Neural architecture in lymphoid organs: Hard‐wired antigen presenting cells and neurite networks in antigen entrance areas

Abstract

IntroductionRecently, we found abundant innervation of antigen presenting cells that were reached and enclosed by single neurites. These neurally hard‐wired antigen presenting cells (wAPC) could be observed in the T‐cell zone of superficial cervical lymph nodes of rats and other mammalians, including humans.MethodsAs a consequence, we investigated lymph nodes at many different anatomical positions as well as all primary and secondary lymphoid organs (SLO) in rodents for a similar morphology of innervation regarding antigen presenting cells known in those tissues.ResultsAs a result, we confirmed wAPC in lymph nodes independent from their draining areas and anatomical positions but also in all other T‐cell zones of lymphoid organs, like Peyer's patches, NALT and BALT, as well as in the thymic medulla. Other cells were innervated in a similar fashion but with seemingly missing antigen presenting capacity. Both types of innervated immune cells were observed as being also present in the dermis of the skin. Only in the spleen wAPC could not be detected. Beyond this systematic finding, we also found another regular phenomenon: a dense network of neurites that stained for neurofilament always in antigen entrance areas of lymphoid organs (subsinoidal layer of lymph nodes, subepithelial dome of Peyer's patches, subsinoidal layer of the splenic white pulp, margins of NALT and BALT). Lastly, also thymic epithelial cells (TEC) restricted to the corticomedullary junction of the thymus showed similar neurofilament staining.ConclusionsTherefore, we propose much more hard‐wired and probably afferent connections between lymphoid organs and the central nervous system than is hitherto known.

Subsecond spontaneous catecholamine release in mesenteric lymph node ex vivo

“…Sympathetic neurons innervate immune organs of the gastrointestinal tract including the mesenteric lymph nodes (MLN) (Murray, Barboza, Rude, Brust‐Mascher, & Reardon, 2019; Wülfing & Günther, 2015; Wülfing, Schuran, Urban, Oehlmann, & Günther, 2018) and Peyer's patches (Bhalla, Murakami, & Owen, 1981) to provide a direct pathway for neuroimmune communication. Sympathetic neurons release norepinephrine (NE) (Livnat, Felten, Carlson, Bellinger, & Felten, 1985; Madden et al 1995; Murray et al., 2019), ATP (Patel, Rogers, Wieder, O’Hare, & Boutelle, 2011), and neuropeptide Y (Mitić, Stanojević, Kuštrimović, Vujić, & Dimitrijević, 2011; Nordlind, Mutt, & Sundström, 1988) to act as immunomodulators.…”

“…Lymph nodes are spatially complex organs with a sophisticated network of signals that regulate immune responses (Felten & Felten, 1988; Murray et al., 2019; Wülfing & Günther, 2015; Wülfing et al., 2018). The MLN’s are the hubs of the immune system in the gut and therefore, an attractive site to study neuroimmune communication (Santiago et al., 2008; Buettner et al 2012).…”

“…These medullary cords are intertwined with noradrenergic (NA) sympathetic nerve fibers that extend deeper into the MLN (Park, Galligan, Fink, & Swain, 2006). NA nerve fibers innervate from the medulla to the T‐cell zone and to the edges of the cortex (Felten & Felten, 1988; Hu et al., 2019; Murray et al., 2019; Popper, Mantyh, Vigna, Maggio, & Mantyh, 1988; Shi et al., 2017; Wülfing & Günther, 2015; Wülfing et al., 2018). The cortex is where B‐cells are packaged in follicles and the site of entrance for transient antigen presenting cells (APC) through the afferent lymphatics (Gretz, Anderson, & Shaw, 1997).…”

“…The cortex is where B‐cells are packaged in follicles and the site of entrance for transient antigen presenting cells (APC) through the afferent lymphatics (Gretz, Anderson, & Shaw, 1997). Neural networks are found where APC’s enter and near resident APC’s at the T‐cell zone (Wülfing et al., 2018). The spatial complexity of the lymph node reinforces the need to make direct measurements within an intact organ.…”

“…In this study, FSCV is used to monitor rapid spontaneous catecholamine signaling in MLN slices ex vivo. The use of carbon‐fiber microelectrodes allows precise positioning within the T‐cell zone where noradrenergic sympathetic projections are prevalent (Murray et al., 2019; Wülfing & Günther, 2015; Wülfing et al., 2018). Rapid unstimulated release was observed in the T‐cell zone with an average of 2.9 ± 0.43 transients per minute ( n = 23).…”