HMGB1 and rheumatoid arthritis: It is proposed that reduced vagal tone triggers increased production of IL-6, TNF-α, MIF and HMGB1 by peripheral leukocytes, monocytes and macrophages; leads to an increase in sympathetic activity (due to the absence of negative feed-back control from the parasympathetic system), and consequent inflammation due to a decrease in the production of anti-inflammatory acetylcholine that ultimately results in systemic inflammation seen in RA and lupus.