Neuroendocrine Phenotypes that Affect Immune Responses in Mammals Found in Avian Species

The LEWIS/FISCHER paradigm

Neuroendocrine Phenotypes Immune Responses Avian Species

A cooperative study by Argentinian and UK research teams published in the PLOS ONE journal showed that the individual’s neuroendocrine phenotypes found in mammals, such as rodents and humans, that influence the host’s immune responses, is an evolutive trait traced back to birds such as quails.

Numerous previous studies indicate that neurohormonal or neuroendocrine factors and mechanisms shape host immunity but also regulate the expression of autoimmune diseases in humans, or experimental autoimmune diseases in animals. Within this framework, the individual’s neurohormonal phenotypes have a strong impact on immune system reactivity, cytokine profiles and disease susceptibility.

Experimental disease models, particularly in inbred rats, provide a powerful approach to investigate relevant mechanisms in human autoimmune diseases. In this context, studies in two inbred rat strains, Lewis (LEW) and Fischer 344 (F344), indicate that they display opposite neuroendocrine immune profiles or phenotypes.

LEW inbred rats are extraordinarily susceptible to experimental autoimmune diseases, such as collagen-induced arthritis (CIA), adjuvant-induced arthritis (AIA) and multiple sclerosis models such as myelin-basic-protein (MBP)–induced experimental autoimmune encephalomyelitis (MBP-EAE). By contrast, F344 are relatively resistant to these disease models.

Interestingly, Lewis and Fischer 344 inbred rats have also been proposed as a model of genetic vulnerability to drug addiction and related to differences in mesolimbic dopamine (DA) transmission, rewarding and emotional function.

Previous studies have shown that LEW, compared with F344 rats, are relatively low corticosterone producers, have smaller adrenal glands and blunted corticosterone in response to different stimuli, but also show minimal circadian variations in plasma corticosterone. Furthermore, it appears that LEW also have low adrenomedullary activity and responsiveness – indicated by lower baseline epinephrine (adrenaline) and norepinephrine (noradrenaline) levels, and profoundly blunted epinephrine response to immobilization test.

Immunologically, LEW rats express higher levels of IL-12 and IFN-γ mRNA and produce more IFN-γ at the protein level than F344; also LEW have higher TNF-α but similar IL-10 production compared to F344 rats.

Figure 1 Neuroendocrine Phenotypes in Avian SpeciesFigure 1. A schematic interpretation of the role of baseline EPI (adrenaline) in shaping innate cytokine responsiveness and cytokine profiles. A) In humans, a relative low activity of the adrenal medulla in some individuals provides low tonic inhibitory input on proinflammatory cytokine production, exerted by endogenous basal EPI and thus conditions peripheral monocytes to produce more IL-12 and TNF-α but less IL-10 upon antigenic stimulation than monocytes in individuals with relatively high adrenomedullary activity. B) Genetically determined hypoactive and hyperactive hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system (SNS) result in low vs high tonic inhibitory input on proinflammatory cytokine production exerted by endogenous basal GCs and CAs and thus determine to a great extend high vs low proinflammatory/Th1 responses in LEW and F344 rats, respectively. Solid lines represent stimulation, while dashed lines represent inhibition. From: Low- versus High-Baseline Epinephrine Output Shapes Opposite Innate Cytokine Profiles: Presence of Lewis- and Fischer-Like Neurohormonal Immune Phenotypes in Humans? Ilia J. Elenkov, Richard Kvetnansky, Akira Hashiramoto, Vladimir K. Bakalov, Amrey A. Link, Keith Zachman, Marianna Crane, Daniela Jezova, Jozef Rovensky, Mariana A. Dimitrov, Philip W. Gold, Sergio Bonini, Thomas Fleisher, George P. Chrousos and Ronald L. Wilder; J Immunol August 1, 2008, 181 (3) 1737-1745; Public Domain, DOI:

Thus, the combination of genetically determined low vs high adrenocortical/adrenomedullary activity may determine, at least in part, the high vs low proinflammatory/Th1 cytokine responses in these inbred rats, and their opposite susceptibility to experimental autoimmune diseases.

It appears that similar traits also exist in humans – in the general population, certain individuals may express opposite LEW- and F344-like neurohormonal immune phenotypes. There, epinephrine (adrenaline)-mediated conditioning of the innate cytokine secretion might represent a hormonal nonimmunological mechanism that is involved in shaping cytokine responsiveness, variability, and profiles. This neuroendocrine mechanism may play a critical role in driving opposite innate cytokine profiles in humans with intrinsic hypo- and hyperactive adrenal medullas.

In the PLOS ONE study the researchers from Argentina and United Kingdom investigated how evolutive hormonal traits influenced the host immune system, evaluated the neuroendocrine-immune phenotype in the captive common quail (Coturnix coturnix) and correlated these results in the context of the LEWIS/FISCHER paradigm.

Figure 2 Neuroendocrine Phenotypes Avian SpeciesFigure 2. Schematic conceptual representation of immune neuroendocrine phenotypes (INPs) in Coturnix coturnix. The variables set to determine the existence of avian INPs in the present study are represented around each bird. The size of the variable indicates if the animals show high or low response in each of the parameters in the INPs. LYMPH: lymphoproliferative response to PHA-P; Ab SRBC: antibody response against SRBC; FLD: frequency of leukocyte distribution; level of expression of mediators: IFN-γ and IL-1β (pro-inflammatory); and IL-4 and 13 (anti-inflammatory). “Fischer-like” quail with high CORT levels also manifest high FLD and IL-13, but low LYMPH, Ab SRBC, IFN-γ and IL-1β levels. “Lewis-like” counterparts have low CORT as well as low FLD and IL-13 responses, but high LYMPH, Ab SRBC, IFN-γ and IL-1β responses. These two extreme groups of birds do not differ in their IL-4 level. From: Immune Neuroendocrine Phenotypes in Coturnix coturnix: Do Avian Species Show LEWIS/FISCHER-Like Profiles? BF. Nicolas Nazar, Bibiana E. Barrios, Pete Kaiser, Raul H. Marin, Silvia G. Correa, Open Access, PLOS ONE

In their study, the authors first distributed quails into two distinct groups based on their low or high corticosterone (CORT) levels. Thus, birds within the top and bottom 16% extremes of the population were designated as High and Low CORT, respectively.

Low basal CORT quails challenged with different immunogenic stimuli showed higher lymphoproliferative swelling responses, increased systemic antibody production and greater frequency of leukocytes subpopulation compared to their high CORT counterparts.

In addition, the low CORT quails presented high levels of IFN-ϒ and IL-1β and low amounts of IL-13 after the immune challenge, while their high CORT counterparts showed opposite results. Of note, IL-4 levels remained the same between low and high CORT quails, indicating that these animals displayed a high and low T helper 1 (Th1) response, respectively, rather than an increased Th2 response in high CORT quails.

Thus, this study, in a population of 60 Japanese quail, showed that the common quail display neuroendocrine-immune phenotypes comparable to their LEW and F344 mammalian counterparts. ‘LEW-like quail’ showed low CORT levels together with high levels of pro-inflammatory mediators and a Th1-like response, whereas the ‘FISCHER-like quail’ showed the opposite profile.

This is perhaps the first evidence that the neuroendocrine-immune phenotypes are not restricted to the mammalian species studied to date (Homo sapiens sapiens and Rattus norvegicus) and that this phenotype trait is conserved along evolution.

The study’s authors discuss that as higher vertebrates had a common reptilian ancestor more than 200 million years ago, these neuroendocrine-immune phenotypes could have been shared as a physiological strategy in three species belonging to two different evolutionary lineages.

Yet, only future studies may reveal whether these phenotypes are a “shared strategy between mammals, birds and their reptilian ancestor or if they are independent outcomes of the interactions between the immune, nervous and endocrine systems in each lineage”.

Source: PLOS One, 2015. DOI: 10.1371/journal.pone.0120712
Read more: PLOS ONE

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