Neural code for immunity

Greetings

A lot of time have I talked about the connection between immune system and nervous system. However, it never occurred to me question, as to why should there be a network sharing between immune and nervous system. As a part of routine, I was browsing through articles online and almost stumbled on NEJM article, that left me venturing.

Fig 1: A model of neuronal regulation.
Source: Kao etal

The idea is that whenever there is a local inflammation peripheral nervous system communicates the information to CNS. This helps in coordinating the response. It is argued that if this code of information can be understood, we could make use of it to our benefit. As Dr. Steinberg puts it, "Timely diagnosis and intervention are essential to minimize deaths and complications. If the neurons are reading this information from an infection in the blood or the liver and we can interrogate the nervous system, we can make a diagnosis in real time". I haven't been able to get the full article to digest the complete information. However, I thought that this probably isn't the first paper in literature.

The best method of studying a very complex system as immune and neural networking is a simple nematode Caenorhabditis elegans. They have a well characterized genome and a immune system representative enough to make a case. It has been shown with a C elegans model, innate response to a variety of pathogens elicit downstream immune regulators that the neuronal system can regulate. A model of this has been explained by Kao etal (See Fig 1). To cite an example, neural circuit involving NPR-1, which encodes a G protein–coupled receptor (GPCR), functions to suppress innate immune responses.

The leading hypothesis is that GPCRs participate in neural circuits that can recognize bacterial pathogens (probably via PAMPs) or receive inputs from non-neuronal infected cells which can then integrate them allowing coordination of appropriate immune responses.

Fig 2: Two way signalling between Neurons
and Immune system.

As a matter of fact, neurons express receptors which otherwise is classically associated with immune system such as toll like receptors, nucleotide binding oligomerization domain receptor etc. On the other hand immune cells express classic neuron related molecules especially neurotransmitter receptors. Clearly its a two way signalling as I have illustrated in Fig 2.

Fig 3: Components of Immunity.

It wouldn't require to convince you more that the same applies to the adaptive immunity, just as in the case of innate. In this light, I want to postulate that we can define 3 types of immunity (in contrast with classic 2 types- cellular and humoral; In reality this isn't my idea, I have already seen a published paper which advocates). The third addition is Neural immunity.

Perhaps in one simple sentence I could sum it up.. "Probably Neural systems are not the immune privileged type, they are the regulators.." More research will tell.

Kawli T, & Tan MW (2008). Neuroendocrine signals modulate the innate immunity of Caenorhabditis elegans through insulin signaling. Nature immunology, 9 (12), 1415-24 PMID: 18854822

Kao, C., Los, F., & Aroian, R. (2008). Nervous about immunity: neuronal signals control innate immune system Nature Immunology, 9 (12), 1329-1330 DOI:10.1038/ni1208-1329

Styer KL, Singh V, Macosko E, Steele SE, Bargmann CI, & Aballay A (2008). Innate immunity in Caenorhabditis elegans is regulated by neurons expressing NPR-1/GPCR. Science, 322 (5900), 460-4 PMID: 18801967

Steinberg BE, Tracey KJ, & Slutsky AS (2014). Bacteria and the neural code. The New England journal of medicine, 371 (22), 2131-3 PMID: 25427116

Andersson U, & Tracey KJ (2012). Neural reflexes in inflammation and immunity. The Journal of experimental medicine, 209 (6), 1057-68 PMID: 22665702