Understanding immunity requires more than immunology

Abstract

Acetylcholine and related neurotransmitters appeared with unicellular life forms, millions of years before innate immunity. Tools and insights are now available for understanding how the evolving nervous system influenced the development of immunity.

Figure 1

Foreign products derived from infecting pathogens and endogenous molecules released from ischemic or ruptured cells converge on the innate immune system, which leads to cytokine release. Tumor necrosis factor (TNF), IL-1, IL-6 and HMGB1 interact with neurons to produce a constellation of signs and symptoms known as ‘sickness behavior’. Because this is the result of cytokines, it is not possible to distinguish between infectious injury and sterile injury as the activating etiology. The nervous system responds to the presence of cytokines and transmits action potentials via the cholinergic anti-inflammatory pathway to downregulate the progression of inflammation. This is a critical gating or controlling step that leads to the resolution of inflammation and prevents further damage. NLR, Nod-like receptor; RIG, retinoic acid inducible gene; Nod, nucleotide-oligomerization domain protein; HMGB1, high-mobility group protein B1.

Figure 2

Neural signals transmitted to spleen down-modulate the inflammatory phenotype of passing lymphocytes and monocytes. The spleen receives 20% of the cardiac output each minute and is uniquely positioned as a porous vascular bed to connect the information it receives from the brain and to relay this to monocytes, lymphocytes and neutrophils as they pass through its matrix. Neural signals derived from the cholinergic anti-inflammatory pathway downregulate surface expression of major histocompatibility complex HLa-DR molecules and other activation markers, producing an undamaging phenotype to the cells exiting the spleen. Downregulated cells departing the spleen fail to contribute to the progression of damaging inflammation at sites of injury and damage. This mechanism can account for less damage at sites of ischemia or sterile inflammation, as occurs in myocardial ischemia and rheumatoid arthritis.