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HA Drexhage

This issue of European Journal of Endocrinology contains two articles which have in common the study in humans of the involvement of TSH receptor antibodies (TSH-R-ab) and T cells in goitrous conditions such as Graves' disease and sporadic goitre.

Aust et al. (1) describe activated, i.e. HLA-DR+, T cells not only in Graves goitres but also—and in the same proportions–in goitrous conditions such as non-toxic multinodular goitre (NTG) and thyroid autonomy (TA). Forty per cent of these activated T cells show an intracellular staining for IFN-γ, whereas half of them co-express another activation marker, i.e. CD69. Both NTG and TA are generally regarded as conditions in which the immune system is not activated ("nonautoimmune"), and hence the presence of activated T cells—although clearly in lower numbers as compared to Graves goitres—was surprising to the authors. Because the activation marker CD69 has also been implicated in tolerance induction in the thymus,

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A Hoek, W Allaerts, PJM Leenen, J Schoemaker and HA Drexhage


Blood monocytes are able to mature into macrophages as well as into dendritic cells. Dendritic cells and macrophages have mainly been studied for their function in the immune response, e.g. in the presentation of antigens to lymphocytes and in the phagocytosis/degradation of unwanted material. The cells are also, however, important producers of a variety of signalling molecules and hormones and are thus involved in other physiological functions such as wound healing, the regulation of the microcirculation and the regulation of the function and growth of endocrine cells. This review summarizes the existing evidence for a regulatory role of dendritic cells and macrophages in the function and growth of hormone-producing cells of the pituitary–gonadal axis. It focusses on the presence, localization and phenotype of dendritic cells and macrophages in the anterior pituitary and the gonads, the endocrine regulatory role of cytokines produced by these cells and the existence of putative feedback mechanisms between endocrine cells of the pituitary–gonadal axis and dendritic cells and macrophages. The recognition of a 'floating endocrine-regulatory force' of monocyte-derived cells that also plays a role in the initiation of immune responses has implications for our understanding of the pathogenesis of gonadal and pituitary autoimmune reactions.

European Journal of Endocrinology 136 8–24

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JL Kuijpens, VJ Pop, HL Vader, HA Drexhage and WM Wiersinga

BACKGROUND: Screening pregnant women for thyroid peroxidase antibodies (TPOAb) to identify those at risk for post partum thyroid dysfunction (PPTD) is controversial, mainly because of the low positive predictive value (ppv) of TPOAb. OBJECTIVES: To evaluate if the ppv of TPOAb can be enhanced, either by taking into account the time of TPOAb testing, or by combining this parameter with other putative determinants of PPTD such as smoking, family history or other autoimmune diseases. METHODS: A prospective study was performed in the Kempenland region (southeastern Netherlands). Three hundred and ten unselected women were visited at 12 and 32 weeks gestation and 4, 12, 20, 28 and 36 weeks post partum. Serial thyroid stimulating hormone (TSH), free thyroxine (fT4) and TPOAb testing was performed. Thyroid dysfunction (TD) was defined as abnormal TSH either in combination with abnormal fT4 (overt TD) or without abnormal fT4 (subclinical TD). PPTD was defined as overt TD post partum. Multivariate regression analysis was performed for determining independent risk factors for PPTD. The sensitivity and specificity of TPOAb at different time points and at different concentrations were calculated and presented in receiver operating characteristic (ROC) curves. Women who had experienced PPTD were followed for 2.5-3 years. RESULTS: Data from 291 women were available for analysis. Serum fT4 declined during pregnancy and returned to baseline values post partum. TD in gestation was present in 23 women (7.9%): serum TSH was transiently decreased in 13 (6 had overt gestational thyrotoxicosis (2.1%)) and increased in 10 (2 had TPOAb). Both point prevalence and concentration of TPOAb decreased during gestation and returned to baseline levels within 12 weeks post partum. TD in post partum was present in 36 women (12.4%): 21 had subclinical and 15 overt TD. Out of the 15 women with overt TD (incidence of PPTD: 5.2%) 10 were positive for TPOAb (TPOAb+): 9 had thyrotoxicosis (4 TPOAb+), 5 hypothyroidism (5 TPOAb+) and 1 thyrotoxicosis followed by hypothyroidism (TPOAb+). Independent risk factors for PPTD were TPOAb (relative risk (RR) = 2 7.2), bottle feeding (RR = 11.1) and smoking habits (ever smoked: RR = 3.1; women with PPTD had smoked more cigarettes for a longer period of time). The sensitivity of TPOAb testing was highest at 12 weeks gestation (0.67). The ppv of TPOAb was 0.31-0.75 (depending on time of testing and concentration), increasing slightly to 0.38-0.80 when combined with bottle feeding or smoking habits. There appeared to be an autoimmune form of PPTD in 2/3 of cases and a non-autoimmune form; women with the autoimmune form were at risk for developing permanent hypothyroidism. CONCLUSIONS: A maximum of 2/3 of PPTD cases can be predicted from the presence of TPOAb because 1/3 remained negative for TPOAb. The most appropriate time for TPOAb testing is in the first trimester of pregnancy. The combination of TPOAb testing with anamnestic determinants of PPTD does not increase ppv substantially.

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MO Canning, K Grotenhuis, HJ de Wit and HA Drexhage

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.

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JL Kuijpens, HL Vader, HA Drexhage, WM Wiersinga, MJ van Son and VJ Pop

OBJECTIVE: Depression is not adequately diagnosed in many cases. Therefore, the question arises as to whether markers exist for depression. We investigated whether the presence of thyroperoxidase antibodies (TPOAbs) during pregnancy can be regarded as a marker for depression in the first year postpartum, particularly in relation to (overt or subclinical) thyroid dysfunction and other determinants of depression. DESIGN: This work was a prospective observational study. PATIENTS: A cohort of 310 unselected women (residing in the Kempen Region, southeastern Netherlands) were visited at 12 and 32 weeks gestation and at 4, 12, 20, 28 and 36 weeks postpartum. METHODS: At each visit, TSH, free thyroxine and TPOAb testing was performed, determinants associated with depression were asked for, and depression was assessed (according to the Research Diagnostic Criteria). Multiple logistic regression was performed to determine independent risk factors (odds ratios, ORs) for depression in gestation and/or postpartum depression. RESULTS: Data for 291 women were available for analysis; 41 women (14.1%) had TPOAbs at one or more time points, and 117 women (40.1%) had depression at one or more time points postpartum. The multiple logistic regression analysis showed that TPOAbs were independently associated with depression at 12 weeks gestation and at 4 and 12 weeks postpartum (OR, 95% confidence interval: 2.4 (1.1-6.0), 3.8 (1.3-7.3) and 3.6 (1.2-7.1) respectively). After the exclusion of women who were depressed at 12 weeks gestation (n=70), the presence of TPOAbs during early pregnancy was still found to be associated with the development of postpartum depression (OR, 95% confidence interval: 2.8 (1.7-4.5); after exclusion of women who had had depression in earlier life (n=51), TPOAb during early gestation was still associated with postpartum depression (OR, 95% confidence interval: 2.9 (1.8-4.3). CONCLUSIONS: The presence of TPOAbs during gestation is associated with the occurrence of subsequent depression during the postpartum period and as such can be regarded as a marker for depression.

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MO Canning, K Grotenhuis, H de Wit, C Ruwhof and HA Drexhage

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.