The sympathetic neuronal control of immunity in primary and secondary lymphoid organs is exerted through “hard-wired” noradrenergic nerve terminals through the release of norepinephrine that interacts with the immune cells. This has been extensively delved into by Felten and their colleagues, and others in thymus and spleen initially and subsequently in lymph nodes, bone marrow and gut in rodents. An increasing number of evidence suggests that lymphoid organs are supplied with autonomic catecholaminergic or peptidergic efferent and afferent sensory innervation depending on whether they are primary or secondary lymphoid organs [1-6]. The neural-immune cross-talk through catecholaminergic systems facilitates a myriad of immune responses including proliferation and differentiation of B and T cells, its trafficking in and out of the lymphoid organ, and interactions between immune cells.
Although the functional significance of sympathetic innervation in all of the lymphoid organs has been explored and understood , detailed neuroanatomical descriptions of the origin of innervation or its role in modulating lymphocyte activity in different lymph nodes, and existence of parasympathetic innervations or afferent pathways to these organs are poorly understood. Retrograde tracing in neurons of lymph nodes suggested that the origin of the sympathetic input is from the post-ganglionic neurons innervating that particular part of the body .
Further, these studies proved the presence of functional sensory input to regional lymph nodes, thus facilitating antigen recognition and processing in the immune cells from skin, muscle and mucosa, which are extensively supplied with afferent sensory nerves. These afferent inputs, possibly from dorsal root ganglia, may be responsible for eliciting immune responses to a localized injury or infection . Moreover, the counter flow mechanisms of lymphocyte and antigen presenting cell (APC) entry into the lymph nodes, via high endothelial venules from blood and from lymph respectively, facilitates rapid selection of the specific lymphocytes, leading to its clonal expansion and differentiation. Thus, examining neural connections to the population of cells in the lymph nodes may be the best targets for understanding neural-immune interactions considering their widely functional divergence and flexibility.
Recently, Scientific Reports published an interesting and narrative study reporting the presence of closely associated meshwork of neuronal fibers in specific regions of lymph nodes, enveloping cells with APC character, which the authors named “wired” APC (wAPC), and which function as afferent sensory network to brain-immune interactions [Clemens Wülfing & Hauke S. Günther, 2015]. They have given the first evidence for the extensive lymph node parenchymal innervation besides the already known neuronal connections associated with vasculature, denying the probability of efferent sympathetic connection, while accentuating “a directed-informational contact” to wAPC, thereby gathering the topographical characteristics of localized immune events and recruiting the specific lymphocyte subset to interact with its respective APC.
Results from the experiments indicate the presence of an intensive amount of short branched axonal structures innervating the T cell-rich region of lymph nodes in a dense and closely associated manner. The neural marker microtubule-associated protein-2 (MAP2) which is crucial in neurogenesis, together with axonal growth cone staining, were used to examine the dynamics, receptiveness, and plasticity of wAPC.
The finding that the innervation of the APC is dynamic, not static, and may depend on immunological activity of the innervated APC, has given an edge in identifying the migratory and resident APC-subtypes, although this classification is not exclusive, where the former connects to neural contacts convey their immunological status to CNS, while the latter remains non-innervated. In view of CNS as an immunologically privileged site that can process and present antigen to immune system through afferent-CNS pathway either via antigen presenting cell (microglia and perivascular cells) in CNS or by lymphocytes in the regional lymph nodes , this finding can partially explain the sensory immunological input to CNS in orchestrating an integrated immune elicit by CNS.
It is incomprehensible as to how the authors’ findings of lack of synaptophysin staining of wAPC but its presence in the vasculature-related neural structures and the anterograde staining enables them to arrive at a definitive conclusion that the wAPCs are devoid of noradrenergic innervation and therefore, these cells are the afferent inputs to CNS. Use of direct markers such as tyrosine hydroxylase for immunofluorescence studies along with neurofilament staining would have further consolidated their observations. Speculative notions about the nerve fibers of wAPC being myelinated and that they correspond to the sensory neurons in the dorsal root ganglia have to be proved by functional studies.
Intravital confocal microscopy or two-photon excitation microscopy could have been used to provide results that support the authors’ claims that innervation of wAPC is dynamic and shows plasticity because of the staining with MAP2 and axonal growth cone markers. Double-staining immunohistochemistry/immunofluorescence with markers for T cells/its subsets along with neurofilament could have provided conclusive evidence for the anatomical localization of wAPCs either in the paracortical or cortical regions of the lymph nodes. Further, as stated by the authors, the limitations of the current study, for instance, fail to identify a specific marker for wAPC and the origin of SIRP-α expression, warrants additional studies.
Barring the above conjectures, the scientific data and their experimental approach were unique in demonstrating the presence of neurofilament-positive structures, and localization of MAP2 and growth cone on the wAPC. The available data unveils a plethora of complexities in possible neural-immune interactions, as from what and where the inputs arise and the targets to these cells. Future studies may have to be conducted to ascertain whether these cells have the afferent/sensory role so that the CNS can respond to any foreign antigen and subsequent orchestration of cell-mediated and humoral immunity.
Srinivasan ThyagaRajan, B.V.Sc., Ph.D. – Integrative Medicine Laboratory, Department of Biotechnology, School of Bioengineering, SRM University, Kattankulathur 603 203, Tamil Nadu, India; Email: email@example.com
Romeo HE, Fink T, Yanaihara N, Weihe E., 1994. Distribution and relative proportions of neuropeptide Y- and proenkephalin-containing noradrenergic neurones in rat superior cervical ganglion: separate projections to submaxillary lymph nodes. 15:1479-1487.
Nance DM, Sanders VM., 2007. Autonomic innervation and regulation of the immune system (1987-2007). Brain Behav. Immun. 21:736-745.
Weller RO, Engelhardt B, Phillips MJ., 1996. Lymphocyte targeting of the central nervous system: a review of afferent and efferent CNS-immune pathways. Brain Pathol. 6:275-288.