Systemic sclerosis with bilateral hilar adenopathy.
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Adult↗
Biomedical subjects
L I Sakkas
Publications and source records attributed to L I Sakkas.
Apoptosis in chronic rejection of human cardiac allografts.
BACKGROUND: We investigated the role of apoptosis (programed cell death) in the pathogenesis of chronic rejection. METHODS: Epicardial coronary arteries from cardiac allografts with chronic rejection were examined for apoptosis by the TUNEL assay. Double labeling was carried out using anti-CD3, anti-CD68, and anti-von Willenbrand factor (vWF) monoclonal antibodies. Additional immunostaining was carried using anti-Fas, anti-Fas-L, and anti-Bcl-2 monoclonal antibodies. Apoptosis-associated oligonucleosomal DNA degradation was assessed by DNA agarose gel electrophoresis. The transcription level of apoptosis-related caspase genes were determined using microarrays. RESULTS: Apoptotic cells (TUNEL+) were detected within the arterial wall and in perivascular areas. Double labeling demonstrated that apoptotic cells included T cells (CD3+), monocyte/macrophages (CD68+), and vascular endothelial cells (VWF+). Numbers and densities of TUNEL+ cells did not correlate with the degree of arterial stenosis. Apoptosis-associated oligonucleosomal DNA degradation was assessed by agarose gel electrophoresis of DNA, which showed DNA fragments of approximately 180 bp and multimers thereof (DNA laddering gel), which are characteristic for DNA fragmentation in apoptotic cells. Microarray analysis demonstrated that the apoptosis related caspases 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, were all transcribed (caspases 8, 9, and 10 were highly up-regulated). These results are consistent with the involvement of apoptosis in chronic rejection. Immunoreactivity for Fas/Fas-L was present at the sites of apoptotic cells. Immunoreactivity for Bcl-2 was present in areas with very few apoptotic cells. CONCLUSIONS: Apoptotic cells include T cells, monocyte/macrophages, and endothelial cells. Apoptosis, likely through the Fas/Fas-L system, is involved in the pathogenesis of chronic rejection in cardiac allografts.
Adult↗
Differential distribution of the neuron-associated class III beta-tubulin in neuroendocrine lung tumors.
OBJECTIVE: To study the immunoreactivity profile of the neuron-associated class III beta-tubulin isotype (beta III) in epithelial lung tumors. DESIGN: One hundred four formalin-fixed, paraffin-embedded primary and metastatic lung cancer specimens were immunostained with an anti-beta III mouse monoclonal antibody (TuJ1) and an anti-beta III affinity-purified rabbit antiserum. Paraffin sections from fetal, infantile, and adult nonneoplastic lung tissues were also examined. RESULTS: In the fetal airway epithelium, beta III staining is detected transiently in rare Kulchitsky-like cells from lung tissues corresponding to the pseudoglandular and canalicular but not the saccular or alveolar stages of development. beta III is absent in healthy, hyperplastic, metaplastic, and dysplastic airway epithelium of the adult lung. In contrast, beta III is highly expressed in small cell lung cancer, large cell neuroendocrine carcinoma, and in some non-small cell lung cancers, particularly adenocarcinomas. There is no correlation between expression of beta III and generic neuroendocrine markers, such as chromogranin A and/or synaptophysin, in pulmonary adenocarcinomas. Also, focal beta III staining is present in primary and metastatic adenocarcinomas (to the lung) originating in the colon, prostate, and ovary. beta III is expressed to a much lesser extent in atypical carcinoids and is rarely detectable in typical carcinoids and squamous cell carcinomas of the lung. The distribution of beta III in small cell lung cancer and adenocarcinoma metastases to regional lymph nodes and brain approaches 100% of tumor cells, which is substantially greater than in the primary tumors. CONCLUSIONS: In the context of neuroendocrine lung tumors, beta III immunoreactivity is a molecular signature of high-grade malignant neoplasms (small cell lung cancer and large cell neuroendocrine carcinoma) although its importance in atypical carcinoids must be evaluated further. In addition, beta III may be a useful diagnostic marker in distinguishing between small cell lung cancers and certain non-small cell lung cancers (poorly differentiated squamous cell carcinomas), especially in small biopsy specimens. To our knowledge, beta III is the only tumor biomarker that exhibits a substantially more widespread distribution in poorly differentiated than in better differentiated pulmonary neuroendocrine tumors. However, the significance of beta III phenotypes in non-small cell lung cancer, particularly adenocarcinoma, with respect to neuroendocrine differentiation and prognostic value, requires further evaluation.
Adult↗
Increased levels of alternatively spliced interleukin 4 (IL-4delta2) transcripts in peripheral blood mononuclear cells from patients with systemic sclerosis.
Recent in vitro studies have shown that interleukin 4 (IL-4) induces and gamma interferon (IFN-gamma) inhibits collagen production. To define the TH1(IFN-gamma) and TH2(IL-4) cytokine profiles in systemic sclerosis (Sscl), a disease characterized by widespread fibrosis, we investigated IL-4 and IFN-gamma transcripts in peripheral blood mononuclear cells and plasma protein levels in 13 patients with Sscl. Two previously identified IL-4 transcripts, a full-length transcript and an alternatively spliced (truncated) transcript (designated IL-4delta2), were identified in patients and normal controls. Significantly increased levels of total IL-4 transcripts (full-length plus IL-4delta2 transcripts) were found in patients with Sscl in comparison to those found in healthy controls (P = 0.003), and this increase was primarily due to an increase in the level of the alternatively spliced IL-4delta2 form. The IL-4delta2/full-length-IL-4 transcript ratio was significantly increased in Sscl patients (P < 0.0001, versus healthy controls). Sequencing analysis revealed that the frequency of IL-4 clones carrying the IL-4delta2 transcript was also substantially increased in patients with Sscl. Plasma IL-4 protein levels were increased in Sscl patients compared to those in healthy controls (P = 0.001) and correlated with total IL-4 transcript levels. The up-regulation of the fibrogenic IL-4 (a TH2 cytokine) in Sscl suggests a pathogenic role for IL-4 in this disease.
Adult↗
Interleukin-12 is expressed by infiltrating macrophages and synovial lining cells in rheumatoid arthritis and osteoarthritis.
TH1 cytokines have recently been detected in rheumatoid arthritis (RA) and osteoarthritis (OA). For this reason we studied the TH-1-promoting cytokine IL-12 in synovial membranes from patients with RA and OA. IL-12 transcripts and protein were analyzed by reverse transcriptase-polymerase chain reaction (PCR) and immunohistochemistry, respectively. In addition, IL-12 transcripts were quantitated by competitive PCR. IL-12 transcripts (p40) were detected in 8 of 13 patients with RA and in 10 of 18 patients with OA. Their levels did not differ significantly between RA and OA. IL-12 heterodimer protein was detected by immunostaining using an anti-IL-12p70 mAb. Double labeling with anti-IL-12p70 and anti-CD68 mAbs showed that synovial lining cells and monocytes/macrophages expressed IL-12 p70 protein. The presence of IL-12 p70 protein in the synovial membranes of patients with RA and OA suggests that IL-12 may play an important immunoregulatory role in these diseases by perpetuating inflammation.
Adult↗
T cells and T-cell cytokine transcripts in the synovial membrane in patients with osteoarthritis.
The synovial membrane in osteoarthritis (OA) often exhibits inflammatory infiltrates, but the role of T cells in these infiltrates is not known. T-cell activation antigens were analyzed by immunohistochemistry, and T-cell cytokine transcripts were measured by competitive PCR in synovial membranes from patients with OA and rheumatoid arthritis (RA). Lymphoid cell aggregates, containing primarily CD3+ T lymphocytes, were found in 65% of patients with OA. Mononuclear cells expressing the activation antigens CD69, CD25, CD38, CD43, CD45RO, and HLA class II were present in both patient groups, although in higher numbers in patients with RA. Interleukin 2 (IL-2) transcripts were found in 10 of 18 patients with OA versus 12 of 13 patients with RA (P = 0.03). Gamma interferon (IFN-gamma) transcripts were detected in 9 of 18 patients with OA versus 10 of 13 patients with RA (not significant), whereas IL-10 transcripts were found in nearly all patients. IL-4 and IL-5 were not detected in any patients. The levels of IFN-gamma and IL-2 transcripts, normalized for T-cell number equivalents, were not statistically different between OA and RA, but the levels of IFN-gamma, normalized for total cell number equivalents, were lower in OA than in RA (P = 0.01). Synovial membranes that expressed IL-2 and IFN-gamma transcripts were more likely to have heavier infiltrations of T cells and cells bearing activation markers than synovial membranes that did not express these cytokines. The presence of activated T cells and TH1 cytokine transcripts in chronic joint lesions of patients with OA suggests that T cells contribute to chronic inflammation in a large proportion of these patients.
Aged↗
Adult onset Still's disease. 16 cases.
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Adult↗
Immunopathogenesis of juvenile rheumatoid arthritis: role of T cells and MHC.
Juvenile rheumatoid arthritis (JRA) is defined as chronic arthritis of unknown etiology appearing in patients less than 16 years of age. The disease is heterogeneous and is classified as pauciarticular, polyarticular, or systemic-onset disease. A few lines of evidence suggest that T cells are involved in the pathogenesis of the disease. T cells infiltrating the synovial membrane bear markers of activation and produce cytokines. The association of particular subtypes of JRA with certain HLA class II alleles provides strong evidence in favor of T cell involvement through an HLA-peptide-T cell receptor complex. Limited data from a few patients with JRA on T cell receptor transcripts from synovial membrane or synovial fluid cells point towards oligoclonality. This further supports the concept that T cells infiltrating the synovial membrane or extravasating into synovial fluid in patients with JRA reflect antigen-driven T cell proliferation.
Adolescent↗
Cancer in families with systemic sclerosis.
In recent reports, researchers described an increased incidence of cancer in patients with systemic sclerosis (SScl). For this article, the authors investigated the frequencies of cancer in first-degree relatives of patients with SScl in a case-control family study. Information was obtained by personal interview of the probands. Fifty-three subjects with cancer were reported among 814 relatives of patients, compared with 17 subjects among 860 relatives of age- and sex-matched control subjects (age and sex adjusted odds ratio = 3.79, 95% confidence interval = 2.16-6.66, P < 0.001). Forty-six patients (27.7%) had one or more relatives with cancer, compared with 15 control subjects (9%). Within the limitations of the methods used, the researchers found an increased risk for cancer in first-degree relatives of patients with SScl. This suggests that a common genetic or environmental factor may be involved in the development of both cancer and SScl.
Adult↗
Consider the study populations when assessing results: comment on the article by Drosos et al.
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Arthritis, Rheumatoid↗
T-cell antigen receptors in rheumatoid arthritis.
Rheumatoid arthritis (RA) is a systemic disease of unknown etiology characterized by chronic inflammation mainly in the joints. Several lines of evidence suggest that T cells are involved in the pathogenesis of the disease. RA is associated with certain HLA-DR alleles. Studies analyzing T-cell receptor transcripts in RA have found biased or preferential usage of certain V alpha and/or V beta gene segments by T cells infiltrating the synovial membrane or extravasating into the synovial fluid compared to peripheral blood. In certain patients few T-cell antigen receptor (TCR) clones dominated the infiltrating T cells, suggesting that T cells from the synovial membrane or the synovial fluid comprise oligoclonal populations of T cells. However, other studies have found a polyclonal population of T cells. In interpreting these results the phase of the disease (early vs. late RA), the source of T cells and the limitations of the methods used in these studies should be taken into consideration. However, it appears that synovial T cells comprise oligoclonal populations of T cells and that there is a bias towards particular TCR gene segments, although a specific TCR gene segment in RA has not emerged.
Arthritis, Rheumatoid↗
Gold induced nephropathy in rheumatoid arthritis and HLA class II genes.
OBJECTIVES: To elucidate the role of HLA-DRB, -DQA, and -DQB genes in patients with rheumatoid arthritis (RA) who developed gold induced nephropathy. METHODS: Southern blot analysis of HLA-DRB, -DQA, and -DQB genes was performed on DNA from 27 patients with RA with gold induced nephropathy, 37 patients with RA who were treated with gold but did not develop nephropathy, and 122 ethnically matched normal subjects. RESULTS: The 4.7 kb DQA1/Taq I band associated with DQA1*0501 and DR3 and DR5 was found in 16 (59%) patients with gold induced nephropathy compared with five (14%) patients without gold induced nephropathy. CONCLUSION: It is concluded that HLA-DQA region genes may be an important susceptibility factor for the development of gold induced nephropathy in patients with RA.
Arthritis, Rheumatoid↗
Pulse cyclophosphamide therapy in Wegener's granulomatosis: a pilot study.
Five patients with Wegener's granulomatosis (WG) have been treated with 6- to 8-monthly pulses of intravenous cyclophosphamide (CP) and glucocorticoids in an open pilot study. One patient achieved complete remission sustained during 30 months of follow-up; one patient had features of active disease after 28 months of remission; two patients after an initial remission had an exacerbation of the disease and received continuous oral administration of CP, and one patient required continuous oral CP to control the symptoms. These results suggest that this regimen may not achieve a high degree of sustained remission in patients with WG.
Administration, Oral↗
Immunoglobulin heavy chain gene polymorphisms in Italian patients with psoriasis and psoriatic arthritis.
A polymorphism of the switch region of the mu IgH gene (S mu) is associated with arthritis in English patients with psoriasis. In this study, Italian patients with psoriasis alone (PS) or psoriatic arthritis (PSA) were analysed by Southern blot using DNA probes for the S mu region and a hypervariable locus 5' of the joining (JH) region of IgH (5' JH). No association between PSA and IgH gene polymorphisms was found. However, an association was found between PS and a genotype of the 5' JH region (Fisher's P = 0.0002, RR = 27). Additional DNA markers around the S mu region may reveal more accurate markers for PS or PSA.
Arthritis, Psoriatic↗
Application of polymerase chain reaction (PCR) to HLA-C locus typing.
Polymerase chain reaction/oligonucleotide typing was used to identify HLA-Cw*0601 (Cw6) in patients with psoriasis and psoriatic arthritis. The assignment of HLA-Cw*0601 was established by the concordant presence of codons for alanine (position 73), lysine (position 80) and tryptophan (position 97). The frequencies of all three codons were increased in the patient groups.
Arthritis, Psoriatic↗
Association of osteoarthritis with homozygosity for a 5.8 kb Taq I fragment of the alpha 1-antichymotrypsin gene.
The genes coding for the protease inhibitors alpha 1-antitrypsin (A1AT) and alpha 1-antichymotrypsin (A1ACT) were analysed by Southern blot in patients with rheumatoid arthritis, psoriatic arthritis, psoriasis without arthritis, polymyalgia rheumatica and generalized osteoarthritis. The probe/restriction enzyme combinations used were the 4.6 kb 5' fragment of the A1AT gene with the Sst I enzyme, the 6.5 kb 3' fragment of the same gene with Taq I and the 3.4 kb fragment of A1ACT with Taq I. The frequency of homozygous genotype for the 5.8 kb A1ACT band was increased in osteoarthritis (62.8% versus 36.8%, P = 0.01, relative risk = 2.9, aetiological fraction = 0.41). No other disease association was found with any marker. This suggests that the A1ACT gene may influence susceptibility to generalized osteoarthritis.
Alleles↗
Immunogenetics of polymyalgia rheumatica.
Evidence suggests that polymyalgia rheumatica (PMR) may be an immune-mediated disease. Therefore, the role of HLA class II genes, the switch region of immunoglobin mu and alpha 1 heavy chain as the T-cell receptor (TcR) genes were investigated by Southern blot analysis. The frequency of DR4 specificity was increased in PMR (67.4% versus 30.3%; P = 0.00017). No association was found with the DQA and DQB genes, the switch region of immunoglobulin mu and alpha 1 heavy chain genes, and the TcR alpha, beta and gamma genes. This study suggests that HLA-DR4 is an important susceptibility factor for PMR. Further studies are needed to elucidate the role of Ig and TcR genes.
Alleles↗
Interferon-gamma activates co-ordinate transcription of HLA-DR, DQ, and DP genes in cultured keratinocytes and requires de novo protein synthesis.
The purpose of this study was to determine the effect of interferon-gamma on keratinocyte major histocompatibility complex class II gene transcription. Transformed human foreskin keratinocytes (SVK14 cells) were incubated with recombinant IFN-gamma in the presence or absence of the protein synthesis inhibitor cycloheximide. Total cellular RNA was extracted from the cells and Northern blot analysis carried out using cDNA probes for all the functional class II genes. We report that 1) there is co-ordinate activation of all the class-II genes; 2) the rate of transcription varies between gene loci after activation; and 3) de novo protein synthesis is required for IFN-gamma activation of class II transcription.
Cell Line, Transformed↗