofloxacin compared to that in untreated controls. Ciprofloxacin increased CAT activity in stimulated lymphocytes transfected with plasmids containing either the IL-2 or metallothionein enhancer. Furthermore, among the transcription factors tested, AP-1 activity was increased in stimulated purified T helper lymphocytes incubated with ciprofloxacin compared to drug-free controls. Taken together, ciprofloxacin increased the levels of immediate-early transcripts, enhanced IL-2 and metallothionein promoter induction, and upregulated AP-1 concentrations in primary lymphocytes, reflecting a program commonly observed in mammalian stress responses.
Anti-Infective Agents↗
Prevalence of IgA-antigliadin antibodies and IgA-antiendomysium antibodies related to celiac disease in children with Down syndrome.
OBJECTIVE: This study was undertaken to investigate the prevalence of celiac disease in children and adolescents with Down syndrome. MATERIAL AND METHODS: Forty-three children and adolescents with Down syndrome were screened for IgA-antigliadin antibodies (AGA) and IgA-antiendomysium antibodies (EMA). Patients found to be either AGA- or EMA-positive were investigated further with intestinal biopsy. RESULTS: None of the 43 patients had known celiac disease at entry into the study; 37% (16/43) were found to have AGA levels above normal, and 16% (7/43) to be EMA-positive. Of the 15 patients who underwent biopsy, 8 manifested villous atrophy. Villous atrophy was present in all 7 of the EMA-positive patients, whereas the villi were normal in 7 of the 13 AGA-positive patients who underwent biopsy. CONCLUSIONS: EMA is a good immunologic marker for use in screening for celiac disease, and screening is justified in patients with Down syndrome.
Adolescent↗
Deficient DNA repair of triple helix-directed double psoralen damage in human cells.
Damage induced by a single psoralen-modified triple helix-forming oligonucleotide has been reported to be efficiently repaired in human cells. In this study we investigated a set of psoralen coupled oligonucleotides introducing multiple lesions into the target DNA. A simian virus 40 (SV40) shuttle vector was in vitro treated with different triple helix-forming oligonucleotides and UVA radiation, leading to double psoralen adducts at the supF mutational target gene of the plasmid. After passage in the Raji human cell line the recovered vector was analysed in an indicator bacterial strain. The results show that double psoralen adducts, located at both ends of a long triple helix, cannot be repaired efficiently in human cells.
Base Sequence↗
Triple helix directed psoralen adducts induce a low frequency of recombination in an SV40 shuttle vector.
Triple helix forming oligonucleotide directed psoralen adducts in a mammalian shuttle vector have been reported to be repaired efficiently in human cells. In this study we examined the role of intermolecular homologous recombination in triple helix targeted psoralen adduct repair. A simian virus 40 (SV40) shuttle vector carrying a mutated supF gene was treated with a triplex forming oligonucleotide psoralen conjugate and cotransfected into human cells with a second plasmid bearing the wild type supF gene. Recombinants with a reactivated marker gene were detected by an X-gal assay in indicator bacteria. We could observe a low frequency of psoralen adduct induced recombination indicating that recombination does not play a major role in triplex directed psoralen adduct repair. The implications for targeted mutagenesis by triple helix forming oligonucleotides are discussed.
Base Sequence↗