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Hemmo A Drexhage

Publications and source records attributed to Hemmo A Drexhage.

At least 19 recordsLinked to original sources
PubMed2006

Is autoimmune thyroiditis part of the genetic vulnerability (or an endophenotype) for bipolar disorder?

BACKGROUND: Both genetic and environmental factors are involved in the etiology of bipolar disorder; however, biological markers for the transmission of the bipolar genotype ("endophenotypes") have not been found. Autoimmune thyroiditis with raised levels of thyroperoxidase antibodies (TPO-Abs) is related to bipolar disorder and may be such an endophenotype. This study was intended to examine whether autoimmune thyroiditis is related to the disease itself, to the (genetic) vulnerability to develop bipolar disorder, or both. METHOD: Blood was collected from 22 monozygotic (MZ) and 29 dizygotic (DZ) bipolar twins and 35 healthy matched control twins to determine TPO-Abs. RESULTS: The TPO-Abs were positive in 27% of the bipolar index twins, 29% of the monozygotic bipolar cotwins, 27% of the monozygotic nonbipolar cotwins, 25% of the dizygotic bipolar cotwins, 17% of the dizygotic nonbipolar cotwins, and in 16% of the control twins. Repeated measures analysis of covariance on log-transformed absolute TPO-Abs values revealed significantly increased mean TPO-Abs levels in discordant twin pairs as compared with healthy twin pairs, whereas no difference was found between bipolar patients and their (discordant) nonbipolar cotwins. CONCLUSIONS: This study shows that autoimmune thyroiditis is related not only to bipolar disorder itself but also to the genetic vulnerability to develop the disorder. Autoimmune thyroiditis, with TPO-Abs as marker, is a possible endophenotype for bipolar disorder.

Adult↗
PubMed2006

Signs of a higher prevalence of autoimmune thyroiditis in female offspring of bipolar parents.

BACKGROUND: Studies are inconsistent as to whether patients with bipolar disorder are more frequently affected by autoimmune thyroiditis. AIM: To study the prevalence of autoimmune thyroiditis in offspring of bipolar patients. METHOD: In 1998 140 children (age 12-21 years) of bipolar parents were evaluated psychiatrically using the K-SADS-PL and blood was drawn to determine thyroperoxidase antibodies (TPO-Abs) and serum TSH. Blood samples of high school students (aged 12-19 years, n=77) and young adults (aged 20-35 years, n=52) were used as comparisons. At follow-up the offspring were psychiatrically evaluated and tested for TPO-Abs and TSH twice (14 months and 55 months after enrollment). RESULTS: TPO-Abs were predominantly found in female bipolar offspring, who had a significantly higher prevalence of positive TPO-Ab titers (9 out of 57 female offspring subjects) as compared to the female high school and young adult comparisons (4 out of 103 female control subjects). In TPO-Ab positive offspring (n=11) a raised prevalence of 55% of thyroid failure (i.e. a raised serum TSH or l-thyroxine treatment) was evident. TPO-Ab positive offspring did not show a raised prevalence of mood disorders (or any psychopathology) as compared to the TPO-Ab negative offspring. CONCLUSION: Our study suggests that bipolar offspring are more vulnerable to develop thyroid autoimmunity independently from the vulnerability to develop psychiatric disorders.

Adolescent↗
PubMed2006

Thyroid hormones, dementia, and atrophy of the medial temporal lobe.

CONTEXT: Thyroid function has been related to Alzheimer disease (AD), but it remains unclear whether thyroid dysfunction results from or contributes to developing AD. OBJECTIVE: The objective of the study was to determine the association between thyroid function and both medial temporal lobe atrophy on brain magnetic resonance imaging (MRI) as putative early sign of AD and risk of dementia. DESIGN AND PARTICIPANTS: This was a population-based cohort study among 1077 elderly subjects aged 60-90 yr and dementia free at baseline (1995-1996). MAIN OUTCOME MEASURES: Nonfasting serum levels of TSH, free T(4) (fT(4)), T(3), and rT(3) were available in 1025 subjects followed up for incident dementia until 2005. In a subset of 489 nondemented elderly, we assessed volumes of the hippocampus and amygdala on brain MRI. Subjects using thyroid medication were excluded. RESULTS: During 5657 person-years of follow-up (mean 5.5 yr), 63 subjects were diagnosed with dementia (46 with AD). TSH and thyroid hormones were not associated with risk of dementia or AD. TSH and T(3) were also not related to brain atrophy, whereas nondemented subjects with higher fT(4) levels had more hippocampal and amygdalar atrophy on MRI. Similar associations were found for rT(3). Excluding subjects with thyroid disorders or incipient AD did not change the results. CONCLUSION: In our study, TSH was related neither to risk of AD nor with early MRI markers thereof, arguing against an important role of thyroid function in the development of AD. Whether the association of higher fT(4) and rT(3) levels with brain atrophy on MRI has functional significance remains to be elucidated.

Aged↗
PubMed2006

A relative resistance of T cells to dexamethasone in bipolar disorder.

OBJECTIVE: A relative resistance of immune cells to steroids has been established in patients with major depression (MD). In this study, we investigated the in vitro responsiveness of T cells to dexamethasone (DEX) of patients with bipolar disorder (BD). METHODS: T cells of outpatients with DSM-IV BD (n = 54) and of healthy control subjects (HC; n = 29) were isolated, cultured and stimulated with phytohemagglutinin (PHA) for 72 h. The suppressive effect of graded concentrations of DEX (5 x 10(-9)-10(-5) M) on PHA-induced CD25 (IL-2R) expression was measured by fluorescence-activated cell sorting (FACS) analysis. Data were correlated to the T-cell activation status in the peripheral blood of the same patients and to their diagnosis, current mood state, ultradian cycling pattern and current use of medication, including lithium. RESULTS: T cells of patients with BD were less sensitive to DEX-induced suppressive effects as compared with T cells of HC. These data were particularly evident at 10(-7) M DEX (mean % suppression +/- SEM BD: 18.9% +/- 3.5 versus HC: 35.8% +/- 4.7, p = 0.001). We found no correlations of this relative in vitro DEX resistance of T cells neither with the previously mentioned clinical characteristics nor with the actual activation status of the T cells in the BD patients. CONCLUSION: A relative T-cell resistance to steroids, as has been observed in MD previously, may be a trait phenomenon of BD, independent of mood state.

Adult↗
PubMed2005

Monocyte-derived dendritic cells in bipolar disorder.

BACKGROUND: Dendritic cells (DC) are key regulators of the immune system, which is compromised in patients with bipolar disorder. We sought to study monocyte-derived DC in bipolar disorder. METHODS: Monocytes purified from blood collected from DSM-IV bipolar disorder outpatients (n = 53, 12 without lithium treatment) and healthy individuals (n = 34) were differentiated into DC via standard granulocyte-macrophpage colony-stimulating factor/interleukin-4 culture (with/without 1, 5, and 10 mmol/L lithium chloride). The DC were analyzed for DC-specific and functional markers and for T-cell stimulatory potency. RESULTS: Monocytes of bipolar patients showed a mild hampering in their differentiation into fully active DC, showing a weak residual expression of the monocyte marker CD14 and a relatively low potency to stimulate autologous T cells. Lithium treatment abolished this mild defect, and monocyte-derived DC of treated bipolar patients showed signs of activation (i.e., an up-regulated potency to stimulate autologous T cells and a higher expression of the DC-specific marker CD1a). This activated phenotype contrasted with the suppressed phenotype of monocyte-derived DC exposed to lithium in vitro (10 mmol/L) during culture. CONCLUSIONS: Dendritic cells show mild aberrancies in bipolar disorder that are fully restored to even activation after in vivo lithium treatment.

Adult↗
PubMed2005

Immunomagnetic selection of functional dendritic cells from human lymph nodes.

It was investigated whether positive immunomagnetic selection with two novel DC-specific mAb allowed purification of functional myeloid dendritic cells (MDC) and plasmacytoid dendritic cells (PDC) from the human lymph nodes (LN). The results were compared with enrichment of DC by low-density Nycodenz gradient centrifugation followed by immunomagnetic depletion of residual B- and T-cells (Nycodenz method). MDC were selected from inguinal LN cell suspensions using CD1c mAb and PDC using anti-BDCA-4 mAb. Immunomagnetic selection with anti-CD1c mAb yielded highly pure MDC preparations (90 +/- 3% MDC; n = 7), provided that the B-cells were thoroughly depleted by using CD19 magnetic beads and Large Depletion (LD) columns prior to selection of MDC. The purified MDC comprised both mature and immature cells and were functional, secreting large amounts of cytokines upon stimulation and strongly stimulating allogeneic T-cell proliferation. Immunomagnetic selection with anti-BDCA-4 mAb enriched PDC 70-fold to a purity of 59 +/- 26% (n = 8). The contamination consisted mainly of BDCA-4(+) T- and NK-cells. The previously used Nycodenz method yielded mixtures of MDC and PDC, not allowing functional studies of MDC and PDC separately. In conclusion, positive immunomagnetic selection with CD1c mAb from human LN cell suspensions yields almost pure MDC preparations, which are, in contrast to those obtained by the Nycodenz method, not contaminated with PDC. Moreover, these MDC are functionally intact. Selection with anti-BDCA-4 mAb does enrich PDC from human LN, but the resulting preparations are contaminated with T- and NK-cells.

Antibodies, Monoclonal↗
PubMed2005

Diabetes-prone NOD mice show an expanded subpopulation of mature circulating monocytes, which preferentially develop into macrophage-like cells in vitro.

In the nonobese diabetic (NOD) mouse, a model of autoimmune diabetes, dendritic cells (DC), and macrophages (Mphi) is important for the initiation and progression of autoimmunity and the final destruction of beta-cells. Previous studies suggested that an aberrant development of DC and Mphi is related to their pathogenic function. To study this in vivo, we investigated NOD mouse monocytes, the direct precursors of DC, and Mphi. The recently described discrimination between immature (Ly-6C(high)) and mature (Ly-6C(low)) monocytes enabled us to investigate the apportioning between blood monocyte populations in the NOD mouse, which had an abnormally high number of mature monocytes in circulation, and this phenomenon appeared to be intrinsic to the NOD background, as nonobese resistant (NOR) and NOD-H2b mice also showed this altered balance. After depletion by apoptosis-inducing liposomes, the reappearance and transition of immature-to-mature monocytes had similar kinetics as control mice but led again to the presence of a larger, mature monocyte compartment in the blood. In addition, although monocytes from C57BL mice down-regulated their capability to adhere to fibronectin and intercellular adhesion molecule-1 upon maturation, the mature NOD monocytes retained their high adhesion capacity, characteristic of immature cells. Furthermore, both monocyte subpopulations of NOD mice showed enhanced differentiation into Mphi-like F4/80(high) cells in vitro. In conclusion, mice with the NOD background have raised numbers of mature monocytes in the circulation and a proinflammatory, Mphi-directed monocyte development.

Animals↗
PubMed2005

NOD mice have a severely impaired ability to recruit leukocytes into sites of inflammation.

The accumulation of macrophages (M Phi) and dendritic cells (DC) in the pancreas plays a crucial role in the pathogenesis of autoimmune diabetes. We studied the recruitment of monocytes, M Phi and DC to sites of inflammation, i.e. the peritoneal cavity and a subcutaneously elicited air pouch in the NOD mouse model of autoimmune diabetes. The leukocyte recruitment was studied from 1 to 7 days after injection of thioglycollate (peritoneum), C5a (peritoneum, air pouch), CCL2 and CCL3 (air pouch). C57BL/6 and BALB/c mice served as controls. Morphological and flow cytometric analysis of the recruited cells was performed, IL-1 beta, TNF-alpha, IL-6, IL-12 and IL-10 in exudates measured, and in vitro CCL2-chemotaxis of exudate M Phi (Boyden chamber) determined. NOD mice were strongly impaired in the recruitment of M Phi, DC, monocytes, and granulocytes. Chemokine-injected air pouches of NOD mice showed an increased IL-10 and a decreased IL-1 beta level, while the other cytokines were normally or very lowly expressed. In addition, NOD exudate M Phi displayed an impaired in vitro CCL2-induced migration. Our data show that NOD mice have an impaired ability to recruit leukocytes into sites of inflammation elicited in the peritoneum and the air pouch. A raised IL-10/IL-1 beta ratio at these sites and a deficient migratory capacity of NOD monocytes are important determinants in this impairment.

Animals↗
PubMed2005

Evidence for an enhanced adhesion of DC to fibronectin and a role of CCL19 and CCL21 in the accumulation of DC around the pre-diabetic islets in NOD mice.

The non-obese diabetic (NOD) mouse is a widely used animal model for the study of human diabetes. The lymphocytic (peri-)insulitis is preceded by an early accumulation of dendritic cells (DC) around the islets of Langerhans. This DC accumulation is thought to derive from an influx of monocytes attracted by pro-inflammatory chemokines. Besides chemokines, extracellular matrix (ECM) proteins play an important role in the accumulation of leukocytes in tissues. We studied the expression of the chemokines CCL2, CCL5, CXCL10, CCL19 and CCL21 over time in pancreases of NOD and control mice by ELISA on pancreas lysates as well as by immunohistochemistry. In addition, we studied the adhesive capacity of bone marrow-derived DC (BMDC) to ECM components. DC in the NOD pancreas accumulated at sites with an intense expression of fibronectin. In vitro, NOD BMDC showed increased fibronectin adhesion and increased VLA-5 expression. At the time of early DC accumulation (<10 wk), the lymphoid tissue-related chemokines CCL19 and CCL21 were increased. Our findings support the view that the early accumulation of DC around the NOD islets is not the consequence of an enhanced attraction of precursors and immature DC by pro-inflammatory chemokines. It rather might be the consequence of an aberrantly enhanced adhesion and retention of NOD DC.

Animals↗
PubMed2005

Defects in differentiation of bone-marrow derived dendritic cells of the BB rat are partly associated with IDDM2 (the lyp gene) and partly associated with other genes in the BB rat background.

BB rats develop various organ-specific autoimmune diseases, e.g. autoimmune diabetes and thyroiditis and have proven important to dissect genetic factors that govern autoimmune disease development. The lymphopenia (lyp) gene (iddm2) is linked to autoimmune disease development and is a major genetic difference between diabetes-resistant (DR) and diabetes-prone (DP) BB rats. To study the effects of the lyp gene and other genes on dendritic cell (DC) differentiation from bone-marrow precursors, such differentiation was studied in BB-DP, BB-DR, Wistar and F344 control rats. DC of BB-DP rats showed a lower MHC class II expression as compared to BB-DR, Wistar and F344 rats. LPS-maturation did not restore this low MHC class II expression. DC of BB-DP rats also showed a poor capability to terminally differentiate into mature T cell stimulatory DC under the influence of LPS and produced significantly lower quantities of IL-10, yet these aberrancies were also found in BB-DR rats but did not occur in control rats. This study thus shows that various aberrancies exist in the differentiation of myeloid DC from bone-marrow precursors in the BB rat model of organ-specific autoimmunity. These aberrancies are multigenically determined and partly associated with iddm2 (lyp gene) and partly associated with other genes in the BB rat.

Animals↗
PubMed2005

Aberrancies in the differentiation and maturation of dendritic cells from bone-marrow precursors are linked to various genes on chromosome 4 and other chromosomes of the BB-DP rat.

BB-Diabetes Prone (BB-DP) rats, a model for endocrine autoimmune diseases, are severely lymphopenic, especially lacking ART2+ regulatory T cells. BB-Diabetes Resistant (DR) rats are not lymphopenic and do not develop autoimmunity. BB-DP and BB-DR rats only differ at the lymphopenia (lyp) gene (iddm2) on chromosome 4. Since BB-DP rats also show aberrancies in the differentiation of dendritic cells (DC) from bone-marrow precursors, we tested the hypothesis that F344 rats congenic for a BB-DP chromosome 4 region (42.5-93.6Mb; including the lyp gene, but also iddm4) display an in vitro DC differentiation different from normal F344 rats. Here we show that the 42.5-93.6Mb BB-DP chromosome 4 region is linked to an increased DC precursor apoptosis, a low MHC class II expression, a reduced IL-10 production and a reduced T cell stimulatory capacity of DC. From our previous report on DC differentiation defects in BB rats (only differing in iddm2) and the present report, we deduce that the abnormal apoptosis and low MHC class II expression is linked to iddm2. The reduced T cell stimulatory capacity is linked to other genes on chromosome 4 (candidate gene: iddm4). The reduced IL-10 production has a complex linkage pattern.

Animals↗
PubMed2005

Dendritic cells and macrophages are essential for the retention of lymphocytes in (peri)-insulitis of the nonobese diabetic mouse: a phagocyte depletion study.

Dendritic cells (DC) and macrophages (Mphi) are present in high numbers in the pancreas of the non-obese diabetic (NOD) mouse during the diabetogenic process from very early stages onwards. In this study, we used clodronate-loaded liposomes to mediate the temporary systemic depletion of these phagocytic cells and monocytic precursors in order to modulate the pancreatic inflammation. Two intraperitoneal injections given with a 2-day interval to 8-week-old NOD mice depleted monocytes from the circulation and monocytes, DC and Mphi from the spleen within the first days after the injections. Monocytes, DC and Mphi reappeared in the circulation and the spleen within one week and had an unchanged phenotype and antigen presenting function. Interestingly, this treatment caused a delayed disappearance (7-21 days postinjection) of DC and Mphi from the endocrine pancreas at a time when monocytes, DC and Mphi had already repopulated the circulation and the spleen. The depletion of DC and Mphi from the endocrine pancreas was accompanied by a total disappearance of lymphocytes from the pancreas. DC, Mphi and lymphocytes reappeared in the pancreatic inflammatory infiltrates in treated mice from 28 days postdepletion onwards. Importantly, the treatment significantly postponed the onset of diabetes, leading to a strongly decreased incidence by 35 weeks of age. Taken together, our data show an essential role of phagocytic cells, that is, DC and Mphi, in the recruitment of lymphocytes to the pancreatic islets in NOD mice.

Animals↗
PubMed2004

A high prevalence of organ-specific autoimmunity in patients with bipolar disorder.

BACKGROUND: In a previous study, we reported an increased prevalence of thyroperoxidase antibodies (TPOA) in patients with bipolar disorder. Here we report the prevalence of other organ-specific autoantibodies: H/K adenosine triphosphatase (ATPA), glutamic acid decarboxylase-65 (GAD65A), and GAD-67 (GAD67A). METHODS: ATPA, GAD65A, and GAD67A were determined (via a commercially available enzyme linked immunosorbent assay for ATPA, and a standardized radio immunoassays for GAD65A and GAD67A)in the sera of 239 patients with DSM-IV bipolar disorder, in 74 patients with DSM-IV schizophrenia, and in 220 healthy control subjects. RESULTS: The positivity prevalences for ATPA and GAD65A (but not GAD67A) were elevated in bipolar patients compared with those in healthy control subjects (11.7 vs. 6.1% and 11.3 vs. 2.6% respectively; p <.05). Schizophrenia patients did not show such statistically higher prevalence. The elevated prevalence of ATPA and GAD65A in bipolar disorder was associated with neither rapid cycling nor the use of lithium. Interestingly, the presence of GAD65A (and not that of TPOA and ATPA) tended to be associated with the activity of bipolar disorder. The level of TPOA was negatively correlated with the serum level of sIL-2R, a measure of T cell activation. CONCLUSION: Bipolar disorder is associated with organ-specific autoimmunity to the antigens TPO, H/K ATPase, and GAD65.

Autoantibodies↗
PubMed2004

Bone marrow precursors of nonobese diabetic mice develop into defective macrophage-like dendritic cells in vitro.

The NOD mouse spontaneously develops autoimmune diabetes. Dendritic cells (DC) play a crucial role in the autoimmune response. Previous studies have reported a defective DC generation in vitro from the NOD mouse bone marrow (BM), but a deviated development of myeloid precursors into non-DC in response to GM-CSF was not considered. In this study, we demonstrate several abnormalities during myeloid differentiation of NOD BM precursors using GM-CSF in vitro. 1) We found reduced proliferation and increased cell death in NOD cultures, which explain the previously reported low yield of DC progeny in NOD. Cell yield in NOR cultures was normal. 2) In a detailed analysis GM-CSF-stimulated cultures, we observed in both NOD and NOR mice an increased frequency of macrophages, identified as CD11c(+)/MHCII(-) cells with typical macrophage morphology, phenotype, and acid phosphatase activity. This points to a preferential maturation of BM precursors into macrophages in mice with the NOD background. 3) The few CD11c(+)/MHCII(high) cells that we obtained from NOD and NOR cultures, which resembled prototypic mature DC, appeared to be defective in stimulating allogeneic T cells. These DC had also strong acid phosphatase activity and elevated expression of monocyte/macrophage markers. In conclusion, in this study we describe a deviated development of myeloid BM precursors of NOD and NOR mice into macrophages and macrophage-like DC in vitro. Potentially, these anomalies contribute to the dysfunctional regulation of tolerance in NOD mice yet are insufficient to induce autoimmune diabetes because they occurred partly in NOR mice.

Acid Phosphatase↗
PubMed2004

Increased serum levels of MRP-8/14 in type 1 diabetes induce an increased expression of CD11b and an enhanced adhesion of circulating monocytes to fibronectin.

The recruitment of monocytes from the bloodstream is crucial in the accumulation of macrophages and dendritic cells in type 1 diabetic pancreases. Adhesion via integrins to endothelium and extracellular matrix proteins, such as fibronectin (FN), and the production of myeloid-related protein (MRP)-8, -14, and -8/14 by recently transmigrated monocytes are thought to be instrumental in such recruitment. We determined the FN-adhesive capacity and integrin expression of monocytes of type 1 and type 2 diabetic patients and related them to the subjects' serum levels of MRP-8, -14 and -8/14. Monocytes of type 1 diabetic patients displayed an increased adhesion to fibronectin in comparison with type 2 patients and healthy control subjects but had a normal expression of the FN binding integrins CD29, CD49a, CD49d, and CD49e (although CD11b and CD18 expression was increased). MRP-8/14, which was increased in the sera of type 1 diabetic patients, induced healthy donor monocytes to adhere to FN and upregulate CD11b expression in a dosage-dependent manner. The observed MRP-induced increased adhesion of monocytes to FN and upregulation of CD11b most likely contributed to a facilitated accumulation of monocytes and monocyte-derived cells at the site of inflammation, in this case the pancreatic islets.

Adult↗
PubMed2003

High numbers of circulating activated T cells and raised levels of serum IL-2 receptor in bipolar disorder.

BACKGROUND: Previously, we found an increased prevalence of thyroid autoantibodies in patients with bipolar disorder. In the present study, we investigated other signs of immune activation in bipolar patients, in particular an activation of the T cell system. METHODS: Fluorescence activated cell scanning (FACS) analysis was performed on lymphocytes of 64 outpatients with DSM-IV bipolar disorder using the T cell marker CD3 in combination with the activation markers MHC-class II, CD25, CD69 or CD71. In 34 patients, these assays were repeated after an interval of 2 years. In addition, T cell activation was determined by measuring serum soluble IL-2 receptor (sIL-2R) in 172 bipolar outpatients. Outcomes were compared with a healthy control group. RESULTS: Significantly higher numbers of circulating activated T cells and raised sIL-2R levels were found in euthymic, manic, and depressed bipolar patients when compared with healthy controls. In general, these abnormalities were stable over time. Manic patients showed significantly higher levels of sIL-2R in comparison with depressed patients. CONCLUSION: The T cell system was found to be activated in both symptomatic and euthymic patients with bipolar disorder. The pathophysiological significance of these findings remains to be explored.

Biomarkers↗