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  1. Article: Aberrancies in antigen-presenting cells and T cells in autoimmune thyroid disease. A role in faulty tolerance induction.

    Canning, M O / Ruwhof, C / Drexhage, H A

    Autoimmunity

    2003  Volume 36, Issue 6-7, Page(s) 429–442

    Abstract: Various thyrocyte, monocyte, macrophage, DC and T cell abnormalities exist in the animal models of spontaneously developing autoimmune thyroiditis and in patients with autoimmune thyroid disease. An aberrant interaction between such abnormal thyrocytes, ... ...

    Abstract Various thyrocyte, monocyte, macrophage, DC and T cell abnormalities exist in the animal models of spontaneously developing autoimmune thyroiditis and in patients with autoimmune thyroid disease. An aberrant interaction between such abnormal thyrocytes, abnormal professional antigen-presenting cells (APC) and abnormal T cells forms the basis for the atypical autoimmune reaction targeting thyroid antigens. In the atypical interaction more than one gene and various environmental factors are involved. The genetic and environmental factors must act together to induce full-blown disease. Although there is a general blueprint for the development of destructive autoimmune thyroiditis, thyrocyte and immune cell abnormalities differ between the various animal models and the various forms of autoimmune thyroid disease (either associated with type 1 diabetes, associated with bipolar disorder or not associated). This tells us that there are different etio-pathogenic forms of destructive autoimmune thyroiditis. Whether such heterogeneity is also the case for the etio-pathogenesis of Graves' disease remains unknown. Animal models of spontaneously developing Graves' disease would be helpful in unraveling this question. If indeed there are various etio-pathogenic routes in different patients that lead to destructive autoimmune thyroiditis, then tailor-made therapeutic approaches need to be carried out in attempts to correct the underlying immune abnormalities in individual patients or to prevent the development of destructive autoimmune thyroiditis in individuals at risk. While in some forms of destructive autoimmune thyroiditis (f.i. those associated with bipolar disorder) immune suppression should be the first choice of intervention, other forms (f.i. those associated with type 1 diabetes) may benefit from immune stimulation in certain pre-stages of the disease (to restore f.i. the faulty APC function characteristic of this condition). Obviously a more precise determination of the spectrum of cell-mediated immune abnormalities is required in individual cases of destructive autoimmune thyroiditis, before therapies that aim at correcting the immune abnormalities can be tested successfully.
    MeSH term(s) Animals ; Antigen-Presenting Cells/immunology ; Disease Models, Animal ; Female ; Graves Disease/immunology ; Humans ; Immune Tolerance ; Male ; Mice ; Mice, Inbred Strains ; T-Lymphocytes/immunology ; Thyroiditis, Autoimmune/immunology
    Language English
    Publishing date 2003-11-05
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 1025450-x
    ISSN 0891-6934
    ISSN 0891-6934
    DOI 10.1080/0891630310001602984
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: 1-alpha,25-Dihydroxyvitamin D3 (1,25(OH)(2)D(3)) hampers the maturation of fully active immature dendritic cells from monocytes.

    Canning, M O / Grotenhuis, K / de Wit, H / Ruwhof, C / Drexhage, H A

    European journal of endocrinology

    2001  Volume 145, Issue 3, Page(s) 351–357

    Abstract: Objective: To study the effects of the active metabolite of vitamin D(3), 1,25(OH)(2)D(3), an immunomodulatory hormone, on the generation of so-called immature dendritic cells (iDCs) generated from monocytes (Mo-iDCs).: Design and methods: Human ... ...

    Abstract Objective: To study the effects of the active metabolite of vitamin D(3), 1,25(OH)(2)D(3), an immunomodulatory hormone, on the generation of so-called immature dendritic cells (iDCs) generated from monocytes (Mo-iDCs).
    Design and methods: Human peripheral blood monocytes were cultured to iDCs in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-4 for 1 week, with or without the extra addition of 10(-8) M 1,25(OH)(2)D(3) to the culture. Their phenotypes (CD14, CD1a, CD83, HLA-DR, CD80, CD86 and CD40 expression) were examined by fluorescence-activated cell sorting, and their T-cell stimulatory potential was investigated in allogeneic mixed lymphocyte reaction (allo-MLR). Additionally, their in vitro production of IL-10, IL-12 and transforming growth factor beta (TGF-beta) were examined by using the enzyme-linked immunosorbent assay.
    Results: When 1,25(OH)(2)D(3) was added to monocytes in culture with GM-CSF and IL-4, it hampered the maturation of Mo-iDCs. First, the phenotype of the 1,25(OH)(2)D(3)-differentiated DCs was affected, there being impaired downregulation of the monocytic marker CD14 and impaired upregulation of the markers CD1a, CD83, HLA-DR, CD80 and CD40. CD86 was expressed on more 1,25(OH)(2)D(3)-differentiated DCs. Secondly, the T-cell stimulatory capability of 1,25(OH)(2)D(3)-differentiated DCs was upregulated relative to the original monocytes to a lesser degree than DCs differentiated without 1,25(OH)(2)D(3) when tested in an allo-MLR. With regard to the production of cytokines, Staphylococcus aureus cowan 1 strain (SAC)-induced IL-10 production, although not enhanced, remained high in 1,25(OH)(2)D(3)-differentiated DCs, but was strongly downregulated in DCs generated in the absence of 1,25(OH)(2)D(3). SAC/interferon-gamma-induced IL-12 production was clearly upregulated in both types of DC relative to those of the original monocytes, and TGF-beta production was downregulated.
    Conclusion: Our data confirm earlier reports showing that 1,25(OH)(2)D(3) hampers the maturation of fully active immunostimulatory major histocompatibility complex (MHC) class II+, CD1a+, CD80+ DCs from monocytes. Our data supplement the data from other reports by showing that the expression of CD86 was upregulated in 1,25(OH)(2)D(3)-differentiated DCs, whilst the capacity for IL-10 production remained high. Collectively, these data are in line with earlier descriptions of suppressive activities of this steroid-like hormone with respect to the stimulation of cell-mediated immunity.
    MeSH term(s) Antigens, CD/analysis ; Antigens, CD1/analysis ; B7-1 Antigen/analysis ; B7-2 Antigen ; CD40 Antigens/analysis ; Calcitriol/pharmacology ; Cell Differentiation/drug effects ; Cells, Cultured ; Dendritic Cells/cytology ; Dendritic Cells/immunology ; Enzyme-Linked Immunosorbent Assay ; Flow Cytometry ; Granulocyte-Macrophage Colony-Stimulating Factor/pharmacology ; HLA-DR Antigens/analysis ; Humans ; Immunoglobulins/analysis ; Immunophenotyping ; Interleukin-10/biosynthesis ; Interleukin-12/biosynthesis ; Interleukin-4/pharmacology ; Lymphocyte Culture Test, Mixed ; Membrane Glycoproteins/analysis ; Monocytes/cytology ; T-Lymphocytes/immunology ; Transforming Growth Factor beta/biosynthesis ; CD83 Antigen
    Chemical Substances Antigens, CD ; Antigens, CD1 ; B7-1 Antigen ; B7-2 Antigen ; CD1a antigen ; CD40 Antigens ; CD86 protein, human ; HLA-DR Antigens ; Immunoglobulins ; Membrane Glycoproteins ; Transforming Growth Factor beta ; Interleukin-10 (130068-27-8) ; Interleukin-12 (187348-17-0) ; Interleukin-4 (207137-56-2) ; Granulocyte-Macrophage Colony-Stimulating Factor (83869-56-1) ; Calcitriol (FXC9231JVH)
    Language English
    Publishing date 2001-08-21
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1183856-5
    ISSN 1479-683X ; 0804-4643
    ISSN (online) 1479-683X
    ISSN 0804-4643
    DOI 10.1530/eje.0.1450351
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: Opposing effects of dehydroepiandrosterone and dexamethasone on the generation of monocyte-derived dendritic cells.

    Canning, M O / Grotenhuis, K / de Wit, H J / Drexhage, H A

    European journal of endocrinology

    2000  Volume 143, Issue 5, Page(s) 687–695

    Abstract: Background: Dehydroepiandrosterone (DHEA) has been suggested as an immunostimulating steroid hormone, of which the effects on the development of dendritic cells (DC) are unknown. The effects of DHEA often oppose those of the other adrenal glucocorticoid, ...

    Abstract Background: Dehydroepiandrosterone (DHEA) has been suggested as an immunostimulating steroid hormone, of which the effects on the development of dendritic cells (DC) are unknown. The effects of DHEA often oppose those of the other adrenal glucocorticoid, cortisol. Glucocorticoids (GC) are known to suppress the immune response at different levels and have recently been shown to modulate the development of DC, thereby influencing the initiation of the immune response. Variations in the duration of exposure to, and doses of, GC (particularly dexamethasone (DEX)) however, have resulted in conflicting effects on DC development.
    Aim: In this study, we describe the effects of a continuous high level of exposure to the adrenal steroid DHEA (10 M) on the generation of immature DC from monocytes, as well as the effects of the opposing steroid DEX on this development.
    Results: The continuous presence of DHEA (10 M) in GM-CSF/IL-4-induced monocyte-derived DC cultures resulted in immature DC with a morphology and functional capabilities similar to those of typical immature DC (T cell stimulation, IL-12/IL-10 production), but with a slightly altered phenotype of increased CD80 and decreased CD43 expression (markers of maturity). The continuous presence of DEX at a concentration of 10 M in the monocyte/DC cultures resulted in the generation of plastic-adherent macrophage-like cells in place of typical immature DC, with increased CD14 expression, but decreased expression of the typical DC markers CD1a, CD40 and CD80. These cells were strongly reactive to acid phosphatase, but equally capable of stimulating T cell proliferation as immature DC. The production of IL-12 by these macrophage-like cells was virtually shut down, whereas the production of IL-10 was significantly higher than that of control immature DC.
    Conclusion: The continuous presence of a high level of GC during the generation of immature DC from monocytes can modulate this development away from DC towards a macrophage-like cell. The combination of a low CD80 expression and a shutdown of IL-12 production suggests the possibility of DEX-generated cells initiating a Th2-biased response. These effects by DEX on DC development contrast with those by DHEA, which resulted in a more typical DC although possessing a phenotype possibly indicating a more mature state of the cell.
    MeSH term(s) Anti-Inflammatory Agents/pharmacology ; Cells, Cultured ; Dehydroepiandrosterone/pharmacology ; Dendritic Cells/drug effects ; Dexamethasone/pharmacology ; Flow Cytometry ; Humans ; Interleukin-10/biosynthesis ; Interleukin-12/biosynthesis ; Lymphocyte Culture Test, Mixed ; Monocytes/drug effects ; Phenotype ; T-Lymphocytes/drug effects
    Chemical Substances Anti-Inflammatory Agents ; Interleukin-10 (130068-27-8) ; Interleukin-12 (187348-17-0) ; Dehydroepiandrosterone (459AG36T1B) ; Dexamethasone (7S5I7G3JQL)
    Language English
    Publishing date 2000-02-23
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1183856-5
    ISSN 1479-683X ; 0804-4643
    ISSN (online) 1479-683X
    ISSN 0804-4643
    DOI 10.1530/eje.0.1430687
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: An abnormal adherence of monocytes to fibronectin in thyroid autoimmunity has consequences for cell polarization and the development of veiled cells.

    Canning, M O / Grotenhuis, K / De Haan-Meulman, M / De Wit, H J / Berghout, A / Drexhage, H A

    Clinical and experimental immunology

    2001  Volume 125, Issue 1, Page(s) 10–18

    Abstract: Blood monocytes of patients with thyroid autoimmune disease (TAID) display defects in rearranging their cortical actomyosin cytoskeleton ('polarize') in response to chemoattractants. Such rearrangements also take place after the adherence of monocytes to ...

    Abstract Blood monocytes of patients with thyroid autoimmune disease (TAID) display defects in rearranging their cortical actomyosin cytoskeleton ('polarize') in response to chemoattractants. Such rearrangements also take place after the adherence of monocytes to the extracellular matrix (ECM). It is therefore not surprising that monocytes are primed after fibronectin (FN) adherence, displaying an enhanced polarization toward chemoattractants. We investigated the integrin expression and chemoattractant-induced polarization of monocytes of TAID patients before and after FN adherence. Since cytoskeletal rearrangements are also required during the transition of monocytes into veiled antigen-presenting cells (VCs), we investigated such transition of FN-adherent monocytes of TAID patients. Adherent and nonadherent monocyte populations from TAID patients and healthy controls were subjected to a polarization test with the chemoattractant fMLP (or MCP-1), FACS analyses (FITC-labelled FN, CD29, CD49e, d, b and a) and tested for their capability to develop into veiled APC. Monocytes of healthy individuals showed an improved chemoattractant-induced cell polarization after FN adherence, not reflected by TAID monocytes, in which chemoattractant-induced polarization worsened. Monocytes of healthy individuals up-regulated CD49e and d integrins and their capability to bind FITC-labelled FN after adherence to a FN-coated plate, as well as enhancing their capability to generate T cell-stimulatory VCs. Monocytes of TAID patients did not. These data indicate that integrin- (and chemokine-) mediated functions are hampered in monocytes of TAID patients. Because integrin action is pivotal to processes such as monocyte adherence to endothelial cells, uropod formation, migration into tissues and differentiation into APC and macrophages, these defects might underly immune dysbalances important in thyroid autoimmune development.
    MeSH term(s) Adult ; Aged ; Cell Adhesion ; Cell Polarity ; Chemotactic Factors/pharmacology ; Female ; Fibronectins/metabolism ; Graves Disease/blood ; Humans ; Hypothyroidism/blood ; Male ; Middle Aged ; Monocytes/drug effects ; Monocytes/metabolism ; Monocytes/physiology ; N-Formylmethionine Leucyl-Phenylalanine/pharmacology ; Receptors, Fibronectin/metabolism ; Thyroid Gland/immunology ; Up-Regulation
    Chemical Substances Chemotactic Factors ; Fibronectins ; Receptors, Fibronectin ; N-Formylmethionine Leucyl-Phenylalanine (59880-97-6)
    Language English
    Publishing date 2001-07
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 218531-3
    ISSN 1365-2249 ; 0009-9104 ; 0964-2536
    ISSN (online) 1365-2249
    ISSN 0009-9104 ; 0964-2536
    DOI 10.1046/j.1365-2249.2001.01583.x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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