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Signaling Mechanisms Intersecting Histamine Receptors and Pattern Recognition Receptor Activation in Dendritic Cells

Final Report Summary - DC-SIGNAL (Signaling Mechanisms Intersecting Histamine Receptors and Pattern Recognition Receptor Activation in Dendritic Cells)

The immune response is a tightly regulated process which normally results in protection from infection and tolerance of innocuous environmental antigens. However, in allergy and asthma patients, the activated immune response results in a chronic pro-inflammatory state characterized by abnormal immune responses to normally well-tolerated substances resulting in tissue inflammation and airway remodeling. One of the cell types, that are very important for appropriate immune responses, are dendritic cells. Dendritic cells are essential for inducing activation and differentiation of effector cells and it is well established that these cells play a pivotal role in the initiation and maintenance of allergic inflammation. However, the molecular basis for aberrant dendritic cell activation within allergy and asthma patients is still poorly defined. One of the chemicals released by the body during allergic responses is histamine. Histamine has a number of different effects on the immune response and we hypothesised that histamine may alter dendritic cell responses, in particular to microbial factors (Figure 1). The overall goal of this project was to definitively characterize the influence of histamine on dendritic cell activation and to define the relevance of this activity for allergic inflammation. In order to achieve this goal the project had three specific aims:
1. Characterise the impact of histamine, in vitro, on dendritic activation and T cell polarization;
2. Elucidate the intracellular signaling mechanisms responsible for linking the histamine receptor(s) and pattern recognition receptors;
3. Determine the in vivo relevance for histamine modulation of dendritic cell activity.
This project was very successful in realising the project aims and goal. In summary, we identified that human dendritic cells respond very differently to microbial ligands, when histamine is present in the microenvironment. Histamine suppresses the pro-inflammatory response to microbial ligands, while enhancing the anti-inflammatory response. This effect was mediated by the histamine receptor 2, not histamine receptors 1 or 4. We characterised the intracellular signaling pathway in detail and these results have been published in the top journal dealing with allergy and asthma (Figure 2). In addition, during the course of these studies, we made a very surprising discovery. Bacteria that are present within the gastrointestinal tract can also make histamine and the histamine secreted from these bacteria have immunoregulatory effects within the mucosa. Finally, we examined the influence of histamine signaling in a mouse model of respiratory allergy. We have discovered that in histamine receptor 2 deficient animals, they develop a much more severe type of allergic inflammation. This is caused by defects in dendritic cell activation and lymphocyte regulation. The results of the animal studies have been submitted for publication in a high impact factor journal.
The findings of this project have altered how researchers view the importance of histamine. Everyone recognises that histamine is important for the symptoms associated with an allergic response. However, our results have demonstrated that histamine is not always the "bad guy". Rather, histamine is important for fine tuning immune responses and histamine activation of histamine receptor 2 is very important for suppressing allergic inflammation, particularly within the lung. This results of this project have prompted us, and others, to look at the potential for histamine receptor 2 agonists in the treatment of allergic airway inflammation.
Another important impact of this project, is the discovery that bacteria within the intestine can also secrete this chemical. Due to the results generated in this project, we have obtained funding from the Swiss National Science Foundation to examine the influence of bacterial-derived histamine in a wide range of inflammatory diseases. We are currently examining samples from asthma patients, IBD patients, IBS patients, food allergy patients and children for the presence of histamine-secreting microbes. We will determine if specifically targeting these microbes might be of benefit for these patient groups.
Already this project has resulted in 5 peer-reviewed publications, 1 book chapter and 25 oral communications and 8 poster presentations. There are 2 more manuscripts that are currently under review and should be published during 2014.
For further information, please contact Dr. Liam O'Mahony, Swiss Institute of Allergy and Asthma Research, University of Zürich, Obere strasse 22, 7270 Davos Platz, Switzerland (e-mail: liam.omahony@siaf.uzh.ch)
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