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.