Prior to the beginning of the twenty-first century, naysayers argued that the immune and central nervous systems do not dialogue with one another.
They advocated maintaining the distinct disciplines of immunology and neuroscience, with little to no communication between the two.
But emerging data demanded a more innovative approach.
Physiology, which is a truly integrative science that spans reciprocal regulatory control systems among all organ systems, was not seriously considered.
The major reasons for the arguments of skeptics were the existence of the blood-brain-barrier (BBB), lack of CNS lymphoid vessels and paucity of antigen-presenting cells in the brain.
The scientific community now accepts that the BBB is much more than a barrier, acting as a true interface between the blood and brain [BBI; (
20)].
Secondly, a century of science was turned upside down by the discoveries of Louveau et al. (
21) and Aspelund et al. (
22) who showed convincing histological evidence and now the functional importance of the meningeal lymphatic system [reviewed by (
23)].
Finally, it is well-documented that microglia, monocytes and dendritic cells in the brain parenchyma can express major histocompatibility antigens that present antigen to T lymphocytes [reviewed in (
24)].
And of course the discovery and identification of 37 cytokines, their receptors and multiple chemokines ushered in a entirely new way of thinking about immune-brain networks.
As shown by the early experiments on sickness behaviors, systemic cytokines alert the brain that insults such as an infection or trauma have occurred in the periphery. Indeed, the brain can synthesize and express several cytokines.
Many other fascinating discoveries have provided entirely new insights into brain-communication systems. They range from links between clinical depression and systemic inflammation [see reviews by (
25,
26)] to the emerging roles of neurotransmitters such as acetylcholine and catecholamines in the development of bioelectronic medicine for treatment of diseases like rheumatoid arthritis and Crohn's disease [reviewed in (
27)].
As such, nearly all of the naysayers have disappeared. The discovery of sickness behaviors in all forms established the powerful role of communication between the immune system and the brain. This is the true legacy of sickness behaviors.
