What organs are involved in the immune system

Anatomical or Functional Evidence for a Neuro-Immune Synapse in the Gut?

The lymphoid organs of the immune system are innervated by cholinergic, catecholaminergic, peptidergic, and other neurons and many neurotransmitters and receptors are shared between the immune system and the nervous system, substantiating claims of a strong regulatory component of the nervous system in immune responses. A good example thereof is the discovery of acetylcholine producing memory T cells in the circulation (Dhawan et al., 2012; Fujii et al., 2012) and spleen (Rosas-Ballina et al., 2011). It is likely that such cells can interact with other antigen-presenting cells or feed back on nerve terminals in primary or secondary lymphoid organs. These evidences of neuro-immune intercommunication in gut immunity are discussed in the subsequent Sections: Sympathetic Regulation of the Mucosal Immune System, The Parasympathetic Control of the Gut Immune System and Noncholinergic Nonadrenergic Receptors; Relevance for Gut.

Most studies of sympathetic innervation of lymphoid organs employed immunohistological techniques in which the rate-limiting enzyme of norepinephrine synthesis, tyrosine hydroxylase, was detected. These studies, that date back to almost 50 years ago (reviewed in Elenkov et al., 2000), demonstrated a rich, sympathetic innervation of all primary (thymus and bone marrow) and secondary (spleen and lymph nodes) lymphoid organs (reviewed in Elenkov et al., 2000). Regarding the possibility of a real neuro-immune synapse, electron microscopic studies of the white pulp reveal that sympathetic nerve terminals are in direct apposition to T cells and adjacent to both dendritic cells (DCs) and B cells (Felten et al., 1985), with the neuro-immune junction being approximately six nanometers wide (Felten et al., 1987), in contrast to a typical CNS synapse that is approximately 20 nm wide. The close proximity of sympathetic nerve terminals to immune cells provides a mechanism not only for specific targeting of norepinephrine release to immune cells, but also for the containment of neurotransmitter release and for interference with immunological synapse-related processes.

Hence, concerning the spleen such a complete “circuit” appears to exist between the immune system and sympathetic neurons, and is most likely projected to intestinal follicles as well.

Introduction

The morphological and functional evolution of immune system organs in mammals is a continual process that commences early in embryonic development, reaches a maximum at some point in early adulthood, maintains at a plateau for an indeterminate period, and then declines. At the time of birth the intrinsically determined development of immune system organs is dramatically altered by the exposure to an enormous array of environmental antigens. At the time of birth the immune system organs are at different stages of development, which is manifested as differences in morphology and function and which can further vary between different mammalian species.

The laboratory rat is commonly utilized in experimental studies but published information on histologic features of developing immune system organs of the rat is generally sparse, consisting primarily of a review of morphology and immunohistochemical (IHC) staining properties of the thymus and spleen of rats at 1, 2, 3, 4, 9, 19, 23, 46, and 57 weeks of age (Kodama et al., 2012), and selected histological observations on the postnatal histogenesis of limited immune system organs of rats (Burns-Naas et al., 2008; Weinstock et al., 2010). Information below regarding postnatal development of immune system organs in the rat is based on studies in which histologic examination was performed on immune system organs from rats at PND 0, 7, 14, 21, 28, 35, and 42 (Parker et al., 2015). Cellular constituents and cellular proliferation were determined by additional IHC staining for B cell, T cell, and proliferation using antibodies against CD45RA, CD3, and Ki67 IHC staining, respectively.

A Spleen

The spleen is an important immune system organ responsible for removing old red blood cells, maintaining a blood reserve, recycling elemental iron, synthesizing antibodies as well as retaining half the body's monocytes, which allows them to move into injured tissues for differentiation into DCs and macrophages. The spleen is richly innervated by the sympathetic nerves, which affects its physiology (Felten et al., 1987). Reports of high transcriptional expression for all three α1-AR subtypes in the spleen have been published (Alonso-Llamazares et al., 1995; Kavelaars, 2002). However, the spleen was one of the first tissues used to demonstrate translational α1-AR homogeneity (Han et al., 1987). Subsequent radioligand binding analysis in bovine and guinea pig spleen also demonstrated a homogenous α1B-AR subtype population (Büscher et al., 1996). Conversely, no specific [3H]-prazosin binding could be observed in a murine (strain HLG) broken cell spleen preparation (Yang et al., 1998).

There is also evidence to suggest functional α1-AR expression in the spleen. Electrical stimulation (ES) of isolated murine spleen slices inhibits basal IL-6 secretion, which is attenuated by phentolamine (Straub et al., 1997). Application of the α1-AR agonist methoxamine mimicked the inhibitory response of ES on basal IL-6 levels. In other studies, NE treatment in the presence of propranolol enhanced the murine IgM antibody response in primary spleen cells immunized with sheep erythrocytes in vitro (Sanders & Munson, 1984). In a subsequent investigation, methoxamine was used to demonstrate that early IgM increases from immunized murine spleen cells were mediated through α1-AR activation, while late IgM changes observed in the presence of clonidine were facilitated by α2-AR stimulation (Sanders & Munson, 1985). Additionally, there is evidence linking changes in spleen α1-AR activation with chronic inflammatory disease states (Straub et al., 2008). In this study, ES of the splenic nerve in an early type II collagen-induced arthritis (CIA) mouse model showed a decrease in IFN-γ secretion compared to control animals, which was partially reversed in the presence of the α1-AR antagonist benoxathian.

Publisher Summary

This chapter focuses on the location of nerves within organs of the immune system and the possible association of these nerves with specific compartments or cellular regions. It also focuses on neurotransmitters in these nerves, which act as signal molecules within the immune system. Lymphoid organs are composed of a reticular stroma that forms a meshwork that provides support for varying populations of cells of the immune system, many of which are mobile cells. Secondary lymphoid organs and accumulations have T-dependent areas and B-dependent areas. It is much more common to find innervation, whether noradrenergic or peptidergic, associated with the T-dependent areas. However, occasional fibers do seem to enter the follicles. There are also areas where T lymphocytes, B lymphocytes, macrophages, and other cells are mixed; these areas often are associated with large blood or lymph sinuses, where antigen presentation takes place, such as the marginal zone of the spleen and the medullary cords of the lymph nodes. These areas also are innervated largely by noradrenergic/NPY-containing fibers.

9.44 Autonomic Innervation of the Immune System and Metabolic Organs

The autonomic nervous system innervates the vasculature, smooth muscle tissue, and parenchyma of organs of the immune system mainly through the sympathetic division. In the bone marrow and thymus, sympathetic fibers modulate cell proliferation, differentiation, and mobilization. In the spleen and lymph nodes, sympathetic fibers modulate innate immune reactivity, and the magnitude and timing of acquired immune responses, particularly the choice of cell-mediated (Th1 cytokines) as opposed to humoral (Th2 cytokines) immunity. Autonomic nerve fibers regulate immune responses and inflammatory responses in the mucosa-associated lymphoid tissue (MALT) in the lungs, the gut-associated lymphoid tissue (GALT), and the skin. Extensive neuropeptidergic innervation, derived from both the autonomic nervous system and the primary sensory neurons, also is present in the parenchyma of lymphoid organs. Many subsets of lymphoid cells express cognate receptors for catecholamines (alpha and beta receptor subsets) and neuropeptides; the expression of these neurotransmitter receptors is highly regulated by both lymphoid and neural molecular signals. Postganglionic sympathetic nerve fibers also directly innervate hepatocytes and fat cells. (Th = T helper cells)

THE LYMPH SYSTEM

In conventional terms the lymph system is part of the circulatory system and is a major organ of the immune system. One of its main jobs is to transport nutrients from the blood to each individual cell and to remove waste. Some of this waste is transported to the intestines via the lacteals, that part of the lymph system that empties into the small intestine. The numerous lymph nodes in the abdomen also become sites for waste and toxins. The San Jiao system may be a complex analog for the lymph system. Both are ubiquitous and complex, both have immune relationships. It seems safe to say that within the Chinese medicine paradigm, the San Jiao system is impacted when toxins are present. The fat cells of the greater omentum and the mesenterium are all part of the San Jiao. These special ‘greasy membranes’ may act as modules for decontaminating toxins.

All of the elements of detoxification already mentioned are important to overall San Jiao functioning. Additionally, it might be of value to include various forms of acupuncture and manual techniques, like lymph drainage techniques, to move and flush toxins from various types of tissue into the lymphatics and along for flushing. Visceral manipulation and lymphatic drainage may be potentiated by herbal medicine and acupuncture as a detoxification process.

Immunotoxicity Testing

According to the guidelines for immunotoxicology evaluation, immunotoxicity parameters (beyond standard clinical pathology and immune system organ weight/histology) do not need to be added to the repeat-dose toxicity studies unless there is a specific cause for concern [34–36]. If specialized end points do need to be added to toxicity studies using NHPs, commonly used end points such as immunophenotyping and the T-cell-dependent antibody response assay have been extensively validated in the cynomolgus monkey [37]. These end points also have been used for common marmosets and rhesus monkeys and should be accepted by health authorities, but they are not as well validated. When planning for a more detailed immunological assessment in NHPs, one consideration is that differences in white blood cell parameters and potentially other immunologic end points do exist between animals from different regions of the world (i.e., cynomolgus monkeys of Chinese origin vs. those of Vietnamese origin) [38]. Therefore, it is recommended that NHPs of the same origin be used throughout the nonclinical program. Another consideration for molecules that might induce a cytokine storm (i.e., drugs that activate the immune system) is that the NHP is not considered a good model and responses may not correlate well with potential responses in humans. However, other species have not been found to be any more predictive of human cytokine storm.

Chronic diarrhea

Immune deficiencies with chronic diarrhea are listed in Table 1.6. The gastrointestinal (GI) tract is the largest organ of the immune system. It functions as a major gateway for the external environment, and contains an extensive network of secondary lymphoid tissue. Intestinal integrity is maintained by several factors, including the epithelial cell layer, innate lymphoid cells, mucus-secreting goblet cells, antimicrobial peptide-producing Paneth cells, IgA-releasing plasma cells, and gut-associated lymphoid tissue such as Peyer's patches.291,292 As the barrier for the systemic immune system, gut-associated lymphoid tissue (GALT) plays a critical role in the balance between inflammation and immune tolerance. Peyer's patches, which are specialized lymphoid follicles in the wall of the small intestine, contain follicular dendritic cells, T cell-rich areas, and naïve B cells. The humoral immune response is actively involved in barrier function. In particular, IgA secreted by intestinal B cells (sIgA) enhances immune exclusion by trapping dietary antigens and microorganisms in the mucus. sIgA usually functions under non-inflammatory conditions and prevents overreaction of the immune system while maintaining protective immunity.293,294 Lately, there has been an increased awareness of the role of the intestine in educating the immune system. The encounter with commensal microbiota results in the peripheral generation of regulatory T cells rather than pathogenic effector T cells, which might have important implications for immune-mediated enteropathies.295 Thus, gut-immune homeostasis is maintained by several components of innate and adaptive immunity interacting in a complex manner. Consistently, a substantial proportion of PID patients present with clinically challenging inflammatory bowel disease (IBD)-like pathology (Chapter 30).296

Table 1.6. Immune deficiencies with chronic diarrhea.

Gastrointestinal disorderFeaturesEarly-onset inflammatory bowel diseaseIL-10 deficiencyPoor response to therapy, fistulaeIL-10R1, IL-10R2 deficiencyPoor response to therapy, fistulaeXIAP deficiencyPoor response to therapyTTC7A deficiencyImmunodeficiency and gut epithelial barrier disfunctionDyskeratosus congenitaUlcerative colitis and GVHD-like pathologyColitisCGDInfections usually precede colitisLADColitis can be severe, dearth of neutrophils on pathologyXLANot typically present at diagnosis of XLACVIDMany histologic typesEnteropathyIPEX, STAT1, STAT5b, CD25Autoimmune enteropathySevere DKCApoptotic cells with a GVHD-like pathologyGiardia susceptibilityXLAFalling IgG levels can accompany Giardia, can be difficult to eradicateImmunoglobulin class switch defectsCan be difficult to eradicateCVIDSusceptibility to CrytosporidiumImmunoglobulin class switch defectsCan be seen in bile ductsCD21 deficiencyVery severeIKBKG deficiency (NEMO)Can be difficult to eradicateCombined immune deficienciesThe greater the T cell defect, the more likely