Adaptive (Hypothalamic) and Innate Immunoregulation

The hypothalamic paraventricular nucleus (PVN) serves as the central regulator and coordinator of neuroimmune host defense. During homeostasis immune derived cytokines are recognized by sensory nerves, which express specific receptors for cytokine stimulation and are able to deliver cytokine signals to the hypothalamic PVN. Sensory nerves innervate mast cells, which serve as sensory organs for antigen-antibody reactions and for noxious stimuli. Mast cells degranulate upon immune or noxious stimulation and the mediators released by them act on sensory nerves, which signal the PVN. Once the signal is transmitted across the blood brain barrier (BBB), the signal travels through the ascending neural pathway as follows: area postrema nucleus tractus solitarius ventrolateral medulla, PVN, which initiates hypothalamic-pituitary-adrenal (HPA) axis responses. Descending pathway: PVN brainstem cell groups, thoracic spinal cord preganglionic neurons via sympathetic projections to the end organs, such as the thymus and spleen. The brain and most if not all other tissues in the body express innate immune receptors, such as toll-like receptors (TLRs), which recognize infectious agents and numerous other pathogenic insults. Thus the brain and in fact the entire host organism participates in the struggle for survival during acute febrile illness. The neuroimmune regulatory network, which exerts coordinative regulatory interaction with the host organism comprises the Neuroimmune Supersytem (NISS). NISS contains superimposed regulatory circuits: 1). The central nervous system (CNS) with its nerves; 2). the pituitary gland with its target glands/tissues; 3). cytokine and chemokine circuits; 4). cells that mediate innate immunity and are capable of autonomous function (most immune and many other type of cells are involved). If a higher circuit fails, TLR and cytokines signal lower circuits in order to keep the immune system functional and to maintain vital bodily functions as much as possible. Cellular receptors also show hierarchy. The most powerful receptors are nuclear regulatory proteins, such as steroid and thyroid hormones and the vitamin A and -D receptors. Peptide hormones and many other mediators act through receptors expressed on the cell membrane. Numerous signals bombard the cells through membrane receptors simultaneously. The cell will collect the activated receptors onto one of its pores (capping) where the stimulatory receptors are activated by phosphorilation (protein kinases are involved) and the inhibitory signals cause de-phosphorilation of the same receptors by phosphatases (Ship). The cell will respond by activation, or suppression, which is dependent on the ratio of stimulatory versus inhibitory signals. During febrile disease (acute phase response, APR) the innate immune system is activated, and phagocytic cells of the monocyte/macrophage series secrete interleukin (IL)-1 beta, IL-6 and tumor necrosis factor (TNF) alpha into the blood and the elevated cytokines act on the CNS directly. Granulocyte macrophage colony stimulation factor (GM-CSF) is also elevated. During APR glucocorticoids (GC) and catecholamines (CAT) amplify innate immunity (INIM) and suppress adaptive immunity (ADIM), which has been coined as immunoconversion. ∗Correspondence to: Istvan Berczi, DVM, PhD, Department of Immunology, Faculty of Medicine, The University of Manitoba, Winnipeg, MB, Canada. E-mail: berczii@ms.umanitba. ca. ISSN 1878-948X/11/$27.50 © 2011 – IOS Press and the authors. All rights reserved 180 I. Berczi et al. / Adaptive (Hypothalamic) and Innate In chronic inflammation VP, and not corticotropin releasing hormone (CRH), regulates the HPA axis. VP also stimulates prolactin (PRL) secretion. This will restore the hormonal milieu for ADIM, and will initiate the healing process (immunoreversion). After recovery, VP will regulate immunocompetence. Therefore, the healing process is also regulated by the PVN in the hypothalamus. Memory T cells survive major disasters and once the disaster is over, regenerate adaptive immunocompetence