Figure 1.

The major neuroendocrine and autonomic pathways that regulate secondary immune organs are illustrated. They include two neuroendocrine pathways, (1) the hypothalamic–pituitary–adrenal axis (HPA) and (2) the sympatho-adrenal medullary (SAM) axis, and two “hardwired” autonomic circuits, (3) the sympathetic nervous system (SNS) and (4) the parasympathetic nervous system (PaSNS). (1) The HPA axis is a feedback system whereby corticotropin-releasing hormone (CRH) is released from neurons in the hypothalamus that project their axons into the anterior pituitary. The release of CRH stimulates the secretion of adrenocorticotropic hormone (ACTH) into the circulation. ACTH stimulates the release of corticosterone (CORT) into the bloodstream. Circulating CORT has systemic effects including effects on secondary immune organs or tissues (Spleen, lymph nodes and gut-associated lymphoid tissue (GALT) are shown in the illustration). (2) In the SAM axis, preganglionic sympathetic neurons secrete acetylcholine in the adrenal medulla, which stimulates the release of catecholamines, predominantly epinephrine (EPI) and, to a much lesser extent, norepinephrine (NE), into the circulation, such as the HPA axis. Circulating NE/EPI can potentiate the actions of sympathetic nerves acting at adrenergic receptors in immune organs. (3) The SNS circuit to the spleen and LNs is a two-neuron chain (green neurons), with preganglionic cholinergic sympathetic neurons innervating postganglionic neurons whose nerve terminals end in the spleen and lymph nodes. The major neurotransmitter of postganglionic neurons is norepinephrine (NE). In secondary lymphoid organs, such as LNs and spleen, NE binds to adrenergic receptors expressed on immune cells, vasculature and connective tissue cells. Ligand binding to adrenergic receptors regulates the cellular responses of the immune cells that express these receptors. The predominant adrenergic receptor subtype expressed on spleen cells is the β₂-adrenergic receptor. (4) The PaSNS is also a two-neuron chain (yellow neurons) of efferent nerves that supply the viscera, in particular the gut. Preganglionic neurons reside in the brainstem (medulla) and exit the central nervous system (CNS) as cranial nerves that end upon postganglionic neurons, most often embedded in the visceral organs they supply. Depicted here is the parasympathetic supply to gut-associated lymphoid tissue (GALT). There is no definitive evidence that the PaSNS innervates the spleen, but the vagus nerve clearly can influence immune responses in the spleen—most likely via the migration of vagally influenced immune cells in the gut that migrate to the spleen. The up or down arrows shown next to these regulatory pathways indicate the most common direction of change in the activity of that pathway in most of the prevalent immune-mediated inflammatory diseases, including rheumatoid arthritis.