Search PubMed⌕ Search

Biomedical subjects

H M Moutsopoulos

Publications and source records attributed to H M Moutsopoulos.

At least 37 records · Page 2Linked to original sources
PubMed2004

Autoimmune manifestations in human myelodysplasia: a positive correlation with interferon regulatory factor-1 (IRF-1) expression.

BACKGROUND: Patients with myelodysplasia may have autoimmune manifestations (AIM). Interferon regulatory factor-1 (IRF-1) is a transcription factor involved in interferon signalling, leukaemogenesis, and the development of the immune system. OBJECTIVES: To determine whether IRF-1 is implicated in the pathophysiology of AIM in myelodysplasia. METHODS: 14 patients with myelodysplasia were studied, seven with AIM and seven without. Five patients with vasculitis and seven normal subjects served as controls. The expression of IRF-1 was studied in bone marrow mononuclear cells taken from patients and controls, using a relative quantitative reverse transcriptase polymerase chain reaction. RESULTS: A 10-fold reduction in full length IRF-1 mRNA was detected in the myelodysplasia patients without AIM compared with the normal controls. In contrast, the group with AIM had increased IRF-1 transcripts, to a level almost equal to that observed in patients with vasculitis and normal controls. CONCLUSIONS: Myelodysplasia patients without IRF-1 expression had a decreased incidence of AIM. Thus the absence of IRF-1 transcription factor appears to protect against the development of autoimmunity in myelodysplasia.

Aged↗
PubMed2004

Presence of systemic autoimmune disorders in patients with autoimmune thyroid diseases.

OBJECTIVE: To evaluate the prevalence of antinuclear antibodies (ANA) in patients with autoimmune thyroid diseases (ATD) and the presence of systemic autoimmune disorders among ANA positive patients with ATD. METHODS: 168 consecutive patients with ATD with positive antithyroid antibodies and 75 healthy subjects were tested for the presence of ANA. ANA positive patients were further evaluated by complete history, physical examination, blood and urine tests, and immunological studies. Patients with subjective xerophthalmia and xerostomia were examined by objective tests. RESULTS: 58/168 (35%) patients with ATD were ANA positive compared with 7/75 (9%) healthy controls (p = 0.001). Of 58 ANA positive patients, 6 (10%) had anti-Ro antibodies, 1 had anti-Ro and anti-La antibodies, 7 (12%) had anti-dsDNA antibodies, and 7 (12%) had medium levels of IgG and/or IgM anticardiolipin antibodies (aCL). No healthy subjects had positive anti-dsDNA, antibodies against the extractable nuclear antigens, or aCL. 5/58 (9%) patients fulfilled the criteria for Sjögren's syndrome (SS). Two patients had features related to systemic lupus erythematosus. No healthy subjects had clinical or laboratory characteristics of systemic autoimmune disorders. CONCLUSION: ANA are detected in 1/3 of patients with ATD. Anti-dsDNA, anti-Ro, and aCL can also be found in ANA positive patients with ATD. SS occurs in about 1/10 of ANA positive patients with ATD.

Adult↗
PubMed2003

Calreticulin binds preferentially with B cell linear epitopes of Ro60 kD autoantigen, enhancing recognition by anti-Ro60 kD autoantibodies.

Calreticulin is a molecular chaperone to newly synthesized polypeptides. Previous studies suggested that calreticulin is probably a protein member of the Ro/La RNP complex. The aims of this study were (a) to investigate whether linear B cell epitopes of the Ro/La RNP complex are bound to calreticulin and (b) if the complex peptide-calreticulin is recognized specifically by anti-Ro autoantibodies. Calreticulin was isolated from either human or pig spleen using a multi-step purification method and found to interact preferentially with biotinylated peptides derived from the sequence of the Ro60 kD 175-184aa(10p) and 216-232aa(17p). The interaction of the peptide-calreticulin complex was favoured by the combination of heat treatment, divalent cations and ATP. La/SSB epitopes did not react with calreticulin. Peptides corresponding to La/SSB epitopes as well as the common epitope of Sm did not interact with calreticulin. Thirty-eight anti-Ro60 KD positive and 23 anti-Ro60 kD negative sera of patients with systemic lupus erythematosus (SLE) and primary Sjögren's syndrome (pSS) were tested. All anti-Ro60 kD positive sera bound the complex calreticulin-17p, while 95% of the same sera had activity against the complex calreticulin - 10p. Tested individually, calreticulin, pep10p and pep17p presented very low reactivity (8%, 11% and 29%, respectively) against anti-Ro60 kD positive sera. Anti-Ro60 KD negative sera did not exhibit significant reactivity either with calreticulin, 10rho and 17rho or with the complexes calreticulin - 10p and calreticulin-17p (<5%). These results suggest that calreticulin can induce conformation-dependent recognition of the Ro60 kD epitopes, leading eventually to their recognition by autoantibodies. This is the first time that such a relationship is shown between a chaperone protein and fragments of an intracellular autoantigen. This work also provides insights into the understanding of mechanisms for autoantibody production. Furthermore, this association can be proved useful for the development of new sensitive assays for autoantibody detection.

Animals↗
PubMed2003

Evaluation of the association of autoantibodies with mortality in the very elderly: a cohort study.

OBJECTIVE: To evaluate whether autoantibodies in the absence of rheumatic diseases increase the risk of mortality among very elderly subjects who are otherwise in good functional condition. METHODS: Autoantibodies were measured in 1987 in 156 elderly nursing home residents (median age 84 yr) who were followed subsequently over 14.6 yr. RESULTS: Eleven subjects had anticardiolipin antibodies, 30 had rheumatoid factor and 19 had antibodies to single-stranded DNA (ssDNA). Other autoantibodies were more rare. During follow-up, 144 subjects died. Adjusting for age as a time-dependent covariate, the hazard ratio for death was 0.71 [95% confidence interval (CI) 0.38-1.32] for anticardiolipin antibodies, 0.93 (95% CI 0.60-1.41) for rheumatoid factor, 1.08 (95% CI 0.65-1.79) for antibodies to ssDNA, and 0.99 (95% CI, 0.70-1.41) for any autoantibody. Hazard ratios were similar when adjusted also for sex and clinical conditions. CONCLUSION: Our results exclude the possibility that the autoantibodies evaluated increase substantially the risk of death among very elderly subjects in good functional condition.

Aged↗
PubMed2003

Atherosclerosis in premenopausal women with antiphospholipid syndrome and systemic lupus erythematosus: a controlled study.

OBJECTIVE: To evaluate whether premenopausal women with antiphospholipid syndrome (APS) or systemic lupus erythematosus (SLE) have increased prevalence of atherosclerosis after adjustment has been made for known cardiovascular risk factors. METHODS: We evaluated premenopausal women with APS in comparison with age-matched groups of patients with SLE [positive or negative for anticardiolipin (aCL) antibodies] or rheumatoid arthritis (RA), and healthy subjects. Thirty-three subjects in each group were assessed for cardiovascular risk factors, including a detailed lipid profile. Ultrasonography of carotid and femoral arteries assessed the intima-media thickness (IMT) and the presence of atherosclerotic plaque. RESULTS: Atherosclerotic plaques were detected in 5, 2, 4, 1 and 1 subject in the five groups respectively. APS patients had significantly more affected vessels than RA patients and healthy controls (P=0.042 and P=0.016, respectively), but not compared with SLE patients. No consistent differences in IMT, traditional cardiovascular risk factors or lipid parameters were detected among the five groups. The odds for atherosclerosis independently increased 1.19-fold per year of increasing age [95% confidence interval (CI) 1.08-1.31; P=0.001), 1.019-fold per 1 mg/dl increase in low-density lipoprotein (LDL) (95% CI 1.003-1.036; P=0.020), 1.035-fold per additional 1 g of methylprednisolone equivalent cumulative corticosteroid dose (95% CI, 0.996-1.074; P=0.074), and 4.35-fold in the presence of APS or SLE (95% CI 0.75-25.2; P=0.10). Neither aCL nor anti-beta(2)GPI antibodies were associated with atherosclerosis. CONCLUSION: Premenopausal APS and SLE women have an increased prevalence of carotid and femoral plaque that is not accounted for by other predictors of atherosclerosis, including age, lipid parameters and cumulative steroid dose.

Adult↗
PubMed2003

Efficacy and safety of the fully human anti-tumour necrosis factor alpha monoclonal antibody adalimumab (D2E7) in DMARD refractory patients with rheumatoid arthritis: a 12 week, phase II study.

OBJECTIVES: To evaluate efficacy, dose response, safety, and tolerability of adalimumab (D2E7) in disease modifying antirheumatic drug (DMARD) refractory patients with longstanding, active rheumatoid arthritis (RA). METHODS: During a 12 week, double blind, placebo controlled study, 284 patients were randomly allocated to receive weekly subcutaneous injections of adalimumab 20 mg (n = 72), 40 mg (n = 70), or 80 mg (n = 72) or placebo (n = 70) without concomitant DMARDs. RESULTS: Adalimumab significantly improved the signs and symptoms of RA for all efficacy measures. ACR20 responses with adalimumab were significant at each assessment versus placebo (p</=0.01). Additionally, ACR responses with adalimumab were achieved more rapidly than with placebo, with 82/115 (71%) of the ultimate ACR20 response rate to adalimumab treatment achieved at week 2. At week 12, for adalimumab 20, 40, and 80 mg, ACR20 response rates were 50.7%, 57.1%, and 54.2%, respectively, versus 10.0% for placebo (p</=0.001 for all comparisons); ACR50 rates were 23.9%, 27.1%, and 19.4%, respectively, versus 1.4% for placebo (p</=0.001 for all comparisons); and ACR70 rates were 11.3%, 10.0%, and 8.3%, respectively, versus 0.0% for placebo (p</=0.05 for all comparisons). All adalimumab doses significantly improved all ACR core criteria at all assessments. The 40 mg and 80 mg doses provided similar benefit. Adalimumab at all doses was generally well tolerated, with only mild or moderate adverse events. Completion rates were 87% for adalimumab and 67% for placebo. CONCLUSIONS: Adalimumab given as monotreatment to patients with longstanding, severe RA refractory to traditional DMARDs produced a rapid, sustained response and was safe and well tolerated, with no dose limiting side effects.

Adalimumab↗
PubMed2003

Familial Mediterranean fever associated pyrin mutations in Greece.

OBJECTIVE: To search for pyrin mutations associated with familial Mediterranean fever (FMF) in Greece. PATIENTS AND METHODS: 62 patients fulfilling the Tel Hashomer diagnostic criteria for definite (33) or probable (29) FMF diagnosis were studied. Eight point mutations of pyrin gene were tested by standard methods. Of the 62 patients tested, 48 were Greek, four were Jewish, seven were Armenian, and three were Arab. RESULTS: 42 patients were found to be homozygotes for pyrin mutations; 11 patients were found to carry only one of the tested mutations; in nine patients no mutations were detected. CONCLUSION: Molecular detection of pyrin gene mutations seems useful in confirming suspected cases, and in detecting asymptomatic cases, of Mediterranean fever in Greece. It may also be used as a screening tool within affected families.

Arabs↗
PubMed2003

Lupus nephritis: current issues.

Despite the development of new modalities, cyclophosphamide (CYC) remains the preferred initial treatment for severe proliferative lupus nephritis. Controversies continue about the best route, dosage, and duration of CYC treatment. For recalcitrant disease, new immunosuppressive and immunomodulating agents, immunoablative high dose CYC, nucleoside analogues, apheresis, and the biological response modifiers can be considered.

Cyclophosphamide↗
PubMed2002

CD40 on salivary gland epithelial cells: high constitutive expression by cultured cells from Sjögren's syndrome patients indicating their intrinsic activation.

CD40 has been identified in an expanding list of haematopoietic and non-haematopoietic cells and has received an increased interest based on its role in a variety of cell-mediated responses and its potential to participate in the pathogenesis of chronic inflammatory disorders. Sjögren's syndrome (SS) is an autoimmune exocrinopathy, which is characterized by chronic lymphocytic infiltration of exocrine glands and aberrant activation of epithelial tissues. We studied the expression of CD40 protein in cultured non-neoplastic salivary gland epithelial cell (SGEC) lines as well as in minor SG biopsies obtained from 17 SS patients and 12 controls. Immunocytochemical and flow cytometric analyses had revealed the occurrence of constitutively expressed CD40 molecules on the surface of long-term cultured SGEC lines, which could be further induced by interferon-gamma (IFN-gamma) and IL-1beta cytokines, but not tumour necrosis factor-alpha (TNF-alpha), IL-4, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF) or IFN-alpha. Triggering of SGEC through CD40 enhanced the surface expression of the adhesion molecule intercellular adhesion molecule-1 (ICAM-1)/CD54, but not MHC class I and class II (HLA-DR) molecules. Spontaneous CD40 expression was significantly higher in SGEC lines derived from SS patients, compared with controls (P < 0.001), which is suggestive of their intrinsically activated status. In SG biopsies, CD40 was constitutively expressed by lymphocytes, ductal epithelial cells and endothelial cells but not by other glandular cell types, such as acinar cells, myoepithelial cells and fibroblasts. In addition, CD40L staining was also detected in 30--50% of the infiltrating lymphocytes in the biopsies of SS patients. Our findings indicate the immunoregulatory potential of SGEC and lend further support to a model of intrinsic activation in salivary epithelia in SS, whereby these cells actively participate in the induction and maintenance of lymphocytic infiltrates of patients.

Autoimmune Diseases↗
PubMed2002

The Th1/Th2 cytokine balance changes with the progress of the immunopathological lesion of Sjogren's syndrome.

Expression of type-1 and type-2 cytokines at the mRNA level in labial salivary glands (LSG) of patients with Sjogren's syndrome (SS), as reported by several groups, have generated conflicting results. In the present study we have directly examined the production of IL-4, IL-13 and IFN-gamma by lymphocytes infiltrating the LSG of 44 consecutive patients referred for SS evaluation. Cytokines production was evaluated following in vitro culture of LSG in the presence of IL-2. IFN-gamma and IL-13 were detected in the majority of SN (24/44 and 26/44, respectively) while IL-4 was present in 5/44 SN. The presence of IFN-gamma was significantly higher in SS patients, as opposed to patients who did not fulfil the criteria for SS (P < 0.01). In addition, almost all cultured lymphocytes expressed mRNA for IFN-gamma (17/19 cultures) and IL-13 (18/19) while IL-4 mRNA was also expressed at high frequency (14/19 cultures). Interestingly, the IFN-gamma mRNA copies in cultured lymphocytes correlated significantly with the intensity of lymphocytic infiltration as evaluated by Chisholm's score (P < 0.01). Furthermore, RT-PCR of RNA extracted from whole LSG from 14 SS patients also demonstrated the presence of all cytokines in the majority of the cases and the prevalence of IFN-gamma in LSG with high-grade infiltration. Because IL-13 was produced by the majority of the cultured LSG, IgE production was also evaluated. Interestingly, IgE was detected in 21/44 LSG culture SN and mainly in those biopsies that had Chisholm's score less than 0.5 (P < 0.05). We conclude that lymphocytes infiltrating the LSG are capable of producing both Th1 and Th2 cytokines and that the balance between them shifts in favour of Th1 in LSG with high infiltration score and in patients with SS.

Cells, Cultured↗
PubMed2002

Risk of myelotoxicity with intravenous cyclophosphamide in patients with systemic lupus erythematosus.

OBJECTIVES: To determine the incidence of serious myelotoxicity from intravenous cyclophosphamide (IC) in systemic lupus erythematosus (SLE). METHODS: In a retrospective study, white blood cell (WBC) counts with differential and platelet counts were determined in 92 SLE patients (96 courses) given 1623 doses of IC. RESULTS: Only one patient developed a total leucocyte count <1000/mm3, one developed a neutrophil count <500/mm3, two had a lymphocyte count <100/mm3 and no patients had platelet counts <50000/mm3 during follow-up. The risk of a neutrophil count <500/mm3 was 0.06 per 100 visits [95% confidence interval (CI) 0.00-0.34]. Two patients discontinued IC due to neutropenia [rate of 0.12 per 100 doses (95% CI 0.01-0.44)]. No clinical consequences were recorded in conjunction with low blood cell counts. In multivariate models, both the cumulative number of IC doses and European Consensus Lupus Activity Measurement (ECLAM) score affected neutrophil and lymphocyte counts adversely. For neutrophils, lowering the ECLAM score by 1 point counteracted four additional doses of IC after adjusting for steroid dose. CONCLUSIONS: IC and SLE disease activity have independent effects in lowering white blood cell counts, but serious myelotoxicity of IC is uncommon.

Adult↗
PubMed2002

Clinical, immunological, and immunogenetic aspects of autoantibody production against Ro/SSA, La/SSB and their linear epitopes in primary Sjögren's syndrome (pSS): a European multicentre study.

OBJECTIVES: To investigate the clinical and immunogenetic aspects of antibody formation against Ro/SSA and La/SSB as well as their linear B cell epitopes in patients with primary Sjögren's syndrome (pSS) from different European countries. PATIENTS AND METHODS: Ninety patients with pSS from six European centres were studied. Serum samples from all patients were tested in a control laboratory for anti-Ro/SSA and anti-La/SSB autoantibodies by RNA precipitation assay and autoantibodies to the previously reported B cell linear epitopes of Ro 60 kDa (p169-190aa and p211-232aa) and La/SSB (p147-154aa, p291-302aa, p301-318aa, and p349-364aa). DNA from 88 patients was used for the determination of HLA-DRB1, -DQA1, and -DQB1 genotypes. Analysis of the results was performed in the 88 patients who were genotyped and tested also for antipeptide antibodies. RESULTS: Antibodies to B cell epitopes of Ro 60 kDa were detected at a low frequency (range 10-37%). In contrast, B cell epitopes of La/SSB were detected frequently (range 58-86%) among the anti-La/SSB positive sera. Autoantibodies to the La/SSB epitope, p349-364aa, were significantly positively associated with longer disease duration (p<0.05), recurrent or permanent parotid gland enlargement (p<0.005), and a higher proportion of non-exocrine manifestations (p<0.005), compared with patients without autoantibodies. The presence of anti-Ro/SSA and anti-La/SSB autoantibodies was significantly associated with the presence of HLA-DRB1*03 and DQB1*02 (p=0.038 and p=0.034, respectively). This association was even more prominent and extended to HLA-DQA1*0501 when patients were stratified according the presence of autoantibodies to discrete La/SSB B cell epitopes in comparison with autoantibody negative patients (p<0.01). They were found also to be highly associated with the alleles HLA-DQB1*02 and HLA-DQA1*0501 as well as the presence of a shared amino acid motif in the region 59-69aa of DQB1 first domain (p<0.01, respectively). CONCLUSIONS: Autoantibodies against La/SSB, binding to four synthetic peptides, derived from the sequence of the La protein were identified with increased frequency in sera of patients with pSS. The formation of autoantibodies against B cell epitope analogues of La/SSB in European patients with pSS may be dependent on the presence of a permissive HLA-DQ heterodimer, most prominently represented by the HLA-DQA1*0501/DQB1*0201 heterodimer, suggesting that a model of HLA restricted presentation of La/SSB peptide determinants is crucial for the autoimmune response against La/SSB.

Aged↗
PubMed2002

Classification criteria for Sjögren's syndrome: a revised version of the European criteria proposed by the American-European Consensus Group.

Classification criteria for Sjögren's syndrome (SS) were developed and validated between 1989 and 1996 by the European Study Group on Classification Criteria for SS, and broadly accepted. These have been re-examined by consensus group members, who have introduced some modifications, more clearly defined the rules for classifying patients with primary or secondary SS, and provided more precise exclusion criteria.

Decision Making↗
PubMed2001

Functional expression of a costimulatory B7.2 (CD86) protein on human salivary gland epithelial cells that interacts with the CD28 receptor, but has reduced binding to CTLA4.

B7 molecules expressed on classic APC play a critical role in the regulation of immune responses by providing activation or inhibitory signals to T cells, through the ligation with CD28 or CTLA4 receptors, respectively. We have recently described the expression of B7 molecules by the salivary gland epithelial cells (SGEC) of patients with Sjögren's syndrome (also termed autoimmune epithelitis). The role of such expression needs to be clarified. Thus, in the present study, we sought to address the existence and function of B7.2 proteins on cultured nonneoplastic SGEC lines derived from Sjögren's syndrome patients. The occurrence of B7.2 proteins on SGEC was verified by flow cytometry, immunocytochemistry, immunoprecipitation, and immunoblotting. The assessment of several cell lines in costimulation assays had revealed that the constitutive expression of B7.2 molecules is sufficient to provide costimulatory signals to anti-CD3-stimulated T cells. SGEC-derived costimulation induced IL-2-dependent proliferation of CD4(+) T cells, which was associated with low production of IL-2, but probably also with the secretion of yet undefined autocrine T cell growth factor(s). B7.2 proteins expressed by SGEC were found to display distinctive binding properties denoted by the functional interaction with CD28 receptor and reduced binding to CTLA4. Finally, the detection of a functional soluble form of B7.2 protein in cell-free culture supernatants of both SGEC and EBV-transformed B cell lines is demonstrated. These findings imply a critical role for epithelial cells in the regulation of local immune responses in the salivary glands.

Abatacept↗
PubMed2001

"Lymphoid" chemokine messenger RNA expression by epithelial cells in the chronic inflammatory lesion of the salivary glands of Sjögren's syndrome patients: possible participation in lymphoid structure formation.

OBJECTIVE: Many studies have shown that the microanatomic organization of infiltrating leukocytes in the salivary gland lesions of patients with Sjögren's syndrome (SS) resembles the structure of lymphoid organs. A newly defined set of chemokines referred to as "lymphoid," which orchestrate leukocyte microenvironmental homing and contribute to the formation of lymphoid structures, provides directional clues. The aim of this study was to investigate the possible existence of "lymphoid" chemokines in the chronic inflammatory lesions of SS patients and thus validate their potential involvement in the disease process. METHODS: Twelve patients with primary SS, 3 patients with secondary SS, 4 patients with other autoimmune disorders, and 4 control individuals were the subjects of this study. Reverse transcriptase-polymerase chain reaction analysis was performed in order to examine the messenger RNA (mRNA) expression of "lymphoid" chemokines. Furthermore, in situ hybridization studies revealed chemokine mRNA localization. Immunohistochemistry was also applied in order to identify the cell types that expressed the chemokine mRNA. RESULTS: STCP-1/monocyte-derived chemokine and TARC mRNA were expressed in the majority of patients with primary and secondary SS, in 2 of 4 patients with other autoimmune disorders, and in 2 of 4 controls. BCA-1, ELC, and PARC mRNA were only detected in patients with primary and secondary SS. SLC mRNA was also detected in 1 non-SS patient. The main cellular sources of chemokine mRNA were ductal epithelial cells and infiltrating mononuclear leukocytes. CONCLUSION: The expression pattern of "lymphoid" chemokine mRNA points further to the role of epithelial cells in the pathogenesis of SS and offers new insight into the potential mechanisms that could be involved in leukocyte attraction and in the in situ formation of secondary lymphoid tissue structures.

Biopsy↗