Gut Mucosa-Associated Lymphoid Tissue: ANS Innervation


Javier Santos, M.D., Ph.D.
Hospital Universitario Valle de Hebron. Digestive System Research Unit. Barcelona, Spain.

Goals and Objectives

1. To understand that immune and nervous systems display a dynamic and interactive communication based upon the presence of common messengers and receptors.

2. This interaction is functionally relevant and may have important clinical implications.

3. Modulation of nerve-immune interactions in the gastrointestinal and respiratory tracts may influence the course of hypersensitivity and inflammatory disorders. Development of new drugs with blocking or enhancing activity against nerve-immune mediators and receptors may contribute to the prevention and treatment of these disorders.


The mucosal surfaces of the body are the first and critical location where immunogenic particles and molecules (food and microorganism-derived antigens) gain access to the immune system. Antigen processing in this region will determine whether an immunological balanced or unbalanced response (anaphylactic reaction) or a permissive one (tolerance) is mounted. Mucosal membranes are covered by epithelial layers. In the gastrointestinal and respiratory systems, classical effector cells of immune reactions (lymphocytes, eosinophils, mast cells, neutrophils, macrophages and dendritic cells) are normally present. Non-traditional immune cells, including epithelial, mesenchymal (fibroblasts, myofibroblasts, muscle cells), endothelial and nerve cells and also acellular components such as the extracellular matrix may also display potentially relevant effector and modulatory functions in antigen processing and immunologic responses. In addition, food itself may be also immunomodulatory.

Our knowledge of the immunoregulatory effects of nerves and neuropeptides has grown tremendously. Considerable and converging evidence has now established the existence of multidirectional communication between the neural and immune systems. This interaction involves most immune cells present in mucosal surfaces, and both the central and peripheral nervous systems, including efferent and afferent subdivisions of the autonomic nervous system, sympathetic and parasympathetic, as well as the enteric nervous system. Moreover, those studies have shown the functional relevance of neuro-immune interactions in regulating immunological and inflammatory events in mucosal surfaces, by influencing the transport of macromolecules across the epithelial surface, the expression of adhesion molecules, the release of cytokines, chemokines, neurotransmitters, neuropeptides, and other regulatory molecules that participate in the trafficking and homing of immune cells in the mucosal layers, the growth and remodeling of nerves, and even the apoptotic cascade. A good clinical correlate are food-allergic reactions that may display a broad spectrum of clinical manifestations involving most tissues in the body, although it is generally accepted that primary events predominantly occur at the level of the gastrointestinal mucosa.

A distinct characteristic of the complex neuroendocrine and immune systems is the high level of integration of both systems which together provide the organism with an ultra-fine homeostatic balance. The neuroendocrine system modulates the function of the immune system through the release of neuropeptides, neurohormones and neurotransmitters. In addition, a primary or counteracting immunoregulatory role for immune cells has also been reported which comprises the effects of mediators released by immunocompetent cells on neuroendocrine function. It is now clear that immune cells are able to synthesize and release neuropeptides and even classical hormones such as growth hormone or prolactin, and that endocrine and neural cells can produce a broad array a cytokines originally described as being part of the repertoire of immune cells. This conference will focus mainly on the efferent limb of the neuro-immune interactions, that is the effect of neural mediators on immune cells, particularly lymphocytes and mast cells. For this purpose anatomical and functional evidence for the presence and relevance of neural and neuropeptide-containing fibers in lymphoid tissues and immunocompetent cells will be reviewed. Finally, experimental and clinical data supporting the potential relevance of this interplay and its significance in the management of food allergy and other inflammatory disorders will be briefly exposed.


Central and peripheral nervous system manipulation by psychological (hypnosis, behavioral conditioning), pharmacological and other modalities of intervention could turn out to be as very valuable weapons against the deleterious effects of environmental stressors on the immune system. In particular, increasing awareness of the major role of gastrointestinal inflammation in the development of local and systemic adverse reactions to food, microbial and chemical components may open new avenues in the treatment and prevention of environmental-related inflammatory disorders.

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