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Biomedical subjects

M N Manoussakis

Publications and source records attributed to M N Manoussakis.

At least 19 recordsLinked to original sources
PubMed2004

Infliximab Therapy for Patients With Active and Refractory Spondyloarthropathies at the Dose of 3 mg/kg: A 20-Month Open Treatment.

BACKGROUND: : Infliximab at the dose of 5 mg/kg per infusion has been shown effective for the treatment of active spondyloarthropathies. It is not clear if the 5 mg/kg is required in most patients. OBJECTIVE: : To evaluate the long-term efficacy and safety of infliximab at the lower dose of 3 mg/kg in patients with active and refractory ankylosing spondylitis (AS) and psoriatic arthritis (PsA). METHODS: : Thirty patients were enrolled in a 78-week, single-center, prospective, open-label pilot study, including 16 patients with severe and active AS and 14 patients with active and refractory PsA. Infliximab (3 mg/kg, in combination with a stable dose of methotrexate was administered intravenously at 0, 2 and 6 weeks, and q8 weeks thereafter (schedule-A) and the improvement of Bath Ankylosing Spondylitis Disease Activity Index (BASDAI; for AS patients) and Patient Global Assessment of Disease Activity (PDA; for PsA patients) was monitored at baseline and at every visit (primary variables). Patients who did not respond sufficiently at 14 weeks, as well as patients who relapsed at any time during follow-up, received infliximab every 4 weeks (treatment schedule-B). Three different statistical approaches (per-protocol, last observation carried forward and by intention-to-treat) were applied. RESULTS: : Ten patients discontinued treatment for various reasons, including 3 (10.0%) because of allergic reactions. Twenty patients (66.7%, 9 with AS and 11 with PsA) had completed 78 weeks of treatment (schedule-A, 11 patients; schedule-B, 9 patients). Of these patients, 18 (90.0%) showed optimal response (improvement >/=50%), including 13 (65.0%) with improvement >/=70%. ASsessments in AS (ASAS) 50% was attained by 7/9 AS patients (77.8%). At 78 weeks of treatment, statistically significant improvement of indices of disease activity, function and quality of life was observed by all statistical approaches applied. CONCLUSIONS: : Infliximab at 3 mg/kg every 8 weeks or, if needed, every 4 weeks appears to be an effective and rather safe treatment of patients with active and refractory AS and PsA after 78 weeks of treatment.

Journal Article↗
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↗
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↗
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

Induction of salivary gland epithelial cell injury in Sjogren's syndrome: in vitro assessment of T cell-derived cytokines and Fas protein expression.

Sjogren's syndrome (SS) is an exocrinopathy characterized by T cell infiltrates, salivary gland epithelial cell (SGEC) apoptosis and high Fas and FasL expression. To address the participation of T cell-derived cytokines and of Fas apoptotic pathway in SS glandular lesions, we utilized non-neoplastic SGEC lines established from SS patients and controls. Possibly attesting to their intrinsic activation, cell lines derived from SS patients displayed significantly higher constitutive Fas and FasL than controls. Surface co-expression of Fas and FasL was not associated with spontaneous fratricide apoptosis. SGEC were resistant to anti-Fas-mediated apoptosis (possibly owing to the constitutive expression of anti-apoptotic proteins cFLIP and Bcl-2), but became sensitive after protein or RNA synthesis inhibition. IFN-gamma and TNF-alpha were able to upregulate surface Fas and FasL, whereas IL-1beta downregulated surface FasL. IFN-gamma (but not several other cytokines) reduced the survival of SGEC in a dose- and time-dependent manner and induced Fas/FasL-mediated apoptosis, directly and via anoikia. Dexamethasone inhibited the upregulation of Fas and FasL by IFN-gamma and the induction of SGEC apoptosis and detachment by anti-Fas mAb or IFN-gamma. Our findings indicate the injurious role of IFN-gamma for the salivary epithelia of SS patients through the induction of Fas-mediated apoptosis and anoikia.

Antibodies, Monoclonal↗
PubMed2001

Activation of epithelial and myoepithelial cells in the salivary glands of patients with Sjögren's syndrome: high expression of intercellular adhesion molecule-1 (ICAM.1) in biopsy specimens and cultured cells.

ICAM.1 (CD54) is a surface protein expressed on epithelial and other nonhematopoietic cells upon activation and is known to play an important role in the stimulation of T cells by the provision of cellular adhesion and costimulatory support. Sjogren's syndrome (SS) is an autoimmune exocrinopathy, which is characterized by chronic lymphocytic infiltration of exocrine glands and aberrant activation of epithelial tissues. To address the contribution of ICAM.1 in the pathogenesis of SS, the expression of this protein was studied by immunohistochemistry and flow cytometry in minor salivary gland (SG) biopsies as well as in cultured SG epithelial cell (SGEC) lines obtained from 18 SS patients and 16 controls. In biopsies from SS patients (but not controls), strong ICAM.1 was expressed by infiltrating mononuclear cells (52%) and by a significant proportion of periacinar myoepithelial cells (18%). In addition, a patchy pattern of moderate ICAM.1 expression was detected in 31% of ductal epithelia of SS patients. These ICAM.1-expressing epithelial and myoepithelial cells were observed throughout glandular tissues and were not confined in areas proximal to lymphoid infiltrates. In support to an intrinsic activation profile of SGEC in SS, long-term cultured non-neoplastic SGEC lines derived from SS patients displayed significantly upregulated spontaneous expression of ICAM.1, compared to controls (P < 0.05). The high expression of ICAM.1 protein by the salivary epithelium of SS patients is likely suggestive of its important role in the pathogenesis of the disorder. Further, our results support a model of intrinsic activation of salivary epithelial and myoepithelial cells in SS, whereby these cells actively participate in the induction and maintenance of lymphocytic infiltrates of patients.

Autoimmune Diseases↗
PubMed2000

Study of antibody and T cell responses in rabbits immunized with synthetic human B cell epitope analogues of La (SSB) autoantigen.

The aim of this study was to investigate the immunogenicity of four synthetic peptides, representing linear B cell epitopes of the human La/SSB autoantigen: 145-164 aa (p1), 289-308 aa (p2), 301-318 aa (p3) and 349-364 aa (p4), in rabbits. New Zealand White rabbits were immunized with each of the above peptides attached in four copies on tetrameric sequential oligopeptide carriers (SOC) in duplicate. Control immunizations were also performed (one rabbit each, immunized with Freud's complete adjuvant alone or with the SOC carrier alone). Animals were bled at regular intervals and sera were analysed for anti-La/SSB activity by ELISA assays using as antigen the various synthetic peptides, as well as the whole La/SSB protein. Four months after the last immunization, the animals were killed and peripheral blood mononuclear and spleen cells were co-cultured with either the peptides, the SOC carrier, or 27 peptides, covering the entire length of the human La/SSB molecule (23 amino acids long, overlapping by eight residues to each other). A specific, IgG, anti-peptide antibody response was detected, initially directed against the priming peptide, and subsequently expanded to the other La/SSB synthetic peptides. The antibody titres remained high, even 4 months after the last immunization. Sera from rabbits immunized with either p2 or p3 reacted also with the whole La/SSB protein, as was demonstrated by ELISA and immunoblot assays. No reactivities against either Ro60 or Ro52 autoantigen were found. Rabbit spleen cell reacted not only with the epitope used for the immunization but also with other La/SSB peptides. Immunization of rabbits with the major human La/SSB B cell antigenic determinants, linked to SOC carrier, induces strong and sustained antibody and T cell responses against multiple epitopes of the human La/SSB protein. Thus, La/SSB B cell linear epitopes are probably capable also of functioning as T cell epitopes, in this experimental animal.

Amino Acid Sequence↗
PubMed2000

Sjögren's syndrome: autoimmune epithelitis.

Sjögren's syndrome (SS) is a chronic autoimmune disorder of the exocrine glands of unknown aetiology, which is typically associated with focal lymphocytic infiltrates of glandular tissues and autoantibody responses against the Ro(SSA) and La(SSB) ribonucleoproteins. In almost one-third of patients disease involves various extraglandular sites, whereas approximately 5% of patients may also develop malignant B-cell lymphoma. In addition, features of SS are frequently encountered (5-20%) in patients with several other autoimmune rheumatic diseases, and in several respects these 'secondary' forms may be distinct from SS found alone (primary-SS), as well as from each other. The correct diagnosis and management of SS may require consideration from various specialists. Differential diagnosis includes adverse effects of drugs, sarcoidosis, lipoproteinaemias, age-related atrophy, chronic graft-versus-host disease, lymphomas, amyloidosis and infection by human immunodeficiency virus or hepatitis C virus. Based on the sequential application of the validated European classification criteria for SS, a practical algorithm for diagnosis is presented. Despite progress in the understanding of the broad clinicopathological spectrum of the entity, its treatment remains largely empirical and symptomatic. To date, the decision for systemic therapeutic intervention is primarily based on the severity of extraglandular manifestations.

Diagnosis, Differential↗
PubMed1999

Expression of B7 costimulatory molecules by salivary gland epithelial cells in patients with Sjögren's syndrome.

OBJECTIVE: To investigate the expression of B7 costimulatory molecules in the lymphoepithelial lesions of salivary gland (SG) biopsy tissues and in SG epithelial cell lines derived from patients with Sjögren's syndrome (SS). METHODS: B7.1 and B7.2 protein expression was studied by immunohistochemistry in minor SGs obtained from 11 patients with SS and 10 disease control patients with nonspecific sialadenitis and in cultured SG epithelial cell lines obtained from minor SGs from 15 SS patients and 15 control patients. B7.1 and B7.2 messenger RNA (mRNA) expression by SG epithelial cell lines was examined by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: In biopsy tissues from SS patients, but not control patients, ductal and acinar epithelial cells showed increased expression of both B7.1 and B7.2. Intense spontaneous B7.1 protein expression (as well as HLA-ABC, but not B7.2 or HLA-DR) was also found in 73% of SG epithelial cell lines from SS patients versus 13% of those from control patients (P < 0.01). Interferon-y treatment induced, or up-regulated, B7.1, B7.2, and HLA-DR expression in all SG epithelial cell lines tested. B7.1 and B7.2 expression by SG epithelial cell lines was also verified at the mRNA level by RT-PCR. CONCLUSION: Human SG epithelia are intrinsically capable of expressing B7 proteins upon activation. In SS patients, the expression of B7 molecules by SG epithelial tissues and by SG epithelial cell lines indicates the activated status of SG epithelial cells in this disorder and, possibly, their capacity for presenting antigens to T cells.

Adolescent↗
PubMed1999

Sjögren's syndrome.

Sjögren's syndrome is a rather common autoimmune disease primarily characterized by the dysfunction and destruction of exocrine glands associated with lymphocytic infiltrations. The disorder has a quite broad clinical presentation, ranging from glandular disease to systemic involvement and to the development of lymphoid malignancy. This article reviews the current aspects in clinical diagnosis and management and the immunopathogenesis of the disorder.

Diagnosis, Differential↗
PubMed1998

Headache in systemic lupus erythematosus: a controlled study.

Intractable headaches, the so-called 'lupus headaches', have been long thought of as a common and characteristic manifestation of systemic lupus erythematosus (SLE). Seventy-eight patients with SLE, including 10 patients with definite central nervous system (CNS) involvement, and 89 healthy individuals matched for age, sex and socioeconomic status, were studied by a specific questionnaire addressing the characteristics and type of headache. Clinical features of SLE, neurological manifestations and treatment, disease severity and autoantibody profiles were correlated to the presence of headache. One year prevalence of headache was similar between patients (32%) and otherwise healthy individuals (30%). No significant differences regarding frequency, family history of headache and need for analgesic medication were observed. Headache refractory to analgesic treatment, but responsive to corticosteroid regimen, was recorded in only one patient. Clinical and serological features of SLE, including Raynaud's phenomenon and the presence of anticardiolipin antibodies, were not significantly different between headache sufferers and non-sufferers. In the majority of patients reporting headache, anxiety and/or depression co-existed. Episodic tension headache was the most frequent type, while migraine was traced in a quarter of headache sufferers. Neither the presence nor the clinical type of headache was related to, or predictive of, the development of seizures or psychosis. These results indicate that headache is not specifically related to SLE expression or severity, and suggest that accepting the presence even of a severe headache as a neurological manifestation of SLE in the absence of seizures or overt psychosis may result in overestimation of the disease status.

Adult↗
PubMed1996

Antimalarials in Sjögren's syndrome--the Greek experience.

Sjögren's syndrome (SS) is a chronic autoimmune rheumatic disorder characterized by lymphocytic infiltration and destruction of exocrine glands, mainly of salivary and lacrimal glands, leading to dryness of mouth and eyes. It can occur either alone (primary SS) or in association with almost every systemic autoimmune rheumatic SS). Usually, SS patients have slowly progressive disease confined in exocrine glands, however, in approximately one third of primary SS patients the disorder presents a systemic and progressive course with involvement of diverse extraglandular sites and in a small but significant number of patients with lymphoid neoplasia development. Although the aetiology of SS remains unknown, chronic immune system stimulation is thought to play a central role in the pathogenesis of the disorder, as illustrated by several indices of immunological hyperactivity, including various autoantibodies, polyclonal hypergammaglobulinemia and circulating paraproteins. To date, treatment of SS remains largely empirical and symptomatic, and no clinical trial has been proved capable to change the course of the disease. Hydroxychloroquine has been successfully applied for the treatment of arthralgias, myalgias and general constitutive symptoms of SS patients. In an initial small open study, hydroxychloroquine administration has been shown to improve features of immunological hyperreactivity, such as hypergammaglobulinaemia and autoantibody levels. However, large prospective double-blind studies are still needed to assess the long-term efficacy of hydroxychloroquine in preventing extraglandular involvement and lymphoma development in primary SS patients.

Antimalarials↗