Hemmo A. Drexhage

Immunohistochemical Characterization of Monocytes-Macrophages and Dendritic Cells Involved in the Initiation of the Insulitis and β-Cell Destruction in NOD Mice

This immunohistochemical study describes the infiltration pattern of monocytes-macrophages and dendritic cells during the development of insulitis and diabetes in the NOD mouse. A panel of monoclonal antibodies (MoAbs) was used to analyze pancreases of nondiabetic (glucosuria negative) male and female NOD mice at 3, 7, 10, and 17 weeks of age. BALB/c female mice 17-weeks-old, diabetic NOD female mice 20- to 30-weeks-old, and nondiabetic NOD male mice 22-weeks-old were used as controls. Three MoAbs (viz., ER-MP23, MOMA1, and BM8) were special and appeared to identify macrophage/dendritic cell subsets that either had a characteristic infiltration pattern in the initial phases of the autoimmune reaction before T-cell infiltration or were typical for the later β-cell destructive insulitis process. 1) Raised numbers of ER-MP23+ and MOMA-1+ dendritic cells/macrophages were characteristic for the initial phases of the NOD insulitis in 3-week-old mice. The cells were found in and near swollen para-insular vessels. In 7-week-old mice, these ER-MP23+ and MOMA-1+ cells had accumulated around the islets and were the first hematopoietic cells detectable at these spots. 2) From 7 weeks of age onward, BM8+ macrophages could be found in the para- and peri-insulitis processes. However, only in females were these BM8+ macrophages found to infiltrate into the islets. In lymphoid tissues, ER-MP23 predominantly reacts with macrophages/dendritic cells present in the subcapsular and interfollicular sinuses of lymph nodes and the T-cell zones of these lymph nodes. ER-MP23 also reacts with tissue macrophages/dendritic cells. MOMA-1 reacts with the marginal metallophilic macrophages of the spleen and with sinus macrophages of the lymph node. Both populations of cells are likely to be involved in antigen presentation in lymphoid tissues as well as in the NOD peri-insulitis. BM8 in lymphoid tissues predominantly reacts with the phagocytosing macrophages present in the red pulp of the spleen. Because β-cell destruction and glucosuria almost exclusively take place in NOD females, our findings suggest that BM8+ macrophage infiltration into the female islets is linked to a β-cell destructive process, either as a destructive type of infiltration or as an infiltration meant to remove the β-cell debris caused by another immune assault.

A discriminating messenger RNA signature for bipolar disorder formed by an aberrant expression of inflammatory genes in monocytes.

CONTEXT Mood disturbances are associated with an activated inflammatory response system. OBJECTIVE To identify a discriminating and coherent expression pattern of proinflammatory genes in monocytes of patients with bipolar disorder. DESIGN A quantitative polymerase chain reaction (Q-PCR) case-control gene expression study on purified monocytes of bipolar patients, the offspring of bipolar patients, and healthy control participants after having selected 22 discriminating inflammatory genes using whole genome analyses. SETTING Academic research setting in The Netherlands. PATIENTS Forty-two bipolar patients with 25 healthy controls, 54 offspring of a bipolar parent (13 had a mood disorder and 3 developed one during follow-up), and 70 healthy children underwent Q-PCR. MAIN OUTCOME MEASURE Inflammatory gene expression levels in monocytes. RESULTS We detected in the monocytes of bipolar patients a coherent mutually correlating set (signature) of 19 aberrantly expressed (P < .01) messenger RNAs of inflammatory (PDE4B, IL1B, IL6, TNF, TNFAIP3, PTGS2, and PTX3), trafficking (CCL2, CCL7, CCL20, CXCL2, CCR2, and CDC42), survival (BCL2A1 and EMP1), and mitogen-activated protein kinase pathway (MAPK6, DUSP2, NAB2, and ATF3) genes. Twenty-three of 42 bipolar patients (55%) had a positive signature test result vs 7 of 38 healthy controls (18%) (positive test result: positivity for PDE4B, ie, a messenger RNA 1 SD higher than the mean level found in healthy controls, plus 25% of the other genes with similar positive findings). Positive signature test results were also present in 11 of 13 offspring with a mood disorder (85%), 3 of 3 offspring developing a mood disorder (100%), and 17 of 38 euthymic offspring (45%) vs 13 of 70 healthy children (19%). Lithium carbonate and antipsychotic treatment downregulated the gene expression of most inflammatory genes. CONCLUSIONS The monocytes of a large proportion of bipolar patients and offspring of bipolar parents showed an inflammatory gene expression signature. This coherent set of genes opens new avenues for biomarker development with possibilities for disease prediction in individuals genetically at risk and for the subclassification of bipolar patients who could possibly benefit from anti-inflammatory treatment.

Subclinical hyperthyroidism and the risk of dementia. The Rotterdam study

We investigated the prospective relationship between thyroid status and the risk of dementia and Alzheimers disease among a random sample of 1843 participants, aged 55 years and over, from the population‐based prospective Rotterdam Study.

The mononuclear phagocyte system and its cytokine inflammatory networks in schizophrenia and bipolar disorder

This review describes patients with schizophrenia and bipolar disorder. In such patients, a high inflammatory set point of circulating monocytes at the transcriptome level is observed, involving various inflammatory transcripts forming distinct fingerprints (the transcriptomic monocyte fingerprint in schizophrenia overlaps with that in bipolar disorder, but also differs with it at points). There are increased levels of compounds of the IL-1, IL-6 and TNF system in the serum (be it modest and inconsistent). There is also evidence that the IL-2 system is activated in patients with schizophrenia (and perhaps those with mania), although independently of the activation of the IL-1, IL-6 and TNF systems, suggesting separate inducing mechanisms for monocyte and T-cell activation. It is not yet known whether such T cell activation involves the Th1/Th2/Th17 or Treg systems.

The immune theory of psychiatric diseases : a key role for activated microglia and circulating monocytes

This review describes a key role for mononuclear phagocytes in the pathogenesis of major psychiatric disorders. There is accumulating evidence for activation of microglia (histopathology and PET scans) and circulating monocytes (enhanced gene expression of immune genes, an overproduction of monocyte/macrophage‐related cytokines) in patients with bipolar disorder, major depressive disorder, and schizophrenia. These data are strengthened by observations in animal models, such as the MIA models, the chronic stress models, and the NOD mouse model. In these animal models of depressive‐, anxiety‐, and schizophrenia‐like behavior, similar activations of microglia and circulating monocytes can be found. These animal models also make in‐depth pathogenic studies possible and show that microglia activation impacts neuronal development and function in brain areas congruent with the altered depressive and schizophrenia‐like behaviors.

High rate of autoimmune thyroiditis in bipolar disorder: lack of association with lithium exposure

BACKGROUND We assessed the prevalence of thyroperoxidase antibodies (TPO-Abs) and thyroid failure in outpatients with bipolar disorder compared with two control groups. METHODS The TPO-Abs of outpatients with DSM-IV bipolar disorder (n = 226), a population control group (n = 252), and psychiatric inpatients of any diagnosis (n = 3190) were measured. Thyroid failure was defined as a raised thyroid stimulating hormone level, previously diagnosed hypothyroidism, or both. Subjects were compared with attention to age, gender, and exposure to lithium. RESULTS The TPO-Abs were more prevalent in bipolar patients (28%) than population and psychiatric controls (3-18%). The presence of TPO-Abs in bipolar patients was associated with thyroid failure, but not with age, gender, mood state, rapid cycling, or lithium exposure. Thyroid failure was present in 17% of bipolar patients and more prevalent in women. It was associated with lithium exposure, especially in the presence of TPO-Abs, but not with current rapid cycling, although an association may have been masked by thyroid hormone replacement. CONCLUSIONS Thyroid autoimmunity was highly prevalent in this sample of outpatients with bipolar disorder and not associated with lithium treatment. These variables appear to be independent risk factors for the development of hypothyroidism, especially in women with bipolar disorder.

Defective maturation and function of antigen-presenting cells in type 1 diabetes.

Macrophages and dendritic cells are important as antigen-presenting cells in the islet autoimmune response. We report decreased maturation of dendritic cells from blood monocytes of 61 patients with type 1 diabetes compared with 31 healthy controls (medians 26 and 35%, respectively, p = 0.0005). The dendritic cells also had reduced ability to cluster (96 and 124 clusters, respectively, p = 0.0005), and to stimulate autologous and allogeneic T cells. Because optimum antigen presentation is primarily required for tolerance induction rather than for immunisation, the defective maturation and function of diabetic dendritic cells might be the basis for disturbed activation of regulatory (suppressor) T cells.

A study of cells present in peripheral lymph of pigs with special reference to a type of cell resembling the langerhans cell

SummaryLarge mononuclear cells with long, actively moving cytoplasmic veils were observed in lymph coming from the skin. The enzyme histochemistry and ultrastructure of these cells suggested that they are related to epidermal Langerhans cells and interdigitating cells in the lymph node. It has been reported that Langerhans cells and interdigitating cells play a role in contact hypersensitivity by taking up antigen and presenting it to thymus-dependent lymphocytes, and it is likely that the veiled cells in the lymph are also involved.After skin-painting with 1-fluoro-2,4-dinitrobenzene (DNFB), the veiled cells in lymph coming from the site of painting became more active and were observed contacting other cells present in the lymph; many large cellular aggregates were found. Since neutrophilic leucocytes and mononuclear phagocytes were the predominating cell types in this lymph, there was no evidence for a massive recruitment of immunocompetent lymphocytes at the site of painting.Neonatally thymectomized pigs do not develop allergic reactivity to DNFB. It is of interest that the number of veiled cells and their ability to form large cellular aggregates was not affected in these animals. Therefore, it is unlikely that the defect in responsiveness can be attributed to a failure in the function of veiled cells.

Autoimmunity, inflammation, and psychosis: a search for peripheral markers.

Accumulating evidence supports the view that deregulation of the immune system represents an important vulnerability factor for psychosis. In a subgroup of psychotic patients, the high comorbidity with autoimmune and chronic inflammatory conditions suggests a common underlying immune abnormality leading to both conditions. The reviewed data of affective and nonaffective psychosis show that if immune biomarkers exist for such immune abnormality, they may be found in raised macrophage/monocyte inflammatory activation patterns (monocytosis, high-inflammatory gene expression, raised glucocorticoid receptor β/glucocorticoid receptor α ratio, and high levels of proinflammatory and anti-inflammatory monocyte/macrophage derived cytokines in serum/plasma), reduced T cell numbers/proliferation, and TH1 skewing. This activation of the inflammatory response system may be suggestive for microglia activation, as these cells are the macrophages of the brain. Indeed, there is some evidence of activation of the microglia as detected in positron emission tomography scans and in histopathology, and it is assumed that this activation disturbs the development and function of neuronal circuits in the brain. Further, animal models of psychotic conditions (maternal stress and inflammation paradigms) suggest that such monocyte/microglia activation could be seen as the result of a combination of genetic predisposition and an immune-mediated two-hit model. Infection but also environmental stressors during gestation/early life activate microglia, perturbing neuronal development, thereby setting the stage for vulnerability for later psychotic disorders. A second hit, such as endocrine changes, stress, or infection, could further activate microglia, leading to functional abnormalities of the neuronal circuitry in the brain and psychosis.

Comparison of placebo with L-thyroxine alone or with carbimazole for treatment of sporadic non-toxic goitre

The efficacy of treatment with TSH-suppressive doses of L-thyroxine (T4, 2.5 micrograms/kg body weight daily) either alone or combined with carbimazole (CBZ, 40 mg daily) was studied in 78 patients with sporadic non-toxic goitre in a prospective placebo-controlled double-blind randomised clinical trial. Treatment was given for 9 months, with 9 months of follow-up. A response to treatment as measured by ultrasonography was found in 58% of the T4 group, in 35% of the T4/CBZ group, and in 5% of the placebo group. The mean (SEM) decrease of thyroid volume at 9 months in the responders was 25% (2). After discontinuation of treatment, thyroid volume increased in the responders and had returned to base-line values after 9 months of follow-up. In the placebo group mean thyroid volume had increased by 6% (4) at 4 months, 20% (7) at 9 months, and 27% (8) at 18 months. The findings show that untreated sporadic non-toxic goitre continues to increase in size; T4 is effective in the treatment of the disorder; and the addition of CBZ has no therapeutic advantage.