Relationships between fear of flying, loudness dependence of auditory evoked potentials and frontal alpha asymmetry.

Previous research has suggested that fear of flying, which is defined as a situational, specific phobia, could overlap with depressive and anxiety disorders. Whether the neuronal dysfunctions including altered serotonergic activity in the brain and altered neural oscillations observed for depressive and anxiety disorders also overlap with alterations in fear of flying is unclear. Here, thirty-six participants with self-reported fear of flying (FF) and forty-one unaffected participants (NFF) were recruited. The participants completed the Beck Depression Inventory (BDI-II), the State-trait Anxiety Inventory (STAI) and the Fear of Flying Scale (FFS). EEG-recording was conducted during resting-state and during presentation of auditory stimuli with varying loudness levels for analysis of the Loudness Dependence of Auditory Evoked Potentials (LDAEP), which is suggested to be inversely related to central serotonergic activity. Participants with fear of flying did not differ from the control group with regard to BDI-II and STAI data. The LDAEP was higher over F4 electrode in the FF group compared to controls, whereas exploratory analysis suggest that differences between groups were conveyed by female participants. Moreover, the FF group showed relatively higher right frontal alpha activity compared to the control group, whereas no difference in frequency power (alpha, beta and theta) was observed. Thus, this study brought the first hint for reduced serotonergic activity in individuals with fear of flying and relatively higher right frontal activity. Thus, based on the preliminary findings, future research should aim to examine the boundaries with anxiety and depressive disorders and to clarify the distinct neural mechanisms.

Importance of the inducible costimulator molecule for the induction of allergic immune responses and its decreased expression on T helper cells after venom immunotherapy.

The inducible costimulator (ICOS), a newly identified member of the CD28 receptor family that is induced after T-cell activation, and its ligand (ICOSL), being expressed on activated monocytes and dendritic cells play a key role in T-cell-mediated immune responses. As ICOS costimulation also seems to regulate T helper 2 effector cells, the aim of this study was to analyse the function of this molecule in allergic immune responses and their specific therapy, mainly venom immunotherapy (VIT). CD4+ T cells from grass pollen-, or bee or wasp venom-allergic donors were stimulated in the presence of autologous mature dendritic cells, which were pulsed with different allergen doses. In this system, costimulation of ICOS strongly enhanced the production of the T helper 2 cytokines interleukin (IL)-4, IL-5 and IL-10 and, to a lesser extent, secretion of the T helper 1 cytokine, interferon-gamma. Expression of ICOS on CD4+ T cells was induced, in a dose-dependent manner, after a few days of stimulation with allergen-pulsed dendritic cells, reaching a peak on day 6. The upregulation of ICOS after stimulation with venom allergens was significantly reduced after VIT. Addition of exogenous IL-10 (which is induced during VIT) to the co-cultures before VIT also led to an inhibition of ICOS expression, while blocking of IL-10 in co-cultures after VIT partially restored the expression of ICOS. These data indicate that the inhibition of T cells after immunotherapy also involves decreased induction of the costimulatory molecule ICOS, which, in turn, seems to be dependent on the presence of IL-10, also associated with the inhibited status of T cells after VIT. This makes the ICOS-ICOSL pathway a potential target for therapeutic intervention in T helper 2-mediated diseases, such as allergic diseases.

Modification of the human allergic immune response by allergen-DNA-transfected dendritic cells in vitro.

BACKGROUND: Atopic-allergic diseases are characterized by T(H)2-dominated immune responses, resulting in IgE production. DNA-based immunotherapies have been shown to shift the immune response toward a T(H)1-type response in animal models. OBJECTIVE: The aim of the study was to analyze whether dendritic cells (DCs) transfected with allergen-DNA conjugates are able to stimulate human autologous CD4(+) T cells, CD8(+) T cells, or both from atopic individuals to produce T(H)1 cytokines instead of T(H)2 cytokines. METHODS: For this purpose, human mature DCs from atopic donors were transfected with an adenovirus encoding the allergen Phl p 1. Autologous CD4(+) and CD8(+) T cells were stimulated with these transfected DCs, and proliferation and cytokine production were measured. RESULTS: By using an adenoviral vector, a transfection rate of 92% could be achieved. The proliferative response of CD4(+) T cells stimulated with autologous transfected DCs was concentration dependent and almost as high as that of T cells stimulated with mature allergen-pulsed DCs. The proliferation of CD8(+) T cells stimulated with transfected DCs, however, was higher than that of cells stimulated with allergen-pulsed DCs. The cytokine pattern showed a shift toward a T(H)1 immune response compared with T cells stimulated with allergen-pulsed DCs. CONCLUSIONS: Human DCs can be transfected with allergen-DNA conjugates very efficiently by using an adenoviral vector yielding DCs with high T-cell stimulatory capacities, directing the atopic-allergic immune response from T(H)2 dominance toward T(H)1 dominance.

Human CD4+CD25+ T cells derived from the majority of atopic donors are able to suppress TH1 and TH2 cytokine production.

BACKGROUND: Recently, it has been established that CD4(+)CD25(+) T cells with regulatory capacity are present in human peripheral blood, inhibiting allogeneic proliferation and cytokine production of preactivated CD4(+)CD25(-) respond-er T cells. OBJECTIVE: The aim of this study was to analyze in an allergen-specific setting whether such regulatory CD4(+)CD25(+) T cells also exist and function normally in atopic individuals, especially concerning the inhibition of T(H)2 cytokines. METHODS: For this purpose, CD4(+)CD25(-) or CD4(+)CD25(+) T cells from donors allergic to grass or birch pollen (mainly with rhinitis) or from healthy nonatopic donors were stimulated in the presence of autologous, mature, monocyte-derived, allergen-pulsed dendritic cells, and the preactivated CD4(+)CD25(+) T cells were added to CD4(+)CD25(-) T cells during restimulation. RESULTS: CD4(+)CD25(+) T cells from the nonatopic donors and from the majority of the patients investigated proliferated poorly, produced fewer cytokines, and inhibited the proliferation and T(H)1 (IFN-gamma) and T(H)2 (IL-4 and IL-5) cytokine production of CD4(+)CD25(-) T cells but not IL-10 production. The suppression of CD4(+)CD25(-) T cells by CD4(+)CD25(+) T cells was at least partially antigen unspecific and not reversible with anti-IL-10, anti-transforming growth factor beta, or anti-cytotoxic T lymphocyte-associated antigen 4 mAb but was reversible with IL-2. In some atopic patients preactivated CD4(+)CD25(+) T cells reproducibly showed strong proliferative responses, produced higher amounts of IL-4 and IL-10 than CD4(+)CD25(-) T cells, and suppressed only the IFN-gamma production of CD4(+)CD25(-) T cells. CONCLUSION: These data indicate that regulatory CD4(+)CD25(+) T cells are present and functional in most atopic patients with allergic rhinitis and are able to inhibit T(H)1, as well as T(H)2, cytokine production.

Production of interleukin-13 by human dendritic cells after stimulation with protein allergens is a key factor for induction of T helper 2 cytokines and is associated with activation of signal transducer and activator of transcription-6.

Dendritic cells (DC) are able to induce not only T helper 1 (Th1) but also Th2 immune responses after stimulation with allergens. While DC-derived interleukin (IL)-12 and IL-18 are the key factors for the induction of Th1 cells, early signals being involved in Th2 differentiation are less well characterized so far. To analyse such early signals we used an antigen-specific setting with CD4+ T cells from atopic donors stimulated in the presence of autologous mature DC, which were pulsed with different allergen doses. The addition of increasing amounts of allergen during DC maturation with tumour necrosis factor-alpha, IL-1beta and prostaglandin E2 resulted in enhanced secretion of IL-6 and IL-12 by DC followed by increased production of Th1 (interferon-gamma; IFN-gamma) as well as Th2 (IL-4, IL-5) cytokines by CD4+ T cells. The coculture of allergen-treated DC and CD4+ T cells also led to a dose-dependent expression of active signal transducer and activator of transcription-6 (STAT6), which was visible already after 1 hr. Additionally, rapid phosphorylation of STAT6 was seen in immature DC after stimulation with allergens but not with lipopolysaccharide or human serum albumin. STAT6 phosphorylation was associated with the production of IL-13 by DC. The addition of neutralizing anti-IL-13 antibodies during maturation of DC inhibited STAT6 phosphorylation in CD4+ T cells as well as the production of IL-4, and to a lesser extent of IL-5, while IFN-gamma production was not affected. Addition of exogenous IL-13 enhanced mainly the secretion of IL-4. Taken together, DC-derived IL-13, which is released after exposure to allergens appears to be one of the critical factors for DC to acquire the capability to induce Th2 cytokine production.