Figure 1

The role of the autonomic nerve system in rheumatoid arthritis. The autonomic nervous system is divided into the sympathetic (left) and parasympathetic (right) nervous system. Cell bodies of preganglionic sympathetic neurons are located in the central nervous system, between the first thoracic (Th1) and third lumbar (L3) spinal cord segments, from where its axon connects to the postganglionic neurons. Parasympathetic preganglionic neurons are found in the brainstem and the second through fourth sacral (S2–S4) spinal cord segments. The parasympathetic nervous system mainly consists of the vagus nerve, the tenth cranial nerve. The heart (A) is innervated by both the sympathetic and parasympathetic nervous system. Heart rate variability (HRV) is a technique to determine the balance of the autonomic nervous system. In rheumatoid arthritis patients, this balance can be altered compared with healthy individuals. This imbalance is caused by a dominant influence of the sympathetic nervous system instead of the parasympathetic nervous system, which under normal conditions, to a great extent, determines HRV. Both lymphoid organs (spleen and lymph nodes) (C) and joints (D) are innervated directly by the sympathetic nervous system, but no innervation of the vagus nerve (parasympathetic nervous system) has been found. Stimulating the vagus nerve and thereby reducing inflammation (a concept known as the cholinergic antiinflammatory pathway) does, however, need the presence of the spleen. Fibers of the vagus nerve end in the celiac-superior mesenteric plexus (B), further innervation of the spleen via the splenic nerve has been found to contain only catecholaminergic fibers from the sympathetic nervous system. It is not known how the vagus nerve can signal via the spleen without direct innervation, but it is proposed that the catecholaminergic splenic nerve transmits the parasympathetic signal toward the spleen. Inflammation is registered in the brain via the circulation, but also via the afferent vagus nerve (E). Subdiaphragmatic vagotomy inhibits signaling of inflammation toward the brain. As the joint is not innervated by the vagus nerve, most likely direct detection of joint inflammation is not possible.