Autonomic (CNS) Regulation of Inflammatory Responses in the Clinical Progression of Rheumatoid Arthritis

Kevin J. Tracey, M.D.

North Shore - LIJ Research Institute

Funded in June, 2003: $300000 for 3 years


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Determining How the Nervous System Controls Inflammation

Rheumatoid arthritis is an autoimmune disease characterized by progressive inflammation in the body's joints. This inflammation involves excessive release of immune system substances called cytokines. Recently, the North Shore researchers unexpectedly found that the release of these immune system cytokines is regulated by the vagus nerve. This nerve is a part of the autonomic nervous system, which controls involuntary functions like heart rate and respiration.

The autonomic nervous system also, according to the researchers' new finding, controls the release of inflammatory cytokines. The autonomic nervous system's vagus nerve uses the neurotransmitter acetycholine to send its signals. The researchers hypothesize that diminished autonomic (vagal nerve) activity contributes to increased cytokine release in patients with progressive rheumatoid arthritis.

Specifically, the researchers hypothesize, insufficient release of acetylocholine (the neurotransmitter used by the vagus nerve to send its signals) allows too much cytokine to be released. This allows too much inflammation to occur, and this excessive inflammation produces progressive rheumatoid arthritis. The investigators plan to determine if this is the case by measuring autonomic functions (such as heart rate and respiration) and cytokine levels in rheumatoid arthritis patients and comparing these to measures in healthy controls.

The investigators also will study the specific immune system receptors that regulate cytokine release, called "monocytes" to see whether the functions of this receptor are altered in rheumatoid arthritis patients. Additionally, the researchers will study the patients' families to explore the genetics associated with potentially altered receptor function.


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Autonomic (CNS) Regulation of Inflammatory Responses in the Clinical Progression of Rheumatoid Arthritis

The autonomic nervous system controls visceral functions from minute to minute, such as heart rate, blood pressure, and respiratory rate. We recently discovered that cholinergic signaling in the vagus nerve (the parasympathetic outflow of the autonomic nervous system) inhibits inflammation and cytokine release (Tracey KJ, Nature 420:853-9, 2002). Acetylcholine binding to macrophage α7 nicotinic acetylcholine receptor subunits inhibits synthesis and release of proinflammatory cytokines. Mice genetically deficient in the α7 subunit are refractory to vagus nerve regulation of inflammation, indicating that this receptor subunit is required for the vagus nerve-to-immune system interaction (Wang et al., Nature 421:384-8, 2003). This mechanism for CNS control of inflammation, termed the "cholinergic anti-inflammatory pathway," has qualitatively expanded understanding of how the central nervous system controls inflammatory responses through a "hard-wired and integrate-able" neural network. Volunteers can be taught to increase (augment) vagus nerve output, but the effects of increased vagus nerve output on inflammation are unknown.

Rheumatoid arthritis is a disabling, costly, and progressive inflammatory disease. We recently established a cytokine role for HMGB1, a 30 kD nuclear protein previously studied for its role in facilitating gene transcription. Antibodies against HMGB1 confer significant protection against lethal endotoxemia (Wang et al., Science, 1999 285:248-51), and established arthritis (CIA) (Kokkola et al., Arthritis and Rheumatism, 2003, in press). HMGB1 levels are increased in the synovial fluid and serum of rheumatoid arthritis patients. Cholinergic agonists inhibit HMGB1 release from macrophages, suggesting that activity in the vagus nerve may modulate HMGB1 release. Earlier clinical studies gave direct evidence of autonomic dysfunction in patients with rheumatoid arthritis, but it is as yet unknown whether suppressed cholinergic activity contributes to increased HMGB1 release in these patients. It is plausible however, that diminished activity in the parasympathetic nervous system facilitates HMGB1 release and contributes to progression of arthritis. This study will address the hypotheses that decreased vagus nerve activity in rheumatoid arthritis patients is associated with increased disease activity and with HMGB1 release.

Specific Aim 1: Assessment of disease activity, vagus nerve activity, and HMGB1 activity in progressive rheumatoid arthritis. Background: Our preliminary results demonstrate that vagus nerve activity is required for maintaining proper immunological homeostasis and modulating cytokine release. We do not know whether rheumatoid arthritis disease activity is higher in patients with diminished vagus nerve activity, or if HMGB1 levels are increased in patients with diminished vagus nerve activity. Plan: Rheumatoid patients and age-matched controls will be enrolled for assessment of disease status and vagus nerve activity. Patients will be studied four times per year for three years, and each visit will include assessment of disease activity, determination of vagus nerve activity, and collection of blood samples for HMGB1 levels.

Specific Aim 2: Assessment of α7 subunit function and expression in patients with rheumatoid arthritis. Background. Our preliminary results indicate that the α7 subunit is required for cholinergic inhibition of HMGB1 release, and to maintain immunological homeostasis in vivo. We do not know whether the function, expression, or activity of this receptor subunit is altered in patients with rheumatoid arthritis. Plan: α7 subunit expression and activity will be measured in rheumatoid arthritis patients and age-matched controls. The α7 subunit, or related genes, will be genotyped to provide data on the genetic component of phenotypic variation in α7 subunit pathways.


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Kevin J. Tracey, M.D.

Kevin J. Tracey, M.D., is a neurosurgeon, Program Director of the General Clinical Research Center, and Head of the Center for Patient Oriented Research at the North Shore -LIJ Research Institute, and Professor of Microbiology and Immunology at the Albert Einstein College of Medicine. Dr. Tracey received a B.S. from Boston College, and an M.D. from Boston University. He completed his clinical training in neurosurgery at the New York Hospital-Cornell University Medical College and was a guest investigator at the Rockefeller University.

His lab focuses on identifying new approaches to prevent the damage caused by excessive or uncontrolled inflammation. He discovered the inflammatory action of TNF in non-malignant disease, and first developed therapeutic monoclonal anti-TNF antibodies. His lab discovered an inhibitor of TNF synthesis that has been used successfully in a Phase II trial of Crohn's disease and continues to be evaluated in clinical trials. They discovered that a protein (HMGB1) is a new therapeutic target for both lethal systemic infection and experimental arthritis. They also discovered a neural-immune connection known as "the inflammatory reflex" that regulates inflammation via the vagus nerve, and have initiated preclinical testing to assess the therapeutic potential of controlling this neural pathway to prevent damaging inflammation in patients by .

Peter K. Gregersen, M.D. is a leading rheumatologist who has been studying the genetic basis for autoimmune and other disorders and is one of the principal experts on the genetics of rheumatoid arthritis, having worked in this area for nearly two decades. He directs a high throughput genotyping laboratory focused on autoimmune diseases, and the North American Rheumatoid Arthritis Consortium (NARAC) mapping project is the largest effort worldwide to pursue a genome-wide screen for linkage and ultimately gene identification in rheumatoid arthritis.

Dr. Gregersen continues to pursue other research projects in areas related to autoimmunity, including studies of human T cells and the role of X linked factors in predisposition to autoimmune diseases. In addition, Dr. Gregersen has successfully collaborated on the development of robotic solutions to large volume sample preparation and storage for population genetic studies.


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Lay Results:
The investigators demonstrated that vagus nerve activity is depressed in patients with RA as compared to the control healthy subjects. They have also demonstrated that blood levels of cytokines correlated with disease activity. A major finding of this study is that the decrease in vagus nerve activity is significantly correlated with elevated levels of cytokines.  These results are consistent with the hypothesis that decreased vagus nerve activity is associated with over-abundant inflammatory response in patients with RA. Based on these results, the investigators plan to conduct additional studies addressing the hypothesis that increasing vagus nerve activity in Rheumatoid Arthritis patients will reduce inflammatory cytokine levels and improve disease activity scores.

Scientific Results:
We studied vagus nerve activity and serum HMGB1 levels in 11 control subjects and 13 patients with RA.  Our results demonstrated that the vagus nerve activity is significantly decreased in RA patients as compared to controls (p<0.0001). Serum levels of HMGB1 significantly correlated with disease activity scores (DAS-28) in patients with RA (p=0.004). A major finding of this study is that elevated levels of HMGB1, a cytokine mediator of inflammation, significantly correlated with decreased vagus nerve activity (p<0.01). These results are consistent with the hypothesis that decreased vagus nerve activity is associated with increased levels of proinflammatory cytokines. This knowledge could be further exploited for developing therapeutic strategies for targeting vagus nerve activity in patients with inflammatory diseases mediated by cytokines. 


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Goldstein R.S., Bruchfeld A., Yang L., Qureshi A.R., Gallowitsch-Puerta M., Patel N.B., Huston B.J., Chavan S., Rosas-Ballina M., Gregersen P.K., Czura C.J., Sloan R.P., Sama A.E., and Tracey K.J.  Cholinergic anti-inflammatory pathway activity and High Mobility Group Box-1 (HMGB1) serum levels in patients with rheumatoid arthritis.  Mol Med. 2007 Mar-Apr;13(3-4):210-5.