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Journal Article 2009; 30(3): 275-283 PubMed PMID: 19855349 Citation  Keywords:  Cell Differentiation, Cell Shape, Dendritic Cells:cytology, Epithelial Cells:cytology, Humans, Macrophages:cytology, T-Lymphocytes:cytology, Thymus Gland:cytology,.   

: The thymus is the central organ of the immune system. It is essential for the development and maintenance of normal immune system, especially cell-mediated immunity. From the morphological point of view, the thymus is divided into two main compartments, cortex and medulla. The thymic microenvironment consists of a network of reticular epithelial cells and other fixed and free cells. The microenvironment of thymus is very important for the selection and maturation of T cells. T cell differentiation occurs via T cell receptors. The major histocompatibility complex participates in interactions between T cells and thymic epithelial cells, in addition to interactions between T cells and dendritic cells, macrophages and myoid cells. The neuroendocrine system regulates early T cell differentiation by the transcription of neuroendocrine genes in the stromal network and expression of cognitive receptors by immature T cells. This work briefly summarizes morphological and ultrastructural characteristics of thymic epithelial cells, dendritic cells, macrophages and myoid cells. It is accompanied by the authors' own photomicrographs and electronmicrograph from a transmission electron microscope. All of these cells play a critical role in the proliferation, differentiation and selection of precursor cells in the T-cell lineage, but the precise mechanisms not well understudood....

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Comparative Study 2008; 29(2): 240-245 PubMed PMID: 18404145 Citation  Keywords:  Adult, Aged, CD4 Lymphocyte Count, CD4-Positive T-Lymphocytes:cytology, Case-Control Studies, Female, Flow Cytometry, Humans, Interleukin-2 Receptor alpha Subunit:metabolism, Male, Middle Aged, Neoplasms:blood, Phenotype, Prognosis, Survival Analysis, T-L.   

AIM: Regulatory T cells (Treg) that prevent autoimmune diseases by suppression of self-reactive T cells may also suppress the immune response against cancer. Experimental tumor models in mice revealed that Tregs are potent inhibitors of an antitumor immune response. The purpose of the study was to identify a CD4+ population of regulatory T cells expressing high levels of CD25(CD4+CD25 high) in the peripheral blood of cancer patients and provide the opportunity to determine whether cancer patients exhibit an expanded CD4+CD25high pool.

METHODS: The frequency of CD4+CD25high in the peripheral blood of 62 cancer patients and 15 healthy donors was determined by flow cytometry.

RESULTS: Compared with healthy donors, cancer patients have an increasing prevalence of CD4+CD25high T cells in the peripheral blood with characteristics of Tregs, i.e. they are CD45-RA(), CD69(-). Among patients, those with higher percentages of CD4+CD25high T cells had a poor prognosis than did those with lower percentages.

CONCLUSION: We provide evidence of an increased pool of CD4+CD25high in the peripheral blood of cancer patients, which may be related to immunosuppression and tumor progress in cancer patients. This finding suggests that the use of immunomodulatory therapy to treat cancer patients may be an effective strategy....

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Journal Article 2007; 28(4): 456-462 PubMed PMID: 17693979 Citation  Keywords:  Adult, Case-Control Studies, Cell Nucleus:physiology, Fatigue Syndrome, Chronic:metabolism, Female, Humans, Inflammation:metabolism, Lymphocytes:drug effects, Male, Middle Aged, NF-kappa B:metabolism, Neurasthenia:physiopathology, Oxidative Stress:physiol.   

: There is now some evidence that chronic fatigue syndrome is accompanied by an activation of the inflammatory response system and by increased oxidative and nitrosative stress. Nuclear factor kappa beta (NFkappabeta) is the major upstream, intracellular mechanism which regulates inflammatory and oxidative stress mediators. In order to examine the role of NFkappabeta in the pathophysiology of CFS, this study examines the production of NFkappabeta p50 in unstimulated, 10 ng/mL TNF-alpha (tumor necrosis factor alpha) and 50 ng/mL PMA (phorbolmyristate acetate) stimulated peripheral blood lymphocytes of 18 unmedicated patients with CFS and 18 age-sex matched controls. The unstimulated (F=19.4, df=1/34, p=0.0002), TNF-alpha-(F=14.0, df=1/34, p=0.0009) and PMA-(F=7.9, df=1/34, p=0.008) stimulated production of NFkappabeta were significantly higher in CFS patients than in controls. There were significant and positive correlations between the production of NFkappabeta and the severity of illness as measured with the FibroFatigue scale and with symptoms, such as aches and pain, muscular tension, fatigue, irritability, sadness, and the subjective feeling of infection. The results show that an intracellular inflammatory response in the white blood cells plays an important role in the pathophysiology of CFS and that previous findings on increased oxidative stress and inflammation in CFS may be attributed to an increased production of NFkappabeta. The results suggest that the symptoms of CFS, such as fatigue, muscular tension, depressive symptoms and the feeling of infection reflect a genuine inflammatory response in those patients. It is suggested that CFS patients should be treated with antioxidants, which inhibit the production of NFkappabeta, such as curcumin, N-Acetyl-Cysteine, quercitin, silimarin, lipoic acid and omega-3 fatty acids....

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Journal Article 2007; 28(4): 463-469 PubMed PMID: 17693978 Citation  Keywords:  Adult, Case-Control Studies, Cyclooxygenase 2:metabolism, Depression:physiopathology, Fatigue:physiopathology, Fatigue Syndrome, Chronic:enzymology, Female, Humans, Inflammation:metabolism, Lymphocytes:metabolism, Male, Middle Aged, NF-kappa B:metabolism,.   

: Chronic fatigue syndrome (CFS) is a medically unexplained disorder, characterized by profound fatigue, infectious, rheumatological and neuropsychiatric symptoms. There is, however, some evidence that CFS is accompanied by signs of increased oxidative stress and inflammation in the peripheral blood. This paper examines the role of the inducible enzymes cyclo-oxygenase (COX-2) and inducible NO synthase (iNOS) in the pathophysiology of CFS. Toward this end we examined the production of COX-2 and iNOS by peripheral blood lymphocytes (PBMC) in 18 CFS patients and 18 normal volunteers and examined the relationships between those inflammatory markers and the severity of illness as measured by means of the FibroFatigue scale and the production of the transcription factor nuclear factor kappa beta (NFkappabeta). We found that the production of COX-2 and iNOS was significantly higher in CFS patients than in normal controls. There were significant and positive intercorrelations between COX-2, iNOS and NFkappabeta and between COX-2 and iNOS, on the one hand, and the severity of illness, on the other. The production of COX-2 and iNOS by PBMCs was significantly related to aches and pain, muscular tension, fatigue, concentration difficulties, failing memory, sadness and a subjective experience of infection. The results suggest that a) an intracellular inflammatory response in the white blood cells plays an important role in the pathophysiology of CFS; b) the inflammatory response in CFS is driven by the transcription factor NFkappabeta; c) symptoms, such as fatigue, pain, cognitive defects and the subjective feeling of infection, indicates the presence of a genuine inflammatory response in CFS patients; and d) CFS patients may be treated with substances that inhibit the production of COX-2 and iNOS....

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Journal Article 2007; 28(4): 477-483 PubMed PMID: 17693977 Citation  Keywords:  Adult, Antigens, CD:metabolism, Antigens, CD19:metabolism, Antigens, CD3:metabolism, Antigens, CD4:metabolism, Antigens, CD8:metabolism, Antigens, Differentiation, T-Lymphocyte:metabolism, Biomarkers:metabolism, Case-Control Studies, Fatigue Syndrome, Chr.   

: There is some evidence that patients with chronic fatigue syndrome (CFS) suffer from immune abnormalities, such as immune activation and decreased immune cell responsivity upon polyclonal stimili. This study was designed to evaluate lymphocyte activation in CFS by using a CD69 expression assay. CD69 acts as a costimulatory molecule for T- and natural killer (NK) cell activation. We collected whole blood from CFS patients, who met CDC criteria, and healthy volunteers. The blood samples were stimulated with mitogens during 18 h and the levels of activated T and NK cells expressing CD69 were measured on a Coulter Epics flow cytometer using a three color immunofluorescence staining protocol. The expression of the CD69 activation marker on T cells (CD3+, CD3+CD4+, and CD3+CD8+) and on NK cells (CD45+CD56+) was significantly lower in CFS patients than in healthy subjects. These differences were significant to the extent that a significant diagnostic performance was obtained, i.e. the area under the ROC curve was around 89%. No differences either in the number of leukocytes or in the number or percentage of lymphocytes, i.e. CD3, CD4, CD8 and CD19, could be found between CFS patients and the controls. Patients with CFS show defects in T- and NK cell activation. Since induction of CD69 surface expression is dependent on the activation of the protein kinase C (PKC) activation pathway, it is suggested that in CFS there is a disorder in the early activation of the immune system involving PKC....

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Journal Article 2007; 28(4): 422-426 PubMed PMID: 17693974 Citation  Keywords:  Adolescent, Anorexia Nervosa:immunology, Antibodies:immunology, Antigens, CD28:immunology, Antigens, CD3:immunology, CD4-Positive T-Lymphocytes:metabolism, Calcium:metabolism, Case-Control Studies, Child, Female, Humans, Interleukin-2:metabolism, Lymphocy.   

OBJECTIVES: Anorexia nervosa (AN), a disease of chronic human starvation has a deep impact on the function of several organ systems. We hypothesized that disturbed cellular activation may contribute to complications in AN. We tested our assumption on short-term activation kinetics of lymphocytes.

PATIENTS AND METHODS: Blood was taken from 11 AN and 10 healthy adolescents. Peripheral blood mononuclear cells were isolated and CD4+ lymphocytes were then activated with phythohemagglutinin for the determination of calcium-influx and membrane potential. Moreover, cells were also activated by anti-CD3/anti-CD28 coated beads and three days after the prevalence of interleukin-2 positive CD4+ cells were determined.

RESULTS: After activation, more time was required to reach maximal calcium content in CD4+ cells of AN patients than in those of controls (control vs. AN (median, range): 86 [45-232] vs. 215 [59-235] second, p<0.05), but the rate of membrane potential alteration was similar. The number of interleukin 2 positive CD4+ cells was lower in AN (11.50 [7.60-15.30] vs. 13.50 [12.00-22.00] %, p<0.05). No association was detected between cell activation and any of clinical or anthropometric data of AN patients.

CONCLUSIONS: These results suggest that AN may have an impact on calcium handling of the cells and, hence, cell activation characteristics. We assume that altered calcium flux kinetics may contribute to complications present in AN....

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Journal Article 2006; 27(Suppl 1): 7-16 PubMed PMID: 17261999 Citation  Keywords:  Biomarkers:blood, Dental Amalgam:toxicity, Environmental Pollutants:toxicity, Humans, Hypersensitivity:diagnosis, Inflammation, Lymphocyte Activation, Metals:toxicity, T-Lymphocytes:immunology, Titanium:toxicity,.   

: Environmental factors are recognized as a cause of the increasing frequency of allergic and autoimmune diseases. In addition to external pollutants, metal ions released from dental restorations or from other body implants might trigger inflammation in susceptible subjects. In humans, genes governing metal-induced inflammation and autoimmunity are not yet known. In clinical praxis, metal-sensitive patients will present various symptoms ranging from oral mucosal changes and skin disease to excessive fatigue and autoimmune diseases. Since genetic markers of genetic susceptibility in man are not known, one has to rely on the phenototypic markers. Such biomarkers might be certain detoxification enzymes but also the presence of metal-specific memory cells in the blood. With the increasing use of metal implants in medicine and dentistry, it is important to have a proper tool for the diagnosis of metal allergy in susceptible subjects. After nickel, gold is now the second most common sensitizer. In addition to patch test, an in vitro blood test, an optimized commercially available lymphocyte transformation test (MELISA) is discussed. Both tests were used for the diagnosis of metal allergy in a selected group of 15 patients who suffered from clinical metal sensitivity in addition to other health problems. The concordance of the two tests was good but MELISA detected more metal allergies than patch test. The removal of incompatible dental material (RID) resulted in long-term health improvement in the majority of patients. We postulate that in vivo, metal ions activate T-cells, initiating systemic inflammation, which, through cytokines, affects the brain and hypothalamus-pituitary-adrenal axis. We postulate that in vivo metal ions will activate T-cells starting systemic inflammation which, through cytokines affect the brain and hypothalamus-pituitary-adrenal (HPA) axis. The treatment and rehabilitation of metal sensitive patients is based on a firm understanding and recognition of individual susceptibility. RID has to be done done with extreme caution and according to standard working protocol. If performed properly, this treatment can result in decreased systemic inflammation and improved health in sensitized patients....

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Case Reports 2006; 27(Suppl 1): 17-24 PubMed PMID: 17261998 Citation  Keywords:  Adult, Aged, Dental Amalgam:toxicity, Environmental Exposure, Female, Humans, Hypersensitivity:diagnosis, Immunoassay:methods, Lymphocyte Activation, Metals:toxicity, Middle Aged, Occupational Exposure, Reproducibility of Results, Sensitivity and Specific.   

OBJECTIVES: Chronic low-level metal exposure may result in metal sensitization and undesirable side-effects. The main sources of metal exposure are from the environment or from corrosion of dental metal alloys. Affected patients are routinely diagnosed with the epicutaneous (patch) test. However, such testing may induce false-positive (irritative) reactions and may in itself sensitize or exacerbate symptoms. Alternatively, MELISA (Memory Lymphocyte ImmunoStimulation Assay), an optimized lymphocyte transformation test (LTT), can be used. In this study we analyzed the overall frequency and distribution of metal sensitization among symptomatic, metal-exposed patients. In addition, we determined the reproducibility of the assay and assessed its clinical relevance for detecting and monitoring hypersensitivity to metals.

METHODS: To analyze the frequency and distribution of metal sensitization, blood from 700 consecutive patients was tested against a total of 26 metals in the validated LTT-MELISA. For reproducibility testing, 391 single metal tests from 63 patients were performed in parallel. Finally, to assess clinical relevance, 14 patients with known metal exposure showing local (dry mouth, Oral Lichen Planus, Burning Mouth Syndrome, eczema) and/or systemic (chronic infections, fatigue, autoimmune disorders, central nervous system disturbances, depression) effects were tested in LTT-MELISA. In 7 cases testing was repeated following removal of the allergy-causing metals or, in 2 additional cases, without therapeutic intervention.

RESULTS: Of the 700 patients tested, 74.6% responded to >/= 1 metal in LTT-MELISA, with a subgroup of 17.9% responding to >/= 3 metals. Reactivity was most frequent to nickel (68.2%), followed by cadmium (23.7%), gold (17.8%), palladium (12.7%), inorganic mercury (11.4%), molybdenum (10.8%), beryllium (9.7%), titanium dioxide (4.2%), lead (3.7%), and platinum (3.4%). Reproducibility was 94.9%, with most discordant results in a low-positive range. Removal of the alloys or prostheses containing allergenic metals resulted in remarkable clinical improvement correlating with a significant reduction or complete normalization of specific lymphocyte reactivity. In contrast, both LTT-MELISA reactivity and clinical symptoms remained unchanged in follow-up samples from the 2 patients who did not remove the source of metal exposure.

CONCLUSION: The optimized LTT-MELISA test is a clinically useful and reliable tool for identifying and monitoring metal sensitization in symptomatic metal-exposed individuals....

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