H J de Wit

Glucocorticoids hamper the ex vivo maturation of lung dendritic cells from their low autofluorescent precursors in the human bronchoalveolar lavage: decreases in allostimulatory capacity and expression of CD80 and CD86

Dendritic cells (DCs) were prepared from human bronchoalveolar lavage (BAL) cells. We previously reported that, in particular, the CD1a fraction of the low autofluorescent (LAF) cells contains the precursors for DCs: after overnight culture, 40% of the LAF cells change into functionally and phenotypically prototypic dendritic/veiled cells. There are, as yet, no data on the modulatory effects of glucocorticoids (GC) on the maturation and function of such DCs isolated from the human lung. Functional tests (allogeneic mixed lymphocyte reaction: allo‐MLR) were therefore performed with CD1a+ LAF cells at different stimulator‐to‐T‐cell ratios and after preincubation with different dexamethasone (DEX) concentrations. DEX caused suppression of the T‐cell stimulatory capacity of CD1a+ LAF cells, which was dose‐dependent, and more evident at the higher stimulator‐to‐T‐cell ratios. Here, we also show that CD80 and CD86 are normally expressed at low levels on CD1a+ LAF cell‐derived DCs compared to other DC populations. This low‐level expression of costimulatory molecules is discussed here in relation to the previously reported low‐level expression of CD80 (and CD86) on lung DCs in experimental animals. This appears to play a role in a predominant Th2 cell stimulating potential of DC from the lung environment. DEX exposure of CD1a+ LAF cells prevented the upregulation of even this low‐level expression of CD80 and CD86. The veiled/dendritic morphology and the expression of other relevant cell surface markers and adhesion molecules was not affected by DEX exposure. It is concluded that DEX hampers the maturation of CD1a+ LAF cells into active lung DCs.

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

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.

A dynamic course of T cell defects in individuals at risk for mood disorders.

OBJECTIVES T cell abnormalities have been repeatedly reported in adult patients with mood disorders, suggesting a role of these cells in the pathogenesis of these disorders. In the present study, we explored the dynamics of circulating T cell subsets over time in a population at high familial risk for developing a mood disorder. METHODS Children of a parent with bipolar disorder (bipolar offspring, N=140) were assessed at three time-points: adolescence, young adulthood and adulthood. We carried out a detailed fluorescence-activated cell sorting (FACS) analysis to determine various T cell subsets from frozen stored peripheral blood mononuclear cells of bipolar offspring and age- and gender-matched healthy controls at each time-point. RESULTS Throughout the period of observation reduced levels of CD3+ and CD3+ CD4+ T cells were observed. In bipolar offspring Th1, Th2, Th17 and natural T regulatory cells (Tregs) followed a dynamic course over time with reduced levels of Tregs in adolescence and a reduced relative number of Th1, Th17 cells in young adulthood. In post hoc analysis Tregs were inversely associated with the pro-inflammatory monocyte state determined previously (rs=-0.220, p=0.001). Significant associations between T cell subset abnormalities and psychopathology such as mood disorders were not found. CONCLUSIONS A subtle partial T cell defect was present in bipolar offspring from adolescence through adulthood. Within this defect the dynamic change of inflammatory and regulatory T cell subsets suggests a high inflammatory state during adolescence, a reduced inflammatory state during young adulthood and a virtually normalized state at adulthood.

A hampered chemoattractant‐induced cytoskeletal rearrangement in granulocytes of patients with unexplained severe chronic and relapsing infections of the upper and lower airways. In vitro restoration by G‐CSF exposure

Granulocytes play a major role in host defense against bacterial infections. Severe inborn defects in granulocyte function are associated with fulminant bacterial infections in early childhood. Subtle disturbances in granulocyte function might contribute to an enhanced susceptibility to bacterial infections in adulthood. We investigated chemoattractant (N‐formyl‐methionyl‐leucyl‐phenylalanine, fMLP and casein) induced cytoskeletal rearrangements (polarization) of blood granulocytes in 77 adults with chronic and recurrent therapy‐resistant infections of the upper and lower airways. These infections could not be explained by B‐ and/or T‐cell defects or local anatomic abnormalities. Besides polarization, chemotaxis of blood granulocytes was measured in 33 patients, as well as granulocyte superoxide production in eight patients.

Immune dysregulation in offspring of a bipolar parent. Altered serum levels of immune growth factors at adolescent age

Immune dysregulation plays a role in the vulnerability for mood disorders. Immune growth factors, such as Stem Cell Factor (SCF), Insulin-like Growth Factor-Binding Protein-2 (IGF-BP2), Epidermal Growth Factor (EGF), IL-7 and sCD25 have repeatedly been reported altered in patients with mood disorders. The aim of this study was to investigate levels of these factors in serum of adolescent bipolar offspring, who have a heightened risk for mood disorder development and to also analyze the data combined with previously published data. Growth factors were assessed by CBA/ELISA in adolescent bipolar offspring (n=96, mean age=16years) and in age- and gender-matched healthy controls (n=50). EGF belonged to a mutually correlating cluster of mainly neurotrophic compounds including S100B and BDNF, which were in general decreased in serum. IL-7, SCF, IGF-BP2 and sCD25, belonged to a different mutually correlating cluster of immune growth factors, which were in general increased: IGF-BP2 significantly in serum of offspring without a mood disorder, IL-7 and SCF in serum of offspring who had experienced a mood episode. This pattern of de- and increases was not different between bipolar offspring that developed or did not develop a mood disorder over time, apart from the IGF-BP2 level, which was near significantly higher in offspring later developing a mood disorder. Correlations with the previously published immune-cellular abnormalities were not found. In conclusion non-affected adolescents at familial mood disorder development risk were characterized by a distinct pattern of a series of compounds operating in a network of hematopoiesis, neurogenesis and inflammation.

Thyroid Hormones and Their Iodinated Breakdown Products Enhance the Capability of Monocytes to Mature Into Veiled Cells. Blocking Effects of α-GM-CSF

Dendritic cells play a crucial role in the initiation of immune responses. The precursor of these cells present in the blood has not yet been characterised. However, we and others, Peters et al, have reported that 30-40 % of cells with a dendritic/veiled morphology, MHC class-II positivity and weak to absent acid phosphatase positivity can be derived from almost pure blood monocyte fractions1 after a pulse with 14. 5% metrizamide and an overnight culture under nonadhering conditions2. These monocyte-derived dendritic/veiled cells are more capable than the original monocytes to act as stimulator cells in a MLR, are less phagocytic and express less CD14. Since metrizamide is an iodinated compound structurally related to the thyroid hormones T3 and T4 it was speculated that these thyroid hormones, their iodinated breakdown products and may be iodine itself might play a role in enhancing the monocyte-dendritic cell transition. In this study we investigated the effect of several iodinated compounds such as T4, T3, reverse T3 (rT3), their degradation products and MIT and DIT on the maturation of human peripheral blood monocytes into dendritic/veiled cells.

Peripheral immune abnormalities in two high-risk populations for bipolar disorder

Background and Aims: Depression and anxiety are risk factors for developing Coronary heart Disease (CHD), and are associated with poor disease outcomes and mortality. However, there is little information describing repeated measures and longitudinal data that may study the trajectories of depression and anxiety over time,how these are manifested in the context of CHD, and their relationship to sociodemographic measures, cardiac risk factors, and measures of disability. Methods: Using a primary care cohort of 803 patients with a diagnosis of CHD, a latent class growth curve model was developed to study the distinct trajectories of depression and anxiety symptoms over a 3 year period, with 7 distinct 6-month follow-up points.Logistic regression analysis was then conducted to study the association between latent classes and baseline risk factors. Results: The 5-class model yielded the best combination of statistical best-fit analysis and clinical correlation. These classes were:‘stable asymptomatic’ (n = 558), ‘increasing symptoms’ (n = 64),‘decreasing symptoms’ (n = 15), ‘chronic highly symptomatic’(n = 55), and ‘fluctuating symptoms’ (n = 111).The comparison group was the ‘stable asymptomatic’ class. Female sex was associated with the ‘fluctuating class’. Non-white ethnicity was associated with ‘chronic high’ and ‘worsening’ class. Current smoking was associated with all classes, particularly the ‘chronic high’ class.Chest pain was associated strongly with ‘chronic high’ class. Multi-variate models will analyse these associations further. Conclusions: The distinct trajectories of depression and anxiety in CHD will provide important information on the specific ways in which these symptoms affect patients, and provide unique insight into the monitoring and management of this comorbidity.