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H M Moutsopoulos

Publications and source records attributed to H M Moutsopoulos.

At least 91 records · Page 5Linked to original sources
PubMed2000

Sjögren's syndrome: autoantibodies to cellular antigens. Clinical and molecular aspects.

Autoantibodies to cellular autoantigens are usually found in sera of patients with systemic autoimmune rheumatic diseases. Patients with Sjögren's syndrome (SS) frequently present autoantibodies to both organ and non-organ-specific autoantigens. The most commonly detected autoantibodies are those directed against the ribonucleoproteins Ro/SSA and La/SSB. The presence of the antibodies in SS is associated with early disease onset, longer disease duration, parotid gland enlargement, higher frequency of extraglandular manifestations and more intense lymphocytic infiltration of the minor salivary glands. Over the past several years, the structure and function of these autoantigens have been extensively studied. Several centers, using different techniques, have investigated the B cell epitopes on the protein components Ro 60 kD, Ro 52kD, and La 48 kD. Finally, increased evidence of direct involvement of anti-Ro/SSA and anti-La/SSB autoantibodies in the pathogenesis of tissue injury has been contributed by several studies.

Amino Acid Sequence↗
PubMed2000

B-Cell epitope mapping of DNA topoisomerase I defines epitopes strongly associated with pulmonary fibrosis in systemic sclerosis.

We hypothesized that B-cell epitope mapping of DNA Topoisomerase I (type-I topoisomerase, or Topo I) may define epitopes strongly associated with pulmonary interstitial fibrosis (PIF) in systemic sclerosis (SSc). B-cell epitope mapping of Topo I was performed using 63 20-mer peptides overlapping by eight residues and spanning the entire length of the Topo I sequence. These peptides, coupled to polystyrene pins, were tested for antibody binding by enzyme-linked immunosorbent assays (ELISAs) using immunoglobulin G fractions from anti-Topo I, anticentromere, anti-U3RNP-positive, and normal sera. Four major epitopes were recognized by anti-Topo I sera, but not from the control sera: WWEEERYPEGIKWKFLEHKG (205-224, epitope I), RIANFKIEPPGLFRGRGNHP (349-368, epitope II), PGHKWKEVRHDNKVTWLVSW (397-416, epitope III), and ELDGQEYVVEFDFLGKDSIR (517-536, epitope IV). Peptide-epitopes were then synthesized in their soluble forms and ELISA systems were developed. Epitopes II to IV are localized at highly exposed sites of the Topo I tertiary structure, whereas epitope I is localized at a less accessible site. In a cohort of 81 patients with SSc with clinical data on the evolution of their disease, patients with antibodies in their sera recognizing at least three of the four epitopes had 3.1 times (P = 0.02) the hazard of developing PIF compared with patients whose sera recognized no epitopes or only one or two of the four epitopes. The discrimination was much stronger than that achieved by the simple determination of Topo I antibodies by counterimmunoelectrophoresis and immunoblot (hazard ratio 1.7, P = 0.30) in the same patients. B-cell epitope mapping of the anti-Topo I response has identified four major epitopes which cumulatively show a strong association with the development of PIF in SSc.

Amino Acid Sequence↗
PubMed1999

Mixed cryoglobulinemia in HIV-1 infection: the role of HIV-1.

BACKGROUND: Cryoglobulins are associated with chronic infections. OBJECTIVE: To investigate the prevalence of mixed cryoglobulinemia in patients with HIV-1 infection, the clinical spectrum of cryoglobulinemia in these patients, and the possible role of HIV-1 in cryoglobulin formation. DESIGN: Prospective cohort study. SETTING: Laiko Hospital, Athens, Greece. PATIENTS: 89 patients with HIV-1 infection. MEASUREMENTS: Serum and cryoglobulins were evaluated for antibodies to HIV and hepatitis C virus (HCV), HIV-1, and HCV viral load. RESULTS: Mixed cryoglobulins were detected in 24 patients with HIV-1 infection (27% [95% CI, 18% to 36%]). The HIV-1 viral load was higher in cryoglobulin-positive patients (median, 38.25 x 10(3) copies/mL [25th, 75th percentiles: 13.8 x 10(3) copies/mL, 78.55 x 10(3) copies/mL]) than in cryoglobulin-negative patients (median, 5.3 x 10(3) copies/mL [25th, 75th percentiles: 0.7 x 10(3) copies/mL, 27.2 x 10(3) copies/mL]) (P = 0.001). Antibodies to HIV were detected in all cryoprecipitates, and HIV-1 RNA sequences were identified in 22 of the 23 cryoprecipitates examined. Nine cryoglobulin-positive patients (38% [CI, 19% to 54%]) had clinical manifestations compatible with cryoglobulinemia. CONCLUSIONS: Mixed cryoglobulinemia is common in patients with HIV-1 infection.

Acquired Immunodeficiency Syndrome↗
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

Lymphoma development in Sjögren's syndrome: novel p53 mutations.

OBJECTIVE: Sjögren's syndrome (SS) is a chronic autoimmune disease characterized by lymphocytic infiltrations of the exocrine glands. Disease progression may lead to uncontrolled clonal proliferation of B lymphocytes and development of lymphoma. This study was undertaken to examine the possible involvement of the cell cycle checkpoint genes p53 and p21 in the pathophysiology of the syndrome. METHODS: Protein expression of p53 and p21 was studied, by immunohistochemistry and Western blot analysis, in minor salivary gland (MSG) biopsy specimens from 7 patients with SS and 5 control subjects. In addition, sequence analysis of the p53 gene was performed on DNA samples obtained from MSG biopsy samples of the same 7 patients with SS and from 4 patients with SS and in situ non-Hodgkin's lymphoma (NHL). RESULTS: The study revealed increased protein expression of p53 and p21 in MSG biopsy specimens from patients as compared with controls, while sequence analysis showed that the p53 gene was of the wild type. Furthermore, sequence analysis of the p53 gene from patients with SS and in situ NHL revealed 2 novel mutations in exon 5 of the p53 gene. These mutations are single-base substitutions and appear to be functional since exon 5 is included in the coding region of the p53 gene. CONCLUSION: This is the first report on wild-type p53 gene activation in SS. Our findings indicate a probable role for the DNA damage response genes in the pathogenesis of this syndrome. The novel mutations of the p53 gene implicate dysregulation of this tumor suppressor gene as a possible mechanism for lymphoma development in SS.

Biopsy↗
PubMed1999

Malignant lymphoma in primary Sjögren's syndrome: a multicenter, retrospective, clinical study by the European Concerted Action on Sjögren's Syndrome.

OBJECTIVE: Several reports have noted an increased incidence of malignant lymphoma in patients with Sjögren's syndrome (SS). Each case series has consisted of a limited number of patients with malignant non-Hodgkin's lymphoma (MNHL). In this report, we describe the disease characteristics, the clinical course, and the evolution in 33 patients followed up in 9 European medical centers. METHODS: The pool of MNHL patients from participating centers in a European Concerted Action on SS were analyzed. We report on the disease characteristics, its evolution, prognosis, current treatment practices, and survival. RESULTS: The MNHLs in this study were primarily situated in the marginal zone (48.5%), with the manifestations mostly extranodal (78.8%) and most often identified in the salivary glands (54.6%). Lymphadenopathy (65.6%), skin vasculitis (33.3%), peripheral nerve involvement (24.2%), low-grade fever (25.0%), anemia (48.1%), and lymphopenia (78.6%) were observed significantly more frequently than in the general SS population. Patients with high-to-intermediate grade lymphoma had significantly worse survival (P = 0.041). The presence of B symptoms (fever, night sweats, and weight loss) and a large tumor diameter (>7 cm) were additional independent risk factors for death. CONCLUSION: The novel observations of this study were those related to the type of MNHL, the survival prognosis, and the very high frequency of skin vasculitis, peripheral nerve involvement, anemia, and lymphopenia. Some of the previously reported results on extranodal manifestations were confirmed.

Follow-Up Studies↗
PubMed1999

Anti-phospholipid antibodies in HIV infection and SLE with or without anti-phospholipid syndrome: comparisons of phospholipid specificity, avidity and reactivity with beta2-GPI.

Increased prevalence of anti-phospholipid antibodies (aPL) and increased levels of lipid peroxidation have been described in patients with HIV infection. To assess the binding specificity and avidity of aPL antibodies in HIV infection, sera from 44 HIV-1 infected patients were evaluated for antibodies to cardiolipin (aCL), phosphatidyl serine (aPS), phosphatidyl inositol (aPI) and phosphatidyl choline (aPC) using enzyme linked immunosorbent assay (ELISA) methods. Sera from 30 patients with systemic lupus erythematosus (SLE), but without features of anti-phospholipid syndrome (APS) (SLE/non APS), six with SLE and secondary APS, (SLE/APS) and 11 with primary APS (PAPS) were also evaluated as controls. The resistance of the aPL antibody binding to dissociating agents was evaluated by treating the ELISA wells, after serum incubation with 2 M urea or 0.6 M NaCl for 10 min. An anti-beta2-glycoprotein-I (beta2-GPI) ELISA was used to assess serum reactivity against beta2-GPI, a plasma protein considered as the true antigen of aCL antibodies occurring in APS and SLE patients. The prevalence of aCL, aPS, aPI and aPC antibodies in HIV-1 infection was 36%, 56%, 34% and 43% respectively, which was comparable to that found in SLE/APS and PAPS patients and significantly higher than that observed in SLE/non-APS patients. Anti-beta2-GPI antibodies occurred in 5% of HIV-1 infected vs. 17% in SLE/non-APS (P=0.11), 50% in SLE/APS (P=0.009) and 70% in PAPS patients (P=0.0014). A significant decrease of aPL binding after urea and NaCl treatment was observed in the sera of HIV-1-infected, compared to that of APS patients, indicating that aPL antibodies from HIV-1 infected individuals have low resistance to dissociating agents. In conclusion, aPL antibodies (1) occur in HIV-1 infection; (2) tend to recognize various phospholipids but not beta2-GPI; and (3) are of low resistance to dissociating agents-a finding probably reflecting low antibody avidity. Finally, these, like the autoimmune-type aCL antibodies, tend to recognize the oxidized CL-a finding probably indicating autoantibody generation as a result of neoepitope formation by oxidized PLs.

Adult↗
PubMed1999

Autoantibodies to La/SSB in patients with primary Sjögren's syndrome (pSS) are associated with upregulation of La/SSB mRNA in minor salivary gland biopsies (MSGs).

Recent studies have shown that minor salivary glands (MSGs) of patients with primary Sjögren's syndrome (pSS) are sites of anti-La/SSB autoantibody production. The aim of this study was to investigate the expression of La/SSB mRNA in MSGs of patients with pSS. La/SSB mRNA expression was studied by in situ hybridization in six biopsies of pSS patients with anti-La/SSB antibodies, nine pSS patients without anti-La/SSB and 10 patients with non-specific sialadenitis. Oligonucleotide probes corresponding to c-DNA encoding four linear epitopes of La/SSB (bp 423-471, bp 861-909, bp 903-954 and bp 1048-1092) were utilized. cDNA encoding linear epitopes of Ro52 (bp 786-837), Ro60 (bp 654-702) and the housekeeping genes of Sm and GAPDH were used as controls. The results were expressed as percent of positive cells by image analysis. Serum levels of anti-La/SSB autoantibodies were correlated with the presence and the intensity of La/SSB mRNA labeling. All pSS patients with anti-La/SSB antibodies in their serum expressed mRNA transcripts of epitopes 301-318 aa and 349-364 aa (encoded by the cDNA probes bp 903-954 and bp 1048-1092 respectively), predominantly in acinar and mononuclear cells of MSGs. These epitopes are the major targets of anti-La/SSB antibodies. Serum levels of anti-La/SSB antibodies were correlated with the number of positively stained cells in MSGs. Two of the nine pSS patients without anti-La/SSB autoantibodies and 2/10 non-pSS patients expressed the mRNA of the La/SSB molecule. The probes of RO52 and Ro60 epitopes did not react, while mRNA encoding the housekeeping genes of Sm and GAPDH was positive in all samples. In conclusion, pSS patients with anti-La/SSB antibodies showed upregulation of La/SSB mRNA in acinar and mononuclear cells of MSGs. Thus, active synthesis of La/SSB in MSGs of pSS seems to play an important role in the autoimmune response of the affected tissues.

Autoantibodies↗
PubMed1999

Peptide carriers: A helicoid-type sequential oligopeptide carrier (SOC(n)) for multiple anchoring of antigenic/immunogenic peptides.

A new peptide carrier with three-dimensional predetermined structural motif has been constructed by the repetitive Lys-Aib-Gly moiety. The sequential oligopeptide carrier (SOC(n)), (Lys-Aib-Gly)(n), adopts a distorted 3(10)-helical conformation and the Lys-N(epsilon)H(2) anchoring groups exhibit defined spatial orientations. Conformational analysis of the SOC(n) conjugates showed that the coupled peptides retain their initial "active" structure, while prevalence of one conformer was also observed. It is concluded that the beneficial structural elements of SOC(n) induce a favorable arrangement of the conjugated peptides, so that potent antigens and immunogens are generated.

Amino Acid Sequence↗
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↗
PubMed1999

HLA associations of anti-beta2 glycoprotein I response in a Greek cohort with antiphospholipid syndrome and meta-analysis of four ethnic groups.

Using molecular typing, we evaluated the strength of class II HLA associations in 67 Greek patients with antiphospholipid syndrome (APS), 54 of whom had antibodies against beta2-glycoprotein I (beta2GPI), as compared to 246 controls. To further clarify and delineate HLA associations of the beta2GPI response, we combined these data with individual patient data from three other ethnic groups including an additional 74 patients with beta2GPI response and 403 ethnically matched controls of white, African-American, and Mexican-American origin in a formal meta-analysis. The major alleles associated with anti-beta2GPI response are HLA-DQA1*03 (in particular *0301) and the HLA-DRB1*1302-DQB1*0604 haplotype, while protection against developing an anti-beta2GPI response is related primarily to the HLA-DRB1*0101-DQA1*0101 haplotype and the HLA-DRB1*1101 allele. These effects are not significantly heterogeneous across ethnic groups. The previously observed association with HLA-DQB1*0302 may simply reflect linkage disequilibrium with HLA-DQA1*0301 and the previously reported HLA-DQB1*06 effect is limited to HLA-DQB1*0604/0605, while HLA-DQB1*0602 is unlikely to be important. The meta-analysis clearly documents that the anti-beta2GPI response is determined by a few specific class II alleles and haplotypes.

Antiphospholipid Syndrome↗
PubMed1999

A new helicoid-type sequential oligopeptide carrier (SOC(n)) for developing potent antigens and immunogens.

A new class of sequential oligopeptide carriers (SOC(n)) for anchoring antigenic/immunogenic peptides has been constructed. The carrier, formed by the repetitive Lys-Aib-Gly moiety, is designed to display a predetermined 3D structure, so that the attached peptides would obtain a defined spatial orientation. Conformational analysis showed that SOC(n) adopt a distorted 3(10)-helical structure, while the coupled peptides preserve their original 'active' structure. Coupling to the carrier may also result to the enhancement of one conformer of the anchored peptide. It is concluded that the structure of SOC(n) offers an optimal presentation of the attached peptides, so that potent antigens or immunogens are generated.

Amino Acid Sequence↗
PubMed1999

Rheumatoid arthritis in the elderly.

Rheumatoid arthritis of late onset (LORA) referred as the subset of rheumatoid arthritis with age of onset over 60 years old, seems to differ from young onset disease (YORA) by a more equal sex distribution, a higher frequency of abrupt disease onset, more large joint complaints and less extraarticular features. Different immunogenetic associations are also reported between the two age groups. The percentages of rheumatoid factor (RF) and C-reactive protein (CRP) positivity differ in various surveys in both groups examined. Favorable prognostic factors could be considered the absence of rheumatoid factor activity and the presence of pitting edema of the hands. Greek patients with LORAS appear not to have differences in comparison to their younger counterparts. Disease modifying drugs and low doses of prednisone are the mainstream of therapy with need for further caution in the aged group.

Age of Onset↗
PubMed1999

CD4 cytotoxic and dendritic cells in the immunopathologic lesion of Sjögren's syndrome.

The existence of CD4+ T lymphocytes with cytotoxic activity in minor salivary gland (MSG) biopsies from Sjögren's syndrome (SS) patients was investigated using in situ double immunohistochemistry technique. The presence of dendritic cells (DC) in SS lesions was examined by using single and double immunohistochemistry methods and a panel of different MoAbs to specific cell surface markers (i.e. CD3, CD11c, DRC). Furthermore, the ultrastructural morphology of DC was characterized by electron microscopy (EM). Immunogold labelling technique using the DRC surface marker was also applied. Finally, we investigated the existence of germinal centres (GC) in the salivary gland lesions of SS patients. Seven patients with primary SS and five patients with non-specific sialadenitis were the subjects of this study. Our results indicate the existence of a CD4+ cytotoxic cell population that utilizes perforin-mediated cell destructions as they expressed perforin mRNA. Quantitative analysis of these cells revealed that they comprised approximately 20% of the existing T lymphocytes. We also identified a population of CD4+ T cells that expressed the CD11c activation marker. Furthermore, we observed a distinct cell subtype which expressed the DRC cell surface marker. These cells had the characteristic ultrastructural morphology of DC and were DRC+ when examined by immunoelectron microscopy. Finally, the formation of GC structures in the histopathologic lesions of the salivary glands was observed. The above findings indicate that both CD4+ cytotoxic T lymphocytes (CTL) and DC may be involved in the initiation and perpetuation of SS pathogenesis. Moreover, the formation of GC in the lesions reveals a possible mechanism for in situ differentiation and proliferation of activated B lymphocytes.

Biopsy↗
PubMed1999

Systemic lupus erythematosus: clinical features in patients with a disease duration of over 10 years, first evaluation.

OBJECTIVE: Most information available about the disease course of patients with systemic lupus erythematosus (SLE) is restricted to the first 5 yr after disease onset. Data about the disease course 10 yr after disease onset are rare. The aim of this multicentre study was to describe the outcome of SLE patients with a disease duration of >10 yr. METHODS: Outcome parameters were the SLE Disease Activity Index (SLEDAI), the European Consensus Lupus Activity Measure (ECLAM), the Systemic Lupus International Collaborative Clinics/American College of Rheumatology Damage Index (SLICC/ACR), a global damage index (DI) and required treatment. In 10 different European rheumatology centres, all SLE patients who were evaluated in the last 3 months of 1994, and who had been diagnosed with SLE at least 10 yr ago, were included in the study. RESULTS: It should be stressed that our results are confined to a patient cohort, defined by a disease duration of at least 10 yr, and who are still under clinical care at the different centres in Europe. These SLE patients still showed some disease activity, related to symptoms of the skin and musculoskeletal systems, next to the presence of renal involvement. A total of 72% of the patients needed treatment with prednisolone (</=7.5 mg). The cumulative damage was overall related to clinical features of the central nervous system (14%) and renal involvement (14%), next to deforming arthritis (14%), osteoporosis (15%) and hypertension (40%). The prevalences of obesity, Cushing appearance and diabetes are highly suggestive that the ongoing treatment and that in the past might have had an impact on the total sum of end-organ damage. CONCLUSIONS: After 10 yr, a high proportion of patients in our cohort continued to show evidence of active disease, defined by the SLEDAI as well as ECLAM. The DI was related to the involvement of the central nervous system, renal involvement and the presence of hypertension.

Adult↗