Neuroimmunoendocrine interaction in autoimmune rheumatic diseases: a new challenge for the rheumatologist

1699-258X/$ see front matter © 2011 Elsevier España, S.L. All rights reserved. A lot of evidence gathered over the last 3 decades indicates that there is bidirectional communication between the central nervous system (CNS), endocrine system and immune system starting during embryonic and neonatal development to the final stages of life. This “neuro-immuno-endocrine” communication is constantly seen in situations of stress as occurs in infections, inflammatory/ autoimmune diseases or trauma, which trigger a series of reactions that activate the neuro-immuno-endocrine system. This system is composed of the following areas: 1. hypothalamic-pituitaryadrenal (HPA) that includes the cortisol, corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH); 2. hypothalamic-pituitary-gonadal (HPG), that includes luteinizing hormone (LH), follicle stimulating hormone (FSH), gonadotropinreleasing hormone (GnRH), oestrogen, progesterone and androgen; 3. Hypothalamic-pituitary-thyroid (HHT) composed of thyroid hormones (T3 and T4) and 4. prolactin/growth hormone (PRL/GH) system. The messengers of this bidirectional communication are the abovementioned hormones, neuropeptides, “pro-inflammatory” and “anti-inflammatory” cytokines as well as neurotransmitters that are synthesised by the cells of the 3 systems. These messengers act via receptors, producing activation or inhibition of the innate and adaptive immune response, from the nervous system and endocrine system. The autonomic nervous system together with the synthesis and release of catecholamines also participate in this communication. The breakdown of this homeostatic-molecular balance shares in the pathogenesis of various inflammatory, autoimmune, neoplastic, infectious, cardiovascular, metabolic and psychiatric processes. The synthesis and release of messengers has 24 hour action cycles when referring to the physiological processes. These variations are called circadian rhythm, and they influence the clinical manifestations of various diseases. This circadian rhythm is generated and controlled by the CNS through the hypothalamus. The synthesis and secretion of hormones and cykotines is a dynamic process that is undertaken in a cellular microenvironment. The cells have receptors for hormones, cykotines and pathogenassociated molecular patterns (PAMPs). They are all activated to physiologically respond to pathogens. When there is a local or systemic inflammatory/immune process, the immune systems cells release proinflammatory cytokines: interleukin 1 beta (IL-1b), tumour necrosis factor (TNF) and interleukin 6 (IL-6), which cross the blood-brain barrier and reach the CNS. The blood-brain barrier breakdown is mediated by lipopolysaccharides and cytokines that activate the CNS functions and produce behavioural and cognitive changes, arthritis, fever and activate systems to respond to stress. We have seen that an IL-1 injection in mice produces activation of the HPA axis releasing ACTH and cortisol, since tests were carried out in the eighties of the last century. This is a hypothesis that was later confirmed by the demonstration that IL-1 activates neurons in the paraventricular nucleus of the hypothalamus that contain CRH. A characteristic of autoimmune rheumatic diseases is the loss of immunological tolerance. The tolerance occurs when antigenpresenting cells process and present to it in the context of a reduced expression of the major histocompatibility complex (MHC) class II in a microenvironment that contains cykotines and anti-inflammatory hormones (IL-4, IL-10, cortisol, progesterone, androgens). If the microenvironment is made up from cytokines and pro-inflammatory hormones (IL-1, TNF-a, IL-6, oestrogen, PRL), the immune response will be exarcerbated and will lead to a loss of tolerance and the development of an autoimmune disease. Therefore, disturbances in these physiological regulatory processes could become a potential risk factor in the development of autoimmune rheumatic diseases. In fact, an abnormal neuro-immunoendocrine response has been found in patients with rheumatoid arthritis (RA), lupus erythematosus (SLE), Sjögren’s syndrome, Editorial