Innervation of lymphoid organs: Clinical implications Denise L. Bellinger a, * , Brooke A. Millar a , Sam Perez a , Jeff Carter a , Carlo Wood a , Srinivasan ThyagaRajan a , Christine Molinaro a , Cheri Lubahn b , Dianne Lorton b a Department of Pathology and Human Anatomy, Loma Linda University School of Medicine, 11021 Campus Street, Alumni Hall 325, Loma Linda, CA 92352, USA b Hoover Arthritis Center, Sun Health Research Institute, Sun City, AZ 85351, USA Abstract Host defense against pathogens is regulated by cross-talk between two major adaptive systems of the body—the nervous and immune systems. This bidirectional communication is essential for maintaining homeostasis. Sympathetic nerves that innervate lymphoid tissues provide one of the major outflows from the brain to regulate tissue repair and host defense. This review focuses on the role of (sympathetic nervous system) SNS in neuroimmune regulation, an area that has received much less attention than the other major immunoregulatory pathway, the hypothalamo–pituitary–adrenal (HPA) axis. Research over the past 25 years has demonstrated that norepinephrine (NE) fulfills the criteria for neurotransmission in lymphoid tissue, with both primary and secondary immune organs receiving an extensive supply of sympathetic nerves that directly contact with immunocytes. Under stimulation, NE released from terminals in secondary lymphoid organs interacts with adrenergic receptors (AR) expressed on immune cells to affect the development, trafficking, circulation, proliferation, cytokine production, and the functional activity of variety of lymphoid and myeloid cells. Our knowledge of the role of sympathetic nerves in modulating hematopoietic functions of primary lymphoid organs (bone marrow and thymus) and mucosal immunity are extremely limited. While the immune system is not absolutely dependent upon signals from the brain to function, sympathetic-immune modulation may drive host defense toward protection against, or progression toward, immune-related diseases. Additionally, signals from the (SNS) may enhance immune readiness during disease- or injury-induced ‘fight-or-flight’ responses. A better understanding of neural–immune interactions may foster the development of strategies for treating immune-mediated diseases, particularly where neuroimmune cross-talk may be dysregulated. q 2006 Association for Research in Nervous and Mental Disease. Published by Elsevier B.V. All rights reserved. Keywords: Noradrenergic; Autonomic; Sympathetic innervation; Lymphoid organs; Immune modulation 1. Introduction Increasing evidence indicates functional bidirectional communication between immune and nervous systems, although the mechanisms of this cross-talking are incom- pletely understood. Primary (bone marrow and thymus) and secondary (spleen and lymph nodes) lymphoid organs are innervated by autonomic (mainly sympathetic) efferent nerves that provide a major pathway through which the brain can alter immune reactivity. In this paper, we review the anatomical studies revealing the origin, pattern of distribution and targets of sympathetic nerve fibers supplying lymphoid organs. Catecholamines of neural (as well as nonneural) origin are released in the lymphoid microenvironment for neuroimmune modulation. Neuro- peptide Y (NPY), ATP, opioid peptides, and vasoactive intestinal peptide (VIP), under certain conditions, may be co-released with norepinephrine (NE) to modify noradren- ergic (NA) signaling of immunocytes. Data demonstrating the expression of specific receptors for these neurotrans- mitters on immune cells in immune organs and mechanisms through which ligand binding to these receptors activates intracellular signaling pathways to alter immune responses are discussed. We also describe research indicating that changes in immune function and normal aging can influence the distribution of nerves and the expression of neural Clinical Neuroscience Research 6 (2006) 3–33 www.elsevier.com/locate/clires 1566-2772/$ - see front matter q 2006 Association for Research in Nervous and Mental Disease. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.cnr.2006.04.003 * Corresponding author. Tel.: C1 909 558 7069; fax: C1 909 558 1432. E-mail address: dbellinger@llu.edu (D.L. Bellinger).