http://repub.eur.nl/res/aut/3835/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/33266/ 2011-10-01T00:00:00Z http://repub.eur.nl/res/pub/23833/ 2011-03-01T00:00:00Z http://repub.eur.nl/res/pub/16529/ 2009-05-01T00:00:00Z BACKGROUND: Serum samples from patients with autoimmune connective tissue diseases that show a finely speckled antinuclear antibody (ANA) on indirect immune-fluorescence often have antibodies against unknown nuclear target antigens. To search for such autoantigens we applied a proteomic approach using sera from patients with a high ANA titer (≥640) and finely speckled fluorescence but in whom no antibodies to extractable nuclear antigens (ENA) could be identified. METHODS: Using an immunoproteomics approach we identified heterogeneous nuclear ribonucleoprotein H1 (hnRNP H1) as a novel nuclear target of autoantibody response. RESULTS: Recombinant rat hnRNP H1 reacted in Western blot analyses with 48% of 93 sera from patients with primary Sjögren syndrome and with 5.2% of 153 sera from patients with other connective tissue diseases (diseased controls). For comparison, the diagnostic sensitivity and specificity of anti-Sjögren syndrome A (SSA) antibodies for primary Sjögren syndrome in the same patient cohort were 88.2% and 76.3%, respectively. Interestingly, 5 of 11 primary Sjögren syndrome patients with no anti-SSA or anti-SSB antibodies had anti-hnRNP H1 antibodies. Anti-hnRNP H1 antibodies were preabsorbed by hnRNP H1, as demonstrated by indirect immunofluorescence. In an evaluation of the presence of anti-hnRNP H1 antibodies in 188 consecutive samples submitted to the clinical laboratory with positive ANA (titer ≥160), anti-hnRNP H1 antibodies were found in 3 of 7 (2 primary and 5 secondary) Sjögren syndrome patients and in 8.3% of the diseased controls. CONCLUSIONS: HnRNP H1 is a newly discovered autoantigen that could become an additional diagnostic marker. http://repub.eur.nl/res/pub/24878/ 2009-03-01T00:00:00Z Objectivas: In the salivary glands of patients with primary Sjögren Syndrome (pSjS) an accumulation of dendritic cells (DCs) is seen, which is thought to play a role in stimulating local inflammation. Aberrancies in subsets of monocytes, generally considered the blood precursors for DCs, may play a role in this accumulation of DCs. This study is aimed at determining the level of mature CD14lowCD16+ monocytes in pSjS and their contribution to the accumulation of DCs in pSjS. Methods: Levels of mature and immature monocytes in patients with pSjS (n = 19) and controls (n = 15) were analysed by flow cytometry. The reverse transmigration system was used for generation of DCs generated from monocyte subsets. The phenotype of DCs in pSjS salivary glands was analysed using immunohistochemlstry. In vivo tracking of monocyte subsets was performed in a mouse model. Results: Increased levels of mature CD14lowCD16+ monocytes were found in patients with pSjS (mean (SD) 14.5 (5.5)% vs 11.4 (3.4)%). These cells showed normal expression of chemokine receptor and adhesion molecules. Mature monocytes partly developed into DC-lysosome-associated membrane glycoprotein (LAMP)+ (19.6 (7.5)%) and CD83+ (16 (9)%) DCs, markers also expressed by DCs in pSjS salivary glands. Monocyte tracking in the non-obese diabetic (NOD) mouse showed that the homologue population of mature mouse monocytes migrated to the salivary glands, and preferentially developed into CD11c+ DCs in vivo. Conclusions: Mature monocytes are increased in pSjS and patient and mouse data support a model where this mature monocyte subset migrates to the salivary glands and develops into DCs. http://repub.eur.nl/res/pub/28922/ 2008-07-01T00:00:00Z In the salivary glands of primary Sjögren's syndrome (pSjS) patients, type I IFN activity is increased, but systemic levels of type I IFN proteins are rarely detected. This study focused on the systemic activity of type I IFN in pSjS, as well as the role of peripheral plasmacytoid dendritic cells (pDC). Monocytes obtained from pSjS patients showed an increased expression of 40 genes. Twenty-three of these genes (58%), including IFI27, IFITM1, IFIT3 and IFI44, were inducible by type I IFN. pSjS serum had an enhanced capability of inducing IFI27, IFITM1, IFIT3 and IFI44 in the monocytic cell line THP-1, likely due to the action of IFN-β. This effect could be inhibited by blocking the type I IFN receptor, supporting a high type I IFN bioactivity in pSjS serum. In addition, circulatory pDC showed increased expression of CD40. This expression was correlated to the expression level of the type I IFN-regulated genes IFI27 and IFITM1 in monocytes of the same individual. This study indicates that the increased type I IFN activity observed in pSjS patients is not only a local but also a systemic phenomenon and points to pDC as a possible source of this activity. http://repub.eur.nl/res/pub/29783/ 2008-05-01T00:00:00Z Sjögren's syndrome is an autoimmune disease characterized by lymphocytic infiltration of the salivary glands. In the NOD mouse, a model for this disease, the development of lymphocytic infiltrates in the salivary glands is preceded by an accumulation of dendritic cells (DC). Given the key importance of DC in regulating the immune response, we characterized the DC isolated from NOD salivary glands. These DC lacked membrane expression of CCR5, whereas DC from control salivary glands did express this molecule. The lack of expression was present already prior to the onset of lymphocytic infiltration, indicating that this was not the result of ongoing inflammation. DC from other sources in the NOD mouse also showed a decrease in CCR5 expression. The lack of CCR5 expression in the NOD salivary gland was accompanied by an increase in inflammatory chemokines. Furthermore, DC from CCR5-/- animals or DC treated with a CCR5 antagonist showed increased secretion of IL-12. Interestingly, in Sjögren's syndrome patients, CCR5 expression on circulating monocytes was decreased and correlated to increased levels of IL-12. These data indicate that CCR5 has regulatory properties and that the lack of CCR5 in NOD DC contributes to the proinflammatory environment in the salivary glands. http://repub.eur.nl/res/pub/29588/ 2008-01-01T00:00:00Z Objectives: Because the term "interstitial cystitis" (IC) has different meanings in different centers and different parts of the world, the European Society for the Study of Interstitial Cystitis (ESSIC) has worked to create a consensus on definitions, diagnosis, and classification in an attempt to overcome the lack of international agreement on various aspects of IC. Methods: ESSIC has discussed definitions, diagnostic criteria, and disease classification in four meetings and extended e-mail correspondence. Results: It was agreed to name the disease bladder pain syndrome (BPS). BPS would be diagnosed on the basis of chronic pelvic pain, pressure, or discomfort perceived to be related to the urinary bladder accompanied by at least one other urinary symptom such as persistent urge to void or urinary frequency. Confusable diseases as the cause of the symptoms must be excluded. Classification of BPS types might be performed according to findings at cystoscopy with hydrodistention and morphologic findings in bladder biopsies. The presence of other organ symptoms as well as cognitive, behavioral, emotional, and sexual symptoms, should be addressed. Conclusions: The name IC has become misleading and is replaced by BPS. This name is in line with recent nomenclature recommendations by the European Association of Urology and is based on the axial structure of the International Association for the Study of Pain classification. To facilitate the change of the name, ESSIC agreed to include IC in the overall term (BPS/IC) during this transition period. http://repub.eur.nl/res/pub/37108/ 2007-09-01T00:00:00Z The cause of interstitial cystitis, a chronic disease that affects the bladder, is unknown. Autoantibodies, such as those against nuclear and bladder epithelium antigens, have been found in patients with interstitial cystitis, but these are likely to be secondary to the disease. No data support a direct causal role of autoimmune reactivity in the pathogenesis of interstitial cystitis. Indirect evidence, however, does support a possible autoimmune nature of interstitial cystitis, such as the strong female preponderance and the clinical association between interstitial cystitis and other known autoimmune diseases within patients and families. The strongest association occurs between interstitial cystitis and Sjögren's syndrome. Increasing evidence suggests a possible role of autoantibodies to the muscarinic M3 receptor in Sjögren's syndrome. The M3 receptor is also located on the detrusor muscle cells of the bladder and mediates cholinergic contraction of the urinary bladder and other smooth muscle tissues. Autoantibodies to the M3 receptor might be important in both the early noninflammatory and the late inflammatory features of interstitial cystitis. http://repub.eur.nl/res/pub/1316/ 2000-01-01T00:00:00Z This is the first report of the double blind randomized clinical trial, in which we investigated the influence of Filgrastim(r) on the quality of life and treatment costs of chronic sinusitis patients who did not respond to regular treatments. The quality of life of 56 patients was assessed 5 times during the 24-week trial with the EuroQol, the SF-36 and the McGill Pain questionnaire. We further controlled for "responsiveness", based on clinical impression. Direct medical and indirect non-medical costs per patient during the trial were analyzed, based on data from clinical record forms and the hospital information system. We further compared the direct medical costs to the costs of regular treatment. The quality of life scores were all below population norm scores. Quality of life scores of the Filgrastim(r) group suggested a better quality of life than the placebo group, although none of the differences were statistically significant. There were indications that controlling for responsiveness increased the power of the design. The difference in costs between the trial groups were driven by the Filgrastim(r) costs (Euro 4899). When Filgrastim(r) costs were neglected, no difference in costs remained. Except for Filgrastim(r), total direct costs summed up to Euro 2712 and the indirect costs to Euro 582. Total direct costs of a 24-week regular treatment were three times lower than the costs of the trial treatment. While significantly increasing treatment costs, Filgrastim(r) administration does not lead to a better quality of life of chronic sinusitis patients, although there were some indications that it might be possible to determine a subpopulation in which the results are better. http://repub.eur.nl/res/pub/31424/ 1980-01-09T00:00:00Z The faecal flora of patients with Crohn's disease has been found to differ from that of healthy subjects in that the numbers of anaerobic gramnegative rods and of gram-positive coccoid anaerobes, belonging to species of Eubacterium and Peptostreptococcus were higher. The flora composition was independent of duration of illness and was not influenced by ileocaecal resection. Serum agglutinins against some strains of coccoid rods were found in a considerable percentage of patients with Crohn's disease, whereas percentages of positive sera were much lower in healthy subjects and in patients with various diseases. The interpretation of these data established by Wensinck and the use of the agglutination reactions as a diagnostic test are the subject of this thesis. In Chapter 2 recent microbiological and immunological findings in patients with Crohn's disease are reviewed. They show that in Crohn's disease as well as in other intestinal diseases, like ulcerative colitis, antibodies to dietary and microbial antigens are found frequently. In Chapter 3 results are presented of investigations on the prevalence of agglutinins to four strains of anaerobic coccoid rods in patients with Crohn's disease, ulcerative colitis, a number of other diseases and in healthy subjects. Antibodies to coccoid rods were found much more frequently in Crohn's disease than in ulcerative colitis and other diseases. Using the interpretation of agglutination reactions as described in Chapter 7, the percentage of false positive results of sera submitted for diagnosis was found to be satisfactorily low. The data in Chapter 4 show that the presence of antibodies to the coccoid rods in patients with Crohn's disease is correlated with colonic disease, the presence of fistulae and with serum immunoglobulin levels. No correlation was found between antibodies and any index of disease activity.