Sympathetic nerves: novel therapeutic targets in the treatment of inflammatory disease? An anatomical study on sympathetic innervation of the human spleen, milky spots, lymph nodes and dorsal root ganglia

Animal studies have demonstrated that various secondary lymphoid organs (including the spleen and lymph nodes) are sympathetically innervated and that these nerves play a crucial role in regulation of immune cell activity via adrenergic receptor signaling. Electrical stimulation of these nerves results in alteration of the immune response, which in case of the splenic nerves, comprises dampening of the systemic inflammatory response. These observations lead to the consideration of electrical stimulation of these nerves as an anti-inflammatory therapy for the treatment of chronic inflammatory diseases (CIDs). Further assessment of the accessibility and therapeutic potential of these lymphoid organ specific nerves in humans requires knowledge on their afferent pathways and innervation patterns. Since this relevant data on human lymphoid organs is limited, this thesis aimed to provide these anatomical details for a subset of these organs, being the spleen, omental milky spots (OMSs) and lymph nodes (LNs).



Conclusion
The human spleen, OMSs and LNs contain sympathetic nerves, not only as perivascular structures but also as discrete nerves in proximity to immune cells, of which at least T cells. The presence of these nerves is encouraging for further exploration of their potential as immunomodulatory therapeutic intervention sites for the treatment of inflammatory diseases. Although promising, neuroimmunomodulation is a relatively new, primarily experimental discipline and further consideration of electrical stimulation of nerves in order to modulate immune responses in humans requires further studies. These studies should aim to increase our understanding of the underlying anti-inflammatory mechanism, provide comparative neuroanatomical data that facilitate translation of data from animal studies to humans, and make an inventory and assessment of all potential risks and side effects associated with surgical procedures, long term implantation of electrodes and electrical nerve stimulation.