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11 Immunologic Function of the Mesentery 89
T cells are either identified as cytotoxic T cells or helper T cells, both of which
rely on T-cell receptors to bind to pathogens by sensing specific protein sequences.
Helper T cells interact with B cells by activating them, attracting macrophages, as
well as secreting cytokines. Cytotoxic T cells effectively kill pathogenic cells by
drilling into cells via ligands and other surface molecules that allow introduction of
chemicals to trigger apoptosis.
Appropriate responses to pathogens and tolerance to commensal organisms
constitutes immune homeostasis and is vitally important for effective immune
function. Immune homeostasis, both innate and adaptive, relies on four primary
components of the immune system. Responses to pathogens is ultimately modeled
as a negative feedback within the components of the immune system (Fig. 11.4).
By contrast, tumor respon ses are characterized by positive feedback system that are
beyond the scope of this chapter.
The model is made up the interplay of four units; sensory, regulator, effector, and
rehabilitator molecules. Sensory molecules consist of cells such as macrophages
and lymphocytes that recognize a pathogenic cell. Regulators represent antigen
presenting cells that investigate the sensory signal and work with the sensor cells to
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EFFECTOR
lymphocytes,
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REGULATOR
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SENSOR
macrophages or
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cytokines
and antigen
Fig. 11.4 Negative feedback mechanism for immune homeostasis. Lymphocytes and macrophages initiate the immune response by performing the sensor function, i.e. initiating a warning
signal via cytokines and antigen presenting cells (APCs). The regulator consists of these APCs as
well as T regulatory cells (Tregs), and myeloid-derived suppressor cells (MDSCs). APCs
determine the type of cytokine that was released and program T helper (Th) cells to the effector
cells, thereby dictating the action that these effectors take. The effector cells then destroy pathogens
and/or host cells and surrounding tissue containing the pathogens as well. The final step, and one
which has recently been recognized, is the action of recovering damaged tissue by repair, or
rehabilitation as labeled in this diagram. Rehabilitator cells consist of M2 macrophages by
mechanisms discussed on the previous page
90 D. H. Kruchko and E. D. Ehrenpreis
appropriately program effector cells. Effector cells consist of programmed macrophages and lymphocytes that function in the elimination of pathogens. Rehabilitator
molecules, representing speci fic types of macrophages known as M2 macrophages,
restrict inflammation and provide functions for repair of tissue damage and
restoration of homeostasis. Tissue repair is a relatively newly identified role of M2
macrophages but considered as critical in restoration of morphological and functional structure after macrophage phagocytosis and destruction of local tissue. Once
tissue damage has been repaired, there are negative feedback signals to the sensor
cells stop the cycle, thus preventing ongoing tissue damage. If this response is
turned off, or positive instead of negative feedback to the sensor cells occurs, the
risk of immune overactivity in the setting of either autoimmunity or carcinogenesis
is increased. Specific macrophages, labeled M2 macrophages, are important components in this transformation to pathogenic positive feedback mechanisms. The
mechanism by which this transformation takes place is hypothesized to be a
response to inappropriate cytokine secretion leading to an influx of immune cells
responding to what appears to be a foreign attack. The model suggests that similar
pathologic positive feedback mechanisms occur in tumor development and
autoimmunity.
Mesenteric-Specific Immune Cells
The pivotal and most extensively studied immune cells of the mesentery are dendritic cells, mesenteric lymph nodes, and T cells – specifically CD4+ T cells.
Dendritic cells are some of the most active antigen presenting cells within the
mesentery. There are three primary signals by which dendritic cells utilize antigen
presenting mechanisms and prepare naive T cells in mesenteric lymph nodes and
intestines. The first signal is T-cell receptor identification on Major Histocompatibility Complex (MHC) molecules. MHC provides a means for identification of
large prote ins within the immune system to identify foreign proteins. Thi s is a vital
role of the mesenteric immune system since it is repeatedly exposed to food proteins and other ingested molecules. The second signal is co-stimulation, which
relies on the expression of several co-stimulatory molecules that are collectively
referred to as cluster of differentiation (CD) molecules. CD28 is a specific molecule
found on both CD4+ T cells as well as CD8+ T cells. There is also an important
peripheral membrane prote in known as B7 that is found on the surface of activated
dendritic and other antigen presenting cells. B7 plays a critical role for either
co-stimulation or co-inhibition of the MHC-TCR signal and allows for dendritic
cells to begin the process of priming naïve T cells as depicted in Fig. 11.5. The third
signal is naive T-cell differentiation by dendritic cells. This determines the differentiation of T-cells into specific effector cells such as CD4+ Th cells or CD8+ cells,
which are labeled as cytotoxic T lymphocytes (CTLs) in Fig. 11.5. CTLs facilitate
killing of infected cells (labeled tumor cells in Fig. 11.5) by antigen-specific
11 Immunologic Function of the Mesentery 91
CD28
DC
MHC II:
HPV Ag
MHC molecules on DCs
present Ag to T cells
B7
TCR
CD8
T cell
+
TCR
MHC I:
HPV Ag
CD4
T cell
CD28
B7
CTL
CTL
Priming of naive T cells
to activated antigen-
specific T cells
+
CD8
T cell
+
+
CD4
T cell
CTL
T helper
cell
CD40L
CD40
Kill
CTLs kill tumor cells
+
CD4
T cell
activate
MHC II
Activated DC
CD4+ T cell help
augments CTL responses
MHC I
CD8
T cell
CTL
+
Fig. 11.5 The role of dendritic cells (DCs) and T cells in cellular immunity activation. As
described in the text, this is a depiction of cellular immunity generation after uptake of the Human
papillomavirus antigen (HPV Ag) by the DC. Key cells of differentiation (CDs) and other surface
proteins (e.g. B7 and CD28) are labeled above and are pivotal in T cell recognition and HPV Ag
presentation. Next, both CD8+ and CD4+ naïve T cells are primed by DCs in order to become
effector cells to participate in killing of infected cells
mechanisms, while Th cells can differentiate into na ïve CTLs and assist with
antigen-specific killing of infected cells.
Lastly, CD80 is a specific molecule found on the surface of DCs and has been
found to play a critical role in immune response. CD80 expression determines
whether the immune system will attack or ignore commensal and/or foreign
organisms. Once CD80 molecules are expressed, priming of naïve T cells begins
which will ultimately promote anergy, or the lack of an immune response by
ignoring a pathogen, as seen in Fig. 11.6. Conversely, overexpression and inappropriate expression of CD80 cells can lead to inapt immune responses to
non-pathogenic, commensal organisms which effectively leads to autoimmunity.
Crohn’s disease is an example of the interplay between mesenteric lymph nodes and
DCs producing CD molecules that ultimately lead to dysregulation of Th cells.
Specifically, Th1 and Th17 dysregulation as a result of any abnormality in the three
aforementioned signals, is a key feature of Crohn’s disease.
92 D. H. Kruchko and E. D. Ehrenpreis
Normal Ignorance
APC
CD80/86
CD28
TCR
T cell
MHC
peptide
Tissue barrier
Activated T cell Non-activated T cell
Fig. 11.6 T cell peripheral tolerance mechanisms. The column labeled “Normal” relies on the
now well described interaction between MHC molecules, co-stimulatory molecules, and peptides
that ultimately lead to T cell activation. The next column, labeled “Ignorance” represents anergy,
described previously as the lack of an immune response by way of ignoring the molecule. This the
prominent CD molecule at play in anergy is CD80 and this has been well documented in the
literature. In order to avoid overactivity from the immune system, CD80 needs to be appropriately
expressed to prevent the inappropriate T cell activation
Mesenteric Immunity and Crohn’s Disease (Also See Chap. 15 Crohn’s Disease)
Recent studies have focused on the interplay between mesenteric lymph nodes and
the pathogenesis of Crohn’s disease. The recruitment of T helper cells, also known
as CD4+ T cells, is largely dependent on proper mesenteric lymph node response.
In normal immunology, mesenteric lymph node recruit CD4+ T cells and thereby
enhance the intercellular communication by production of cytokines (e.g.
interferon-gamma, or c-interferon) and glycoproteins (e.g. interleukin-17, IL-17). In
the setting of Crohn’s disease, there is also an increased production of c-interferon.
11 Immunologic Function of the Mesentery 93
Lymphatic
vessels
Mesenteric
lymph nodes
Intestinal
lumen
Peyer’s
patch
T cell
Dendritic cell
Food protein
Epithelium
B cell
Fig. 11.7 Food tolerance and generation of immune response involving mesenteric lymph nodes
after exposure to benign food proteins. This is a great depiction of initial, nonspecific immune
responses after ingestion of benign food proteins. Dendritic cells can be seen bringing the food
proteins to the Peyer’s patch via lymphatic channels in order for sampling and determination if it
warrants immune response. There are two separate clusters of T cell proliferation illustrated in this
figure to show that although this is a benign particle, the immune system will frequently err on the
side of caution and mount a mild initial response. Despite these small clusters of T cell
proliferation, this is an accurate depiction of systemic tolerance and the lack of any real immune
response. The food-containing DCs then travel to the mesenteric lymph nodes, which mediate
systemic tolerance via further sampling and are then circulated freely via efferent channels of the
lymphatic system
Increased c-interferon has been implicated in mesenteric fibrosis, fat wrapping, and
transmural inflammation. Another potential relationship between the mesenteric
system and the pathogenesis of Crohn’s disease is the mesenteric production of
C-reactive protein (CRP). CRP production by mesenteric adipocytes may be triggered by local inflammation and bacterial translocation to mesenteric fat. Subsequent mesenteric fat hyperplasia may contribute to the inflammatory response in
Crohn’s disease.
94 D. H. Kruchko and E. D. Ehrenpreis
Lastly, CD4+ T cells determine the MHC molecule to present on its surface in
order to promote hyposensitivity to food and allow for appropriate food tolerance.
This effectively prevents overwhelming inflammatory states after ingesting benign
food particles as illustrated in Fig. 11.7. Inappropriate presentations of MHC
molecules by CD4+ T cells, as seen in inflammatory bowel disease such as Crohn’s
disease, leads to food hypersensitivity resulting in inflammatory and potentially
ongoing autoimmune states ranging from mild to severe. In these circumstances,
mesenteric lymph nodes are vulnerable to acute inflammation after exposure to
benign particles. This is due to the intimate interplay between mesenteric lymph
nodes and the GI tract and can be seen grossly and scattered throughout the
mesentery.
Summary
The mesentery plays a vital role in the host’s immune response to invading
pathogens. It is the anatomic site of cells of both the innate and adaptive immune
system. Its sprawling anatomy provides the optimal location throughout the GI tract
to sample foreign objects and mount an immune response if necessary. With the
assistance of mesenteric lymph nodes, the mesentery can prevent overwhelming
infections by recruiting systemic cells to localized regions wi thin the GI tract.
Mesenteric lymph nodes can also prevent such systemic reactions by correctly
identifying benign organisms.
Suggested Reading
1. Wu HJ, Wu E. The role of gut microbiota in immune homeostasis and autoimmunity. Gut
Microbes. 2012;3(1):4 – 14.
2. Coffey JC, O’Leary DP. The mesentery: structure, function, and role in disease. Lancet
Gastroenterol Hepatol. 2016;1(3):238–47.
3. Thomason RT, Bader DM, Winters NI. Comprehensive timeline of mesodermal development
in the quail small intestine. Dev Dyn Off Publ Am Assoc Anat. 2012;241(11):1678–94.
4. Hikspoors JPJM, Kruepunga N, Mommen GMC, Peeters JPWU, Hulsman CJM, Eleonore
Kohler S, Lamers WH. The development of the dorsal mesentery in human embryos and
fetuses. Semin Cell Dev Biol. 2018.
5. Isaza-Restrepo A, Martin-Saavedra JS, Velez-Leal JL, Vargas-Barato F, Riveros-Dueñas R.
The peritoneum: beyond the tissue—a review. Front Physiol. 2018;9:738.
6. Macpherson AJ, Smith K. Mesenteric lymph nodes at the center of immune anatomy. J Exp
Med. 2006;203(3):497–500.
7. Janeway CA Jr, Travers P, Walport M, et al. Immunobiology: the immune system in health
and disease. 5th ed. New York: Garland Science; 2001.
8. Malyshev IY, Manukhina EB, Malyshev YI. Physiological organization of immune response
based on the homeostatic mechanism of matrix reprogramming: implication in tumor and
biotechnology. Med Hypotheses. 2014;82(6):754–65.
11 Immunologic Function of the Mesentery 95
9. Sakuraba A, Sato T, Kamada N, Kitazume M, Sugita A, Hibi T. Th1/Th17 immune response
is induced by mesenteric lymph node dendritic cells in Crohn’ s disease. Gastroenterology.
2009;137(5):1736–45.
10. Peyrin-Biroulet L, et al. Mesenteric fat as a source of C reactive protein and as a target for
bacterial translocation in Crohn’s Disease. Gut. 2012;61(1):78–85.
Neurophysiologic Function of the Mesentery
Amir Patel, Jeffrey Prochot, and Eli D. Ehrenpreis
Anatomy
A basic understanding of the neuroanatomy of the abdomen is required to fully
appreciate the physiologic functions of the mesenteric nervous system. autonomic
nervous system supplies the entire gastrointestinal tract and runs through the two
peritoneal layers of the mesentery. A representation of the sympathetic and
parasympathetic nervous systems is shown in Fig. 12.1.
The Sympathetic Nervous System
Sympathetic trunks track a path from the base of the skull to the coccyx in a parallel
fashion along both sides of the spinal columns. Preganglionic fibers exit the anterior
(ventral) branch of the spinal cord and run through the white rami to reach the
sympathetic trunk. Extending off the sympathetic trunk are the preganglionic thoracic splanchnic nerves, which consist of the greater, lesser, and least splanchnic
nerves. These will continue unti l they reach the network of nerves called the
abdominal prevertebral plexus.
12
A. Patel
Department of Gastroenterology and Hepatology, Medical College of Wisconsin/Froedtert
Hospital, Milwaukee, WI, USA
e-mail: ampatel@mcw.edu
J. Prochot
Department of Internal Medicine, Advocate Lutheran General Hospital, 1775 Dempster St, 6
South, Park Ridge, IL 60068, USA
E. D. Ehrenpreis (&)
Department of Medicine, Advocate Lutheran General Hospital, 1775 Dempster St, 6 South,
Park Ridge, IL 60068, USA
e-mail: e2bioconsultants@gmail.com
© Springer Nature Switzerland AG 2021
E. D. Ehrenpreis et al. (eds.), The Mesenteric Organ in Health and Disease,
https://doi.org/10.1007/978-3-030-71963-0_12
97
98 A. Patel et al.
Key
Parasympathetic motor fibers
Sympathetic
trunk
Vagus n,
Sympathetic motor fibers
Somatic motor fibers
Sensory fibers
T5
T6
T7
T8
T9
T10
T11
T12
L1
L2
L3
L4
L5
S1
S2
S3
S4
Spinal cord
Splanchnic
nn.
Greater
Lesser
Least
Lumbar
spianchnic
nn.
Sacral
spianchnic nn.
Pelvic splanchnic nn.
(parsympathetics)
Celiac ganglion
Superior mesenteric
ganglion and a.
Aorticorenal
ganglion
Inferior
mesenteric
ganglion and a.
Ascending
colon
Superior
hypogastric
plexus
Hypogastric nn.
Inferior hypogastric
plexus
Duodenum
Cecum
Transverse colon
Ileum
PerineumPudendal n.
Stomach
Sigmoid colon
Levator
ani m.
External anala
sphincter m,
Fig. 12.1 The components of the sympathetic and parasympathetic nervous systems
The abdominal prevertebral plexus has three major divisions. The celiac plexus
contains the celiac ganglion, superior mesenteric ganglion and aoritco-renal ganglion. The aortic plexus contains the inferior mesenteric ganglion and root of the
inferior mesenteric artery. The superior hypogastric plexus comprises the third
division.
Preganglionic nerve fibers synapse in their corresponding ganglion and are
distributed through the mesentery to their destination along the intestine and
abdominal compartments. The celiac ganglion distributes sympathetic nerve
impulses to stomach, liver, pancreas, adrenals, and upper half of duodenum. The
superior mesenteric ganglion supplies the lower half of the duodenum as well as
jejunum, ileum, ascending and transverse colon. The inferior mesenteric ganglion
distributes to descending colon and upper portion of rectum.
12 Neurophysiologic Function of the Mesentery 99
The Parasympathetic Nervous System
Parasympathetic innervation to the abdominal organs is supplied by the vagus nerve
and pelvic splanchnic nerves. However, innervation through the mesentery consists
of solely the vagus nerve. The vagus nerve enters the abdomen through the diaphragm and sends preganglionic parasympathetic branches to the prevertebral
plexus. From this point, they are distributed to their respective sites in the midgut
including the myenteric plexus within the smooth muscle of gut wall and Meissner’s plexus to the glands of the mucosae in the intestine.
Neurologic Regulation of Mesenteric Blood Flow
Arterial and Venous Innervation
An important aspect of the neurologic function of the mesentery is regulation of
blood flow within the mesentery itself. The splanchnic circulation receives about
sixty percent of cardiac output and can hold up to one third of the total blood
volume. Thus, the splanchnic circulation is a large reservoir for blood. With the aid
of neurologic regulation, large amounts of blood can be allocated during a stress
response when high cardiac output is required, or for digestion after a meal.
The splanchnic circulation is innervated by both the sympathetic division of the
autonomic nervous system and by spinal sensory nerves. Postganglionic nerve
fibers from the celiac, superior, and inferior mesenteric ganglion synapse on the
vasculature. The sympathetic and sensory innervation of the mesenteric circulation
consists of prevertebral sympathetic ganglion and dorsal root ganglion neurons,
respectively. The axons of the neurons travel to the mesenteric arteries and veins in
the paravascular nerves, which divide in the adventitia of the blood vessels to form
the perivascular nerve plexus. Ultimately these axons distribute into terminal axons,
loose their Schwann cell sheath, and form neuroeffector junctions with vascular
smooth muscle cells.
Sympathetic stimulation of the vasculature is accomplished by the release of
norepinephrine-mediated alpha-adrenergic vasoconstriction. Sympathetic nerves are
primarily vasoconstrictor in their action while the sensory nerves are vasodilatory.
Sympathetic nerve stimulation increases peripheral resistance and mobilizes up two
thirds of the reserve blood volum e in the veins. Local activation of sensory neurons
has vasodilatory effects.
Parasympathetic stimulation of vasculature is less well understood. While
postganglionic nerves from the vagus and pelvic splanchnic nerves synapse on the
walls of the intestine themselves, it is not clear that they produce a direct
parasympathetic stimulation of the vasculature. It is thought that the stimulation of
intestinal wall and secretions in the myenteric and Meissner's plexus indirectly