The sensation of itch - defined as unpleasant sensation inducing the urge to scratch - is processed by a network of different brain regions contributing to the encoding of sensory, emotional, attention-dependent, cognitive-evaluative and motivational patterns. Patients with atopic eczema show different activation patterns and kinetics compared to healthy volunteers. This review summarizes current studies investigating itch in the brain.

Allergy is an instructive model to study neuroendocrine-immune interaction in chronic inflammation, a key research task taken on by a relatively new scientific field: psychoneuroimmunology (PNI). Itch, as the prime symptom of many chronic inflammatory diseases but especially of allergic inflammation, hints at the prominent role of neurogenic inflammation in the course of the disease. Environmental factors ranging from allergens to perceived stress can trigger the release of neuropeptides from peripheral nerve endings that than activate mast cells and induce an exaggerated alarm response in peripheral organs such as the skin. Beyond this innate immune response, neuroendocrine-immune interaction regulates specific immune balance. Depending on intensity and timing of neuroendocrine activation, especially neuropeptides and neurotrophins either enhance or suppress tissue regeneration and inflammation, the conditions of which will be discussed in detail here. Allergic inflammation thus serves to understand the clinical and therapeutic implications of neuroendocrine-immune interaction in chronic inflammatory disease and its implications for future treatment strategies.

Food allergy accounts for a great number of reactions leading to diminished quality of life in western countries. There has been an abundance of reports of behavioral changes, as well as psychiatric conditions associated with food allergy over the past decades. Most of this field inspired little medical attention for its lack of a solid scientific ground. We review the literature on the association of food allergy and brain activity, leading to changes in emotion and behavior. Moreover, we describe an experimental paradigm employed to dissect the biological relevance of this association. Mice allergic to ovalbumin avoid a palatable sweet solution in order to escape contact with antigen. This choice is associated with increased levels of anxiety, compatible with a conflicting situation. These responses are associated with increased activity in brain areas associated with emotional and affective behavior, which are also important for anxiety and stress responses. Higher levels of corticosterone accompany these changes in behavior. These responses are mediated by specific antibodies and prevented by depletion or immunological tolerance. They are also partially mediated by C-sensitive afferents and mast cells. Far from anecdote, neural repercussions of food allergy should be considered when planning a therapeutic strategy in affected individuals.

A key characteristic of mast cells appears to be an ability to span the division between nervous and immune system. Indeed, much of our understanding of the bi-directional relationship between the nervous and immune systems has come from the study of mast cell-nerve interaction. Although differences in species have been reported, morphologic as well as functional associations between mast cell and nerves are found in most tissues in many mammalian species, including humans. These interactions are involved in the regulation of physiologic homeostatic processes as well as in disease mechanisms. Here we discuss the influence of cholinergic and sensory neurons on mast cells as well as the importance of mast cell nerve interactions at specific tissue sites, including the brain.

The cervical sympathetic nerves which innervate the medial basal hypothalamus-hypophyseal complex, primary and secondary lymph organs, and numerous glands, such as the pineal, thyroid, parathyroid and salivary glands form a relevant neuroimmunoendocrine structure that is involved in the regulation of systemic homeostasis. The superior cervical ganglia and the submandibular glands form a 'neuroendocrine axis' called the cervical sympathetic trunk submandibular gland (CST-SMG) axis. The identification of this axis usurps the traditional view of salivary glands as accessory digestive structures and reinforces the view that they are important sources of systemically active immunoregulatory and anti-inflammatory factors whose release is intimately controlled by the autonomic nervous system, and in particular the sympathetic branch. An end component of the CST-SMG axis is the synthesis, processing and release of submandibular rat-1 protein (SMR1), a prohormone, that generates several different peptides, one from near its N-terminus called sialorphin and another from its C-terminus called - submandibular gland peptide-T (SGP-T). SGP-T formed the template for tripeptide fragment (FEG) and its metabolically stable D-isomeric peptide feG, which are potent inhibitors of allergy and asthma (IgE-mediated allergic reactions) and several non-IgE-mediated inflammations. The translation from rat genetics and proteomics to humans has yielded structural and functional correlates that hopefully will lead to the development of new medications and therapeutic approaches for difficult to treat disorders. Although the CST-SMG axis has barely been explored in humans recognition of the importance of this axis could facilitate an understanding and improved management of periodontal disease, and other diseases with a more systemic and nervous system basis such as asthma, autoimmunity, graft-versus-host disease and even Parkinson's disease.

There has been an increasing and intense interest in the role that gut bacteria play in maintaining the health of the host. Gut microbiota have an estimated mass of 1-2 kg, number 100 trillion and together possess 100 times the number of genes in the human genome. In addition to their well-established role in the postnatal maturation of the mammalian immune system, they are also responsible for an enormous array of metabolic activities that include effects on the digestion of food and the production of a host of biologically active substances. Moreover, it is also rapidly becoming apparent that the gut microbiome plays a major role in the development and regulation of neuroendocrine systems such as the hypothalamic-pituitary-adrenal axis, a central integrative system crucial for the successful physiological adaptation of the organism to stress. In fact, our previous study on gnotobiotic mice demonstrated that exposure to gut microbes is a postnatal environmental determinant that regulates the development of the hypothalamic-pituitary-adrenal axis stress response and also the set point for this axis.

Many of the symptoms of allergic airway disease such as sneezing, coughing, excessive secretions, reflex bronchoconstriction, and dyspnea occur secondary to changes in the activity of the airway nervous system. In addition, many subjects with allergic airway disease have a heightened sensitivity to non-immunologic irritants in the environment. The symptoms and heightened sensitivities may be explained largely as a consequence of allergen-induced neuromodulation. Mediators associated with allergic inflammation can modulate primary afferent nerves, their connecting neurons in the central nervous system, as well as efferent autonomic neurons innervating the airways. This modulation can take the form of acute electrophysiological changes, or more persistent phenotypic changes at the level of gene transcription, i.e. neuroplasticity. Some of the known mechanisms that underlie this modulation are reviewed here.

Bronchopulmonary inflammation, such as that associated with asthma, activates afferent neural pathways. We recently demonstrated that localized inflammation in the lungs, induced by intratracheal administration of ovalbumin in ovalbumin-preimmunized mice (an animal model of asthma) results in activation of the dorsolateral part of the nucleus of the solitary tract, a major target of vagal afferent fibers innervating the lungs and airways. Activation of the nucleus of the solitary tract was evident in the absence of activation of the area postrema, a circumventricular organ, consistent with the hypothesis that localized inflammation in the bronchopulmonary system can signal to the central nervous system via specific neural pathways, in the absence of circulating proinflammatory mediators. The pattern of brain activation in ovalbumin-challenged mice differs from the pattern of activation in mice challenged with heat-killed Mycobacterium vaccae, suggesting that qualitative aspects of bronchopulmonary inflammation determine the overall pattern of brain activation. The mechanisms through which localized bronchopulmonary inflammation signals to the central nervous system is poorly understood, but appears to involve both vagal and spinal afferent pathways. In this chapter, we review our current understanding of the anatomical pathways through which localized inflammation in the bronchopulmonary system influences central nervous system function.

Allergic asthma is a chronic inflammatory disease characterized by the production of allergen-specific IgE antibodies, TH2 inflammation, airway hyperresponsiveness and airway remodeling. Airway remodeling represents the disease-limiting stage during disease progression, and the underlying cellular molecular network resulting in airway remodeling are still poorly defined. In addition to the well-established TH2-dependent inflammatory response, several lines of investigation reveal that this regulation in the peripheral central nervous system contributes to disease development, exacerbation and progression. Several members of the neurotrophin family (e.g. nerve growth factor, brain-derived neurotrophic factor) are important transmitters of signals between the immune and the nervous system. Recent data indicate that NGF contributes to the development of airway remodeling in an inflammation and TGF-independent manner. These and other data open the opportunity to therapeutically interfere also on this level of regulation as a novel approach.

DNA methylation is an enzymatic modification of the DNA molecule that confers unique differential identities upon similar DNA sequences. DNA methylation plays a critical role in cellular differentiation by conferring cell-type identity upon differentiated tissues in multicellular organisms by an innate developmentally programmed process. Recent data points to the possibility that DNA methylation plays a role in responding to external cues and conferring environment-context identity to DNA. DNA methylation is implicated in the response to early life social environment and might be playing an important role in setting up stable behavioral phenotypes in response to early-life social environment. The critical question is whether these responses are limited to the brain or involve the immune system as well. Addressing this question has important implications on understanding the mechanisms involved in DNA methylation mediated responses to the environment and how they impact the phenotype as well as on the possibility of studying the associations between DNA methylation and behavior and behavioral pathologies in living humans. A model is presented suggesting that DNA methylation acts as a mechanism of genome adaptation to the environment that is genomewide and systemwide. New data suggesting associations between DNA methylation patterns in white blood cells and the social environment will be discussed.