Named Series: Twenty Years of Brain, Behavior, and ImmunityBrain-immune communication pathways
Introduction
The concept that the brain and immune systems communicate lies at the heart of neuroimmunology. Indeed, the current power and future hope of this field lies in the strength it derives from the realization that the three great systems, the nervous, the endocrine, and the immune, by which the body communicates and regulates also communicate with one another. The last 20 years has witnessed the birth and the transformation of the field of neuroimmune communication. Of course, neuroimmunology existed long before that. But early neuroimmunologists generally treated the immune and the nervous systems as separate entities. Only disease conditions involving infection or immunological pathology within the nervous system were studied. These conditions were considered as a consequence of a breach of the insulation that isolated these two systems, thereby pathological in nature.
The concept that neuroimmune communication as an integrated part of a physiological supra-system that included both the immune and the nervous system distinguished the new neuroimmunology from its predecessor. This novel perspective met with considerable resistance and skepticism from its parent fields of neuroscience and immunology. For many traditional immunologists, meddling with the intricately organized immunological processes by the whim of neurotransmitters and neuropeptides seemed counterintuitive and an unneeded level of complexity. For the neuroscience of the time, the immune system also seemed an unlikely target to regulate. The nervous system was characterized by a speed of communication through a hardwired network of immobile neurons, whereas immune cells were built to move and roam, engulf pathogens and secret antibodies. For the nervous system to receive input from immune cells, one had to envision nerve terminals “synapsed” onto the mobile immune cells. This was certainly heresy at the time. In addition, most of the known immunological activities could be demonstrated in vitro without the help of neurons. Therefore, the need for the nervous system to respond to signals from the immune system was not obvious. The progress made in the field of neuroimmune communication has certainly cleared these hurdles to establish that these two systems do crosstalk extensively via multiple pathways. Such communication is not accidental, but plays significant physiological roles in optimizing the function of both systems and indeed the health of the entire organism.
We have chosen to examine four of the mechanisms by which these systems interact. As Fig. 1 and Table 1 illustrates, these areas have seen a substantial increase in interest as indicated by the number of publications in related fields. Although not inclusive, they together constitute much of the history of neuroimmunology and track very different courses in their developments, struggles for acceptance, and current applications to biological problems (Fig. 2).
Section snippets
Overview: To 1987
To talk, or not to talk, that was the question. The CNS was viewed as largely inaccessible by the immune system behind the blood–brain barrier, existing as an immunologically privileged site. Experimental support for this notion came from tissue transplant studies in which implanted tumor or normal tissue to the brain survived better in the brain than in other tissues such as the skin (Medawar, 1948) Before the inception of the field of neuroimmune communication, however, immunologists already
Overview: 1988–1997
Cytokines came to dominate thinking during this era. The ability of both the CNS and immune cells to secrete and respond to them provided a mechanism by which the two systems could be linked. Injection of interleukin-1 (IL-1) into the brain produced almost all of the behavioral, neuroendocrine, and autonomic responses that animals typically display when they are infected. This fostered the idea that all of these responses were a coordinated, adaptive behavior, termed sickness behavior. Such
Overview: 1998–2007
This decade saw confirmation of the discovered neuroimmune pathways and extension of their actions to new functions. Increasingly, views such as sickness behavior being adaptive rather than pathologic, involvement of TNF in physiologic as well as pathologic sleep, immune cell surveillance of the CNS occurring under normal conditions, and secretion and response being a part of normal cellular function subtly changed neuroimmunology from a field primarily focused on pathology to one increasingly
Beyond 2007: Future directions for BBB transport of cytokines
Research in the last twenty years has clearly demonstrated that neuroimmune communication exists via multiple pathways. Both neural and humoral pathways are involved in relating information between the nervous and the immune systems. Afferent pathways are able to provide inflammatory signals to the brain and efferent transmission is able to profoundly modulate both innate and adaptive immunity. Within the neuroimmune system, a signaling molecule can arise from multiple sources to act at
Conclusions
Understanding how the immune and central nervous systems communicate with one another is central to understanding the interactions between brain, behavior, and immunity. We examined here four major pathways by which such communications can occur: neural routes, circumventricular organs, cytokine transport across the BBB, and secretion of immune-active substances by the cells which constitute the BBBs. All these areas have seen tremendous development in the last 10 years. All face important
Acknowledgments
This work was supported by R01 NS40098 (N.Q.), R01 AI059089 (N.Q.), VA Merit Review (W.A.B.), R21 DA019396 (W.A.B.), R01 NS050547 (W.A.B.), R01 NS051334 (W.A.B.).
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