Review
Sympathetic modulation of immunity: Relevance to disease

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Abstract

Optimal host defense against pathogens requires cross-talk between the nervous and immune systems. This paper reviews sympathetic-immune interaction, one major communication pathway, and its importance for health and disease. Sympathetic innervation of primary and secondary immune organs is described, as well as evidence for neurotransmission with cells of the immune system as targets. Most research thus far has focused on neural-immune modulation in secondary lymphoid organs, has revealed complex sympathetic modulation resulting in both potentiation and inhibition of immune functions. SNS–immune interaction may enhance immune readiness during disease- or injury-induced ‘fight’ responses. Research also indicate that dysregulation of the SNS can significantly affect the progression of immune-mediated diseases. However, a better understanding of neural-immune interactions is needed to develop strategies for treatment of immune-mediated diseases that are designed to return homeostasis and restore normal functioning neural-immune networks.

Introduction

Autonomic (mainly sympathetic) efferent nerves innervate primary (bone marrow and thymus) and secondary (spleen and lymph nodes) lymphoid organs, providing a conduit for the brain to alter immune reactivity. The origin, pattern of distribution and targets of sympathetic nerves in primary and secondary lymphoid organs across life span are reviewed here. Sympathetic nerves release norepinephrine (NE), as their primary neurotransmitter, into the lymphoid microenvironment to affect the functioning of cells of the immune system. Thus, noradrenergic (NA) influences on immunity, while still not entirely understood, have been the most extensively investigated. Neural regulation of immune function by peptide neurotransmitters that co-localize with NE, such as neuropeptide Y (NPY), adenosine triphosphate (ATP), opioid peptides, corticotropin-releasing hormone (CRH) and vasoactive intestinal peptide (VIP), and their affect on NA-immune modulation is much less understood. Studies reporting the expression and location of the neurotransmitter-specific receptors on immune cells and ligand–receptor mediated intracellular signaling to alter immune responses are also described here. Finally, we discuss the functional and clinical significance of aging-induced changes in sympathetic-immune interactions and the consequences of sympathetic dysregulation in the development and progression of immune-mediated diseases such as rheumatoid arthritis, infections, cancer, and after major injury.

Section snippets

Sympathetic neurotransmission in bone marrow

Lymphohematopoietic stem cells in the bone marrow replenish the immune cells in the adult immune system throughout life. Regulation of hemato- and lymphopoiesis via brain-immune signaling occurs through nerves that innervate bone marrow cells, as well as neuroendocrine hormones that circulate in the blood. Efferent sympathetic nerves enter the nutrient foramina of long bones, course along blood vessels in the Haversian and Volkmann’s canals to distribute to bone marrow [1], [2], [3], [4], [5],

Sympathetic neurotransmission in the thymus

The thymus is the primary site for differentiation and maturation of T lymphocytes, whereby they can selectively recognize and respond appropriately to foreign antigen—a process call T cell “education”. Developing and differentiating thymocytes do not respond to foreign substances, because foreign antigens cannot cross the blood-thymic barrier to enter the thymic microenvironment. Intrathymic T cell precursors undergo a complex series of programmed developmental changes resulting in the

The spleen

The spleen receives a rich supply of sympathetic nerves primarily from the superior mesenteric and celiac ganglionic plexuses [85], [86], [87] and to a lesser extent, the sympathetic trunk [86], [88]. In fact approximately 98% of the nerve fibers in the splenic nerve are sympathetic [89]. In the rat spleen, NA innervation primarily develops postnatally [90], [91]. The splenic nerve enters the spleen as perivascular plexuses coursing along the splenic artery, and in the splenic capsule and

T lymphocytes

Human and murine T lymphocytes express β2-AR [54], [55], [126], [127], [128], [129], [130], [131], [132], [133], [134], [135], [136], [137], [138], [139], [140]. T helper (Th)1 and Th2 cell clones generated from naïve cells differentially express β2-AR [141]. In contrast, normal T cells do not possess functional high-affinity β1-AR or β3-AR. Collectively, these reports indicate a range of 500-2500 β2-AR binding sites on CD8+ T lymphocytes, and 200-750 binding sites on CD4+ T lymphocytes.

Functional significance of sympathetic innervation of secondary lymphoid organs

Immunocompetent cells in secondary lymphoid organs provide for host defense against pathogens. Foreign substances in the blood are filtered through the spleen. Blood flows through the white pulp and continues into the red pulp where macrophages remove foreign substances, and signal other cells of the immune system to help with removal. Like the spleen, lymph nodes filter regionally draining lymph, with the purpose of detecting and removing bacteria and foreign materials. Diffuse lymphatic

SNS and infections

The adaptive response that develops after host invasion is governed by the predominant Th cell population, Th1 versus Th2, and will determine the outcome of infectious diseases [274], [275], [276]. Catecholamines suppress cellular and enhance humoral immunity by inhibiting type 1 and augmenting type 2 cytokine production. This Th1/Th2 balance is regulated in healthy rodents, through the increase in SNS activity following an immune challenge [reviewed in 277]. In individuals whose immune systems

Summary and concluding remarks

The SNS innervates all primary and secondary immune organs (bone marrow, thymus, spleen, lymph nodes and gut-associated lymphoid tissue) and releases catecholamines to modulate immune functions. Further, some immune cells synthesize, store and release catecholamines that can act as autocrine and/or paracrine factors to regulate immune function. The literature summarized and discussed above overwhelmingly indicates that even small effects of catecholamines on immune responses can have

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