Integrative Immunology and Behavior---An Interdisciplinary Science at the Origin of a Paradigmatic Revolution in Pathophysiology

Chronic, multi-factorial diseases are plaguing our health care system because not only of the organ dysfunction they are causing but also because of the symptom burden they are associated with. Nonspecific symptoms of illness seriously compromise the quality of life of patients. Patients with cancer, viral and bacterial infections, autoimmune diseases, and chronic inflammatory disorders are in pain, feel fatigued, do not sleep well, and experience profound changes in mood and cognition. These apparently disparate symptoms are now known to be the result of the dysregulation of the communication pathways that exist between the innate immune system and the brain. The immune system is geared to fight infectious pathogens and in order to do so in the most efficient manner, it needs to inform the brain that an infection is developing and new priorities for the functioning of the organism need to be established. In addition to setting up these new priorities, the brain is engaged in the regulation of activity of the immune system.

The fact that pathogenic factors target not only specific organs but also the regulatory pathways between different organs and in particular those regulatory pathways that allow visceral organs to communicate with the brain has opened a new paradigm in biomedical sciences and pathophysiology. Promoting health and wellbeing can therefore be achieved only if the biology of these regulatory pathways is fully understood, and if basic and clinical research scientists are trained to consider the patient as a whole, instead of just a body with a diseased organ. This is the strategy embraced by a new, rapidly emerging interdisciplinary scientific domain that explores the pathways of neural and humoral communication that link the immune system and brain. Historically, immunologists and neuroscientists have worked independently but barriers separating these disciplines are falling by the wayside. Studying the biology of those pathways that link the immune system and brain is now considered vitally important for understanding the pathophysiology of non specific symptoms of illness, what Hans Selye called “the syndrome of just being sick.” Even the neurobehavioral deficits that materialize during aging or psychosocial stress have been linked to dysregulation of immune-to-brain communication pathways.

In contrast to what was initially thought, the pathways of communication between the brain and the immune system are not limited to the influences of the brain on the immune system which account for the effects of stress on immunity. The peripheral innate immune system is also able to “talk” to the brain when an inflammatory episode occurs. The pro-inflammatory cytokines that are produced at the periphery by activated leukocytes not only mediate the peripheral inflammatory response but also act on the brain to induce local production of the same cytokines that are produced at the periphery. It is now clearly established that the peripheral immune message is relayed to the brain via both neural and humoral pathways. This ability of the brain to represent at the molecular and cellular levels the ongoing peripheral immune response enables this organ to initiate a set of coordinated metabolic, behavioral and subjective responses that form the core of what used to be called “the systemic acute phase reaction.” Sick individuals develop a fever, sleep less well and in a fragmented manner and reorganize their attention toward their body to the detriment of their physical and social environment. This response to an infection is as normal as the fear response to a threat. Engaging in an episode of sickness enables the organism to better cope with infections and to ultimately recover. However, it can become disproportionate and maladaptive either because it is out of proportion with the peripheral immune response or it becomes chronic. The signs of sickness that are normally reversible then persist and can get worse to the point of culminating in pathological fatigue, mood disorders and irreversible cognitive alterations.

Training an Interdisciplinary Workforce to Solve Complex Health Problems

A multidisciplinary research approach amasses experts from diverse disciplines to address a common complex problem, each bringing to bear his or her unique expertise. In contrast, in interdisciplinary research scientists work across disciplinary boundaries and meld two or more disciplines to create a new science.  The NIH roadmap recognizes the need for interdisciplinary research to solve the puzzle of complex multi-factorial diseases.  The University of Illinois’ Integrative Immunology and Behavior Program is home to a relatively large assemblage of interdisciplinary research scientists in psychoneuroimmunology and is one of only a few programs that is prepared to address this area of need.  Participating research scientists represent five departments within four colleges at the UIUC campus.  These scientists share common research interests in inflammation, infectious and noninfectious diseases or other conditions such as obesity and aging that lead to chronic inflammation, behavioral and cognitive disorders associated with inflammation, application of imaging techniques to explore effects of inflammation on brain structure and function, and therapies that reduce inflammation and improve mental health and wellness.  The strengths of the Illinois program are in studies at the molecular, cellular and organismic levels on the role of pro-inflammatory cytokines in promoting resistance to the major growth promoters, growth hormone, IGF-I and insulin, and the effects of cytokines on the brain, including the aging brain. An integrated program on the role of physical exercise on immunity and human behavior is in place and this program is moving toward the study of mechanisms, such as the role of moderate exercise in enhancing the production of critical growth factors in the aged. Functional brain imaging studies enable the visualization of those brain areas involved in exercise-improved cognitive processes. Other areas of related interest include the role of peripheral and central inflammation in the pathophysiology of type 2 diabetes and the mechanisms by which non-immune stimuli such as hypoxia can activate the peripheral and/or central cytokine signaling system. Members of the program are collaborating with clinicians from other universities to test their mechanistic hypothesis in patients and with colleagues from the industry including pharmaceutical companies and agrobusiness to study new interventions targeting inflammation for preventive or curative treatment of mood and cognition disorders.

The overall goal of the interdisciplinary program in Integrative Immunology and Behavior is to prepare exceptionally qualified graduate students, medical scientist trainees, and post-doctoral fellows to become productive research scientists capable of establishing scientific careers that further the need of NIH to understand the complex interactions between chronic inflammation and mental health.  The Integrative Immunology and Behavior program recruits pre-doctoral students (including M.D./Ph.D. students) through the Department of Animal Sciences, Neuroscience Program, Medical Science Program, and Division of Nutritional Sciences, and is specifically designed to address workforce deficiencies highlighted by NIH.  The program extends across campus and brings together faculty and trainees who are concerned with chronic inflammation, cognition and mental health, and novel interventions to improve health and wellness.  Thus, the Integrative Immunology and Behavior Program provides an outstanding environment for comprehensive training at the interface of immunology, psychology, and neuroscience where trainees actively engage in research and other program activities aimed at addressing an emerging health crisis that is related to chronic inflammation and symptom burden in various disease contexts.