The immune system under stress THE IMMUNE CONCEPTS THREATENED I mmune system has traditionally been regarded as an autonomous, self-protecting system with the self-nonself discriminating capacity (1). Since its most obvious effector function is biodestructive in nature, it must be tightly regulated as not to damage the host. Autoregulatory mechanisms are manifold, including inactivation/deletion of self-reac- tive clones (2), regulatory/suppressor activity of the effector T cell class (3, 4), effector class (Th1/Th2) switching (5), controlled expression and recruitment of activating and/or inhibitory receptors (6, 7), and pleth- ora of regulatory humoral mediators (cytokines, chemokines, comple- ment, immunoglobulins), all intertwined in a complex modulatory network. The idea of an autonomous, self-regulating, immune system was challenged in the mid 1970s with the discovery of a link between the nervous, endocrine and immune systems (8–10). More recent evi- dences support functional and anatomical connections between neuro- endocrine and immune systems (11–15) with neurotransmitters, neuro- peptides, hormones (16), and immune mediators as common messengers that sustain mutual communication. The neuroendocrine mediators reach the cells of the immune system either through the peripheral cir- culation or through direct sympathetic innervation of primary and sec- ondary lymphoid organs and peripheral tissues, where immune reac- tions are taking place (17, 18). Therefore, it is reasonable to conclude that the neuroendocrine messengers released during a stressful event could modulate immune function and subsequently alter the course of immune-based diseases. On the other hand, cytokines produced by the immune cells, peripherally, stimulate the afferent nerves locally, or reach the central nervous system (CNS) by the bloodstream, and pass- ing the blood-brain barrier (19–21), inform the brain of non-cognitive events, resulting in behavioral changes (22) and profound neuroendo- crine alterations in hypothalamo-pituitary-adrenal (HPA) axis, thus closing the circuit of mutual communication. Moreover, immune cells and tissues can produce neuropeptides (e.g. endorphins, somatostatin) and hormones, including cortisol, adrenocorticotropic hormone (ACTH), growth hormone (GH), corticotropin-releasing hormone (CRH), thy- roid-stimulating hormone (TSH), and reproductive hormones (23), while CNS cells can produce various cytokines (24). Further challenge to one of the fundamental tenets of immunology (self-nonself discrimination principle) emerged in the nineties by the proposition of danger (25, 26) and integrity (27, 28) models, with a vig- orous debate about fundamental nature of immunology still going on (29–32). Both, the self-nonself concept proponents and opponents chiefly agree that two signals (at least) are crucial for regulation of im- mune response (33). The first one, signal[1], is specific and delivered by ANTE SABIONCELLO KATJA GOTOVAC AN\ELKO VIDOVI] ALENKA GAGRO ALEMKA MARKOTI] SABINA RABATI] DRAGAN DEKARIS Institute of Immunology Rockefellerova 10 10000 Zagreb Croatia Correspondence: Ante Sabioncello Institute of Immunology Rockefellerova 10 10000 Zagreb Croatia E-mail:asabioncello@imz.hr Key words: immune-neuroendocrine connections, regulation, self-nonself discrimination, danger, integrity, homeostasis, allostasis, stress Received September 18, 2004. PERIODICUM BIOLOGORUM UDC 57:61 VOL. 106, No 4, 317–323, 2004 CODEN PDBIAD ISSN 0031-5362 Leading Article