One of the curious aspects of modern biomedicine is the “cultural separation” of immunology research from neurobiology and physiology research. One can argue that the failure to link the immune system to the brain (and vice versa) has played a role in the immunology’s minimal progress from the bench to the bedside over the last 60 years. In this article we would like to discuss some factors that likely contribute to this failure to integrate the immune system into the body as a whole and to better understand its regulation.
From our experience we can state that one factor contributing to cultural separation is the reluctance of immunologists to add the complexities of organismic biology to the already highly complex immune system. In 2004, one of us (GM) published in Nature Immunol. , a letter entitled “immunology needs the mind” in which it was pointed out the existence of a kind of cultural separation between the so-called “mainstream immunology” and the research dealing with the real biological defense mechanisms of the body. Quoting Maestroni:
“Early during my scientific career, a common referee response to my grant applications or manuscripts sounded like this: ‘The immune system is already very complex. I see no interest or benefit in adding new and fancy intricacies.’ Nature obviously had a different idea about the physiology of the immune and nervous systems.”
Another factor that probably plays a major role in creating the cultural separation between immunologists and physiologists is the academic training of the two groups. Immunologists are traditionally trained in microbiology departments that focus on autonomous entities such as bacteria, so it is not surprising that immune cells are thought to operate independently of the rest of the body. Immunologists generally receive no training in mammalian anatomy, physiology or neurobiology.
Thus, they may have difficulty conceptualizing the fact that the immune organs are innervated just as other organs are, and that those nerves and their neuromediators play a central role in immune function. Further, the languages of physiology and neurobiology are foreign to immunologists. On the other hand, few physiologists receive the training in immunology that allows them to approach the massively complex immune system with confidence or even comprehend the immunology literature.
Yet another important factor is separation of research on the immune system and its physiology within the scientific literature. This is revealed by the results of a PubMed search using key words such as “nervous “ and “immune” or “sympathetic” and “immune”, limited to reviews in the preceding five years .
The search was aimed at assessing the distribution of the publications among immunology and non-immunology journals. From the results obtained it was clear that immunology journals represented a tiny minority in comparison to non-immunology journals. So, 5 years ago the cultural separation was clearly there! But what about today? To check the situation, we repeated the search using slightly more specific key words, i.e. “nervous” and “immune response”, “endocrine” and “immune response” or “sympathetic“ and “immune response”. This search was extended for 10 years and also limited to reviews. The PubMed citations were also sorted by the two journals devoted to the field of neuroendocrine immunology, Neuroimmunomodulation (NIM) and Brain, Behavior and Immunology (BBI). The results shown in Table 1 demonstrate that nothing has changed: Immunology journals still publish very little neuro-endocrine immunology research compared to non-immunology journals:
No of reviews
NIM + BBI
Nervous and immune response
Endocrine and immune response
Sympathetic and immune response
There is a growing awareness that systems biology strategies offers a means of dealing with massively complex disciplines. According to the systems biology approach , the defense machinery of our body must involve the brain and the immune system. The brain can generate the self in its widest and most general meaning, which includes the self/non-self immune discrimination. But why has this fascinating and highly functional concept received, and still continues to receive, so little attention by mainstream immunologists? The weakness of the reductionistic approach in immunology (as well as, we fear, in most other biological disciplines) can be described by two very simple considerations:
A rough estimate of the number of immunology papers published every year all over the world is well over 20,000. Over one million papers in MEDLINE cite immunology as a key word.
In spite of the immense amount of data produced each year for more than six decades, the advancement of our understanding and ability to control immunity leaves much to be desired. Consider our poor understanding of autoimmunity, our inability to induce tolerance, to boost specific T cell immunity against cancer, malaria, tuberculosis or simply to instruct the immune system to mount an appropriate, but harmless inflammatory response to control infections. The mainstream therapy for the majority of diseases involving the immune system remains, after 60 years of immunology research, pharmacological (and often toxic) doses of glucocorticoids.
A possible, though simplistic answer to the question why immunologists remain uninterested in physiological control of immune responses could be that the reductionist approach that prevails in modern biology is inappropriate for understanding the interactions of such complex systems as the immune and the nervous systems. This situation might be ameliorated by a kind of “hermeneutic” of the scientific results. Such an “hermeneutic” will have to involve, in our opinion, the systems biology approach and its principles . The first principle is that biological functionality is multilevel. From this obviously true principle follow all the others discussed in Ref. 2.
This would also mean that, to be functional, the immune response has to engage biological mechanisms at levels different from that of immunocompetent cells. Take for example, the acute phase response. This fundamental multilevel response involves interactions between the brain, the bone marrow, the liver and the endocrine system. The acute phase response represents the first line of defense against inflammatory stimuli such as infections or tissue damage, and sets the stage for acquired immune responses such as antibody formation .
The proinflammatory cytokines that represent a major clinical target today were discovered in the context of research into fever, the most intensively studied behavioral acute phase response. The action of those cytokines on the brain is widely recognized as key to both their physiological and pathological outcomes. Research on the acute phase response has also led to the definition of the receptors such as Toll-like receptors that allow the organism to recognize foreign invaders. The clinical potential of exploiting these pathogen recognition receptors as therapeutic targets is in its infancy.
Though it would be reasonable to assume that the acute phase response is widely studied by immunologists, a MEDLINE search (November 2009) reveals that over 3,000 papers cite the term “acute phase response,” but only 33 of them are published in the Journal of Immunology, the primary journal of immunology research. The other papers are scattered among numerous journals including BBI and NIM, but are rarely found in immunology journals per se.
A consequence of this isolation of studies of the innate immune system from those of the acquired immune system (that comprise 95% of mainstream immunology research) is a failure to recognize until this decade that the innate immune system is central to host resistance to disease, control of pathogenic acute inflammation, and development of effective acquired immunity. If the history of immunology research had evolved differently one could speculate that we might be closer to controlling such chronic inflammatory diseases as multiple sclerosis if we understood the physiology of inflammation as a whole.
It is not unreasonable to state that the cultural separation of immunology research from research on the physiology of immunoregulatory processes impedes the development of effective (and physiological) immunotherapeutic approaches. Eliminating this cultural separation requires development of tools for improved communication among the relevant disciplines, such as the Website on which this opinion piece is published. Recognizing the existence of cultural separation and the reasons why it has developed is the first step.
G Maestroni – Section of Experimental and Clinical Pharmacology, Department of Clinical Medicine, University of Insubria, 21100 Varese, Italy
JA Majde – College of Veterinary Medicine, Washington State University, Pullman, WA 99164-6520, USA
Maestroni G. Immunology needs the mind. Nat Immunol, 2004, 5: 763.
Noble D. Claude Bernard, the first systems biologist, and the future of physiology. Exp Physiol, 2008, 93: 16-26.
Germain RN. An innately interesting decade of research in immunology. Nat Med, 2004, 10: 1307-1320.