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Chapter 14
Specialized Immunity at Epithelial Barriers
and in Immune Privileged Tissues

Regional immune systems include:

mucosal
immune
system,
which
protects
the
gastrointestinal,
bronchopulmonary, and genitourinary mucosal barriers, and

cutaneous (skin) immune system
IMMUNITY IN THE GASTROINTESTINAL SYSTEM

Perspective of the immunologist, the gastrointestinal tract has two
remarkable properties:

First, the combined mucosa of the small and large bowel has a total
surface area of more than 200 m2 (the size of a tennis court), made up
mostly of small intestinal villi and microvilli

Second, the lumen of the gut is teeming with microbes, many of which are
ingested along with food and most of which are continuously growing on
the mucosal surface in healthy individuals as commensals
Innate Immunity in the Gastrointestinal Tract

Intestinal epithelial cells lining the small and large bowel are an integral
part of the gastrointestinal innate immune system, involved in responses to
pathogens, tolerance to commensal organisms, and antigen sampling for
delivery to the adaptive immune system in the gut

Several different types of intestinal epithelial cells: mucus-secreting
goblet cells, which reside at the top of the intestinal villi; cytokinesecreting absorptive epithelial cells; antigen sampling M cells, found in
specialized dome structures overlying lymphoid tissues; and
antibacterial peptide secreting Paneth cells, found at the bottom of the
crypts

Several different extensively glycosylated proteins, called mucins, form a
viscous physical barrier that prevents microbes from contacting the cells
of the gastrointestinal tract

The secreted mucins, including MUC2, MUC5, and MUC6

Several different environmental and immune stimuli can induce dramatic
increases in mucin production. These stimuli include cytokines (IL-1, IL-4,
IL-6, IL-9, IL-13, tumor necrosis factor [TNF], and type I interferons),
neutrophil products (such as elastase), and microbial adhesive proteins

Defensins produced by intestinal epithelial cells

Toll-like receptors (TLRs) and cytoplasmic Nod-like receptors (NLRs)
expressed by intestinal epithelial cells promote immune responses to
invasive pathogens but are also regulated to limit inflammatory responses
to commensal bacteria

In healthy individuals, lamina propria DCs and macrophages in the gut
inhibit inflammation and serve to maintain homeostasis
Mechanism of regulation of innate immune responses in the
intestinal mucosa
Adaptive Immunity in the Gastrointestinal Tract

The major form of adaptive immunity in the gut is humoral immunity
directed at microbes in the lumen, which prevents commensals and
pathogens from colonizing and invading through the mucosal epithelial
barrier

This function is mediated by dimeric IgA antibodies that are secreted into
the lumen of the gut or, in the case of breast-feeding infants, IgA that is
secreted into colostrum and mother’s milk and ingested by the infant.

Significant quantities of IgG and IgM antibodies are also present in the
gut lumen and contribute to humoral immunity in this location

Dominant protective cell-mediated immune response consists of TH17
effector cells

Suppress potential immune responses to food antigens and commensal
microbial antigens to prevent inflammatory reactions that would
compromise the mucosal barrier

A major mechanism for controlling responses in the gut is the activation of
regulatory T cells (Treg), and some subsets of Treg are more abundant in
mucosa-associated lymphoid tissues (MALT) than in other lymphoid
organs
The gastrointestinal immune system
M cells in the small intestine
DCs in the intestinal mucosa
Homing properties of intestinal lymphocytes
Humoral Immunity in the Gastrointestinal Tract

Humoral immunity in the gut is dominated by production of secretory IgA
in the GALT and transport of the antibody across the mucosal epithelium
into the lumen

Smaller but significant quantities of IgG and IgM are also secreted into
the gut lumen

Antibodies bind to microbes and toxins and neutralize them by
preventing their binding to receptors on host cells. This form of
humoral immunity is sometimes called secretory immunity

IgA is produced in larger amounts than any other antibody isotype

The dominance of IgA production by intestinal plasma cells is due in part
to selective induction of IgA isotype switching in B cells in GALT and
mesenteric lymph nodes
IgA class switching in the Gut
Transport of IgA across epithelial cells
T Cell–Mediated Immunity in the Gastrointestinal Tract

T cells are found within the gut epithelial layer, scattered throughout the lamina
propria and submucosa, and within Peyer’s patches and other organized collections of
follicles

In humans, most of the intraepithelial T cells are CD8+ cells. In mice, about 50% of
intraepithelial lymphocytes express the γδ form of the TCR

TH17 cells appear to play a special role in maintaining mucosal epithelial barrier
function because of the actions of the two signature cytokines they produce, IL-17
and IL-22

TH2 cells. Intestinal helminthic infections induce strong TH2 responses, which are
effective in eliminating the worms
Regulation of Immunity in the Gastrointestinal Tract
by Regulatory T Cells and Cytokines

Regulatory T cells are abundant in GALT and prevent inflammatory
reactions against intestinal commensal microbes

Several cytokines, including TGF-β, IL-10, and IL-2, appear to play
crucial roles in maintaining homeostasis in the gut immune system, and
deficiencies in these cytokines or their receptors result in pathologic bowel
inflammation.
Oral Tolerance and Oral Vaccines

Oral tolerance is systemic adaptive immune tolerance to antigens that are
ingested or otherwise administered orally and is a potential way of
treating diseases in which unwanted immune responses occur, such as
autoimmunity

Oral administration of antigen in the setting of concomitant stimulation of
innate immunity can lead to productive adaptive immune responses, as in
the use of oral viral vaccines to induce protective antibody responses to
viruses
The Role of the Commensal Microbiome in Immune Regulation

The human intestinal microbiome includes all of the commensal bacteria
that normally reside in the intestines as well as thousands of species of
viruses, fungi, and protozoans

Commensal organisms in the intestines are required for and regulate
innate immune responses in the gut, and also influence systemic innate
immunity

Intestinal commensal organisms influence local and systemic adaptive
immune responses
Diseases Related to Immune Responses in the Gut

Inflammatory bowel disease (IBD) is a heterogeneous group of disorders
characterized by chronic remitting inflammation in the small or large
bowel, likely due to poorly regulated responses to commensal bacteria

Crohn’s disease, which can affect the entire thickness of the bowel wall
tissue in any part of the gastrointestinal tract but most frequently involves
the terminal ileum, and ulcerative colitis, which is restricted to the colonic
mucosa

Defects in innate immunity to gut commensals

Abnormal TH17 and TH1 responses

Defective function of regulatory T cells that cause the disease called
immune dysregulation, polyendocrinopathy, enteropathy, X-linked
(IPEX),

Polymorphisms of genes that are associated with macroautophagy and the
unfolded protein response to endoplasmic reticulum stress are risk factors
for IBD

Celiac disease (gluten-sensitive enteropathy or nontropical sprue) is an
inflammatory disease of the small bowel mucosa caused by immune
responses against ingested gluten proteins present in wheat

Patients produce IgA and IgG antibodies specific for gluten as well as IgA
and IgG autoantibodies specific for transglutaminase 2A

CD4+ T cell responses to gliadin are involved in disease pathogenesis

Food allergies are caused by TH2 responses to many different food
proteins and cause acute inflammatory responses locally in the gut and
systemically on ingestion of these proteins

Prolonged immune responses to gastrointestinal microbes can lead to
tumors arising in the gastrointestinal tract (H. pylori)
Mucosal Immunity in the Respiratory System

Innate responses in the alveolus serve antimicrobial functions but are
tightly controlled to prevent inflammation, which would impair gas
exchange

Surfactant proteins A (SP-A) and D (SP-D), which are secreted into the
alveolar spaces, are members of the collectin family

These surfactants are involved in viral neutralization and clearance of
microbes from the airspaces, but they also suppress inflammatory and
allergic responses in the lung

SP-A inhibits TLR2 and TLR4 signaling and inflammatory cytokine
expression in alveolar macrophages, and SP-A also binds to TLR4 and
inhibits lipopolysaccharide binding. SP-A and SP-D reduce the phagocytic
activity of alveolar macrophages

Alveolar macrophages represent the majority of free cells within the
alveolar spaces. These cells are functionally distinct from macrophages in
most other tissues in that they maintain an anti-inflammatory phenotype.
They express IL-10, nitric oxide, and TGF-β and are poorly phagocytic
compared with resident macrophages in other tissues, such as spleen and
liver. Alveolar macrophages inhibit T cell responses as well as the antigen
presentation function of CD103+ airway DCs.

Protective humoral immunity in the airways is dominated by secretory
IgA, as in other mucosal tissues, although the amount of IgA secreted is
much less than in the gastrointestinal tract

Secretory IgG plays an important role in the upper airway

T cell responses in the lung are initiated by DC sampling of airway
antigens and presentation of these antigens to naive T cells in
peribronchial and mediastinal lymph nodes
Mucosal Immunity in the Genitourinary System

Stratified squamous epithelium lines the vaginal mucosa and terminal
male urethra,

The vaginal epithelium contains Langerhans cells, and a variety of DCs
and macrophages

IgA is the dominant antibody isotype, most of the antibodies in genital
secretions are IgGs
THE CUTANEOUS IMMUNE SYSTEM
Homing properties of skin lymphocytes
Diseases Related to Immune Responses in the Skin

Psoriasis, a chronic inflammatory disorder of the skin characterized by
red scaly plaques, is caused by dysregulated innate and T cell–mediated
immune responses triggered by various environmental stimuli

Atopic dermatitis is a chronic inflammatory disease of the skin
characterized by itchy rashes, in which IgE specific for environmental
antigens and cells expressing high-affinity Fc receptors for IgE (FcεRI)
play a central role.
IMMUNE PRIVILEGED TISSUES

The Nobel laureate immunologist Sir Peter Medawar coined the term
immune privilege in the 1940s to describe the lack of immune responses to
tissue transplanted into the brain or the anterior chamber of the eye of
experimental animals

The Eye. There are several soluble factors with immunosuppressive/antiinflammatory properties in the aqueous humor that fills the anterior chamber,
including neuropeptides (α-melanocyte–stimulating hormone, vasointestinal
peptide, somatostatin), TGF-β, and indolamine 2,3-dioxygenase (IDO). Cells lining
the anterior chamber, including the epithelium of the iris and the endothelium,
constitutively express Fas ligand and PD-L1, which can induce death or
inactivation of T cells, respectively

Anterior chamber–associated immune deviation, may be mediated by Treg, is a
phenomenon in which introduction of foreign protein antigen into the anterior of
the eye actively induces systemic tolerance to that antigen

The Brain. Inflammation in the brain can lead to functional derangement and
death of neurons, with disastrous consequences. Anatomic features of the brain
that impair initiation of adaptive immunity to antigens include an absence of
conventional lymphatic drainage and a scarcity of DCs

The Testis. Immune privilege in the testis serves to limit inflammation that may
impair male fertility. Many self antigens in the adult testis are first expressed at
the time of puberty, well after the development of a competent immune system,
which may include testis antigen–specific precursor T and B cells
Immune Privilege of the Mammalian Fetus

Several experimental observations indicate that the anatomic location of the fetus is a
critical factor in the absence of rejection

The uterine decidua may be a site where immune responses are functionally inhibited

Immune responses to the fetus may be regulated by local concentrations of indolamine
2,3-dioxygenase (IDO) catabolizes tryptophan and T cell responses to the fetus are
normally blocked because decidual tryptophan levels are kept low or the levels of toxic
metabolites are high

Trophoblast and decidua may also be resistant to complement-mediated damage
activation