Chapter 10 – The Body’s Defenses Against Infection
Preventing Infection at Mucosal Surfaces
I.
II.
III.
The communication functions of mucosal surfaces render them vulnerable to infection
a. The mucosae are continually bathed in a layer of thick fluid that they secrete – mucus
i. Mucus contains glycoproteins , proteoglycans, peptides and enzymes that protect epithelial cells
from damage and help limit infection
ii. Because of their physiological function of gas exchange (lungs), food absorption (gut), sensory
activity (eyes, nose, mouth, and throat), and reproduction (uterus, vagina, and breast), the
mucosal surfaces are by necessity dynamic, thin, permeable barriers to the interior of the body
b. The major challenge is to make immune responses that eliminate pathogenic organisms as well as limit the
growth and location of commensal microorganisms.
The gastrointestinal tract is invested with distinctive secondary lymphoid tissues
a. Physiological purpose is to take food and process it into nutrients that are absorbed by the body and waste
that is excreted – hence the alternative name, the alimentary canal
b. To provide prompt defense against infection, secondary lymphoid tissues and immune-system cells are
spread throughout the gut and other mucosal tissues
i. Present within surface epithelium and also in the underlying connective tissue called the lamina
propria
ii. Mesenteric lymph nodes – largest nodes in the body, specifically defend the gut
1. Situated in a chain within the mesentery that holds the gut in place
iii. Presence of secondary lymphoid tissue within the mucosa means that adaptive immune response
can be initiated locally, as well as in the draining mesenteric lymph nodes – unlike in the rest of
the body
c. At the back of the mouth and guarding the entrance to the gut and their airways are the palantine tonsils,
adenoids and lingual tonsils – form Waldeyer’s ring
d. The small intestine is the major site of food absorption and is the part of the gut most heavily invested with
lymphoid tissue
i. Peyer’s patches – integrated into the intestinal wall and have a distinct appearance, forming
dome-like aggregates of lymphocytes that bulfe into the intestinal lumen
ii. Overlying the lymphocytes and separating them from the gut lumen is a layer of follicle-associated
epithelium that contains conventional absorptive intestinal epithelial cells known as enterocytes
and a smaller number of specialized epithelial cells called Microfold cells (M cells)
1. M cells do not secrete digestive enzymes or mucus, lack a thick surface glycocalyx and
have a weak system of lysosomes – enabling M cells to take up intact microorganisms
and particulate antigens from the gut lumen and transfer them directly to Peyer’s patch
to initiate an adaptive immune response
iii. In addition to Peyer’s patches, the small intestine contains isolated lymphoid follicles – comprise
a single follicle, consisting mostly of B cells, that is overlaid by epithelium containing M cells – also
present in the large intestine
e. The immune responses that are generated against antigens in gut-associated lymphoid tissues are
qualitatively distinct from those in the spleen or lymph nodes draining the skin or muscle
i. GALT have their own content of lymphoid cells, hormones and other immunomodulatory factors
ii. During fetal development, mesenteric lymph nodes and Peyer’s patches differentiate
independently of the spleen and other lymph nodes and under the guidance of different
chemokines and receptors for cytokines of the tumor necrosis factor family
M cells and dendritic cells facilitate transport of microbes from the gut lumen to gut-associated lymphoid tissues
a. M cells of the Peyer’s patches and isolated lymphoid follicles are specialized
for the uptake of pathoges from the intestinal lumen and their transcytosis
into the lymphoid tissue
b.
IV.
V.
Transcytosis releases microorganisms at the M cells basal membrane. Here, dendritic cells take up microbes
to process and present their antigens to naïve T cells
i. Antigen-loaded dendritic cells either migrate from the dome region to the T cell area of the
Peyer’s patch, or via the draining lymphatics to a mesenteric lymph node, where they meet and
stimulate antigen-specific naïve T cells
c. Dendritic cells resident in the lamina propria outside the organized lymphoid tissues can also capture
pathogens independently of M cells
i. In response to infection these dendritic cells become more mobile – move into epithelial wall or
send processes through it that can capture microbes and antigens without disturbing the integrity
of the epithelial barrier
ii. The dendritic cells then move into the T cell area of the GALT or travel into draining lymph to the T
cell area of a mesenteric lymph node, to stimulate antigen specific T cells
Effector lymphocytes populate healthy mucosal tissue in the absence of infection
a. Integrated into the epithelial layer of the small intestine is a distinctive type of CD8 T cell called the
intraepithelial lymphocyte – which have been actiated by antigen and contain intracellular granules like
those of CD8 cytotoxic T cells
i. Intraepithelial lymphocytes can either be α:β CD8 T cells or ϒ:δ CD8 T cells
ii. Express T cell receptors with a limited range of antigen specificities and they have a distinctive
combination of chemokine receptors and adhesion molecules that enables them to take up their
unique position within the intestinal epithelium
b. The lamina propria contains a variety of effector lymphocytes – CD4 T cells, CD8 T cells and plasma cells - as
well as dendritic cells and the occasional eosinophils or mast cell
c. In contrast to skin and other tissues, the healthy intestinal mucosa sustains a chronic adaptive immune
response
i. Achieved by constant sampling of gut’s contents by M cells and dendritic cells, as well as the
continual stimulation of B and T cells in a myriad of local immune responses in the GALT
1. Most of the foreign antigens are innocuous – do not create a state of inflammation of
symptoms of disease
ii. Because of their chronic state of stimulation, lymphocytes in the mucosal surface are able to
respond quickly to any breach of the mucosal barrier and prevent inundation of the mucosal
tissue with the gut contents
B cells and T cells commit to mucosal lymphoid tissues after they encounter their specific antigen
a. Naïve B and T cells that emerge from primary lymphoid organs are not restricted in their recirculation – can
recirculate via the lymph and blood through both the mucosal and systemic compartments of the immune
system
i. Naïve B and T cells enter the Peyer’s patches and mesenteric lymph nodes from the blood via high
endothelial venules, attracted by chemokines CCL21 and CCL19, which are released by the
lymphoid organ and bind CCR7 on naïve lymphocytes
1. If the lymphocyte does not recognize specific antigen – continues recirculation
2. If the lymphocyte does recognize specific antigen – retained in Peyer’s
patches/mesenteric lymph node and is activated to proliferate and differentiate into
effector and memory lymphocytes
a. Activation is accompanied by loss of CCR7 and cell-adhesion molecule Lselectin, and thus the ability to enter secondary lymphoid tissues from blood
b. B and T cells activated in a Peyer’s patch leave in the lymph and travel via
mesenteric lymph nodes to the thoracic duct to the blood ; those activated in
mesenteric lymph node leave in efferent lymph and them reach the blood
c. Once in the bloodstream, mucosally activated lymphocytes home to the type
of mucosa in which they were activated and enter it from the blood
i.
VI.
VII.
Gut homing effector lymphocytes express integrin α4:β7, which
binds specifically to the mucosal vascular addressin MAdCAM-1
present on endothelial cells of blood vessels in the gut wall
ii. Guiding lymphocytes into gut tissue is chemokine CCL25, which is
secreted by epithelium of the small intestine and binds CCR9 on
effector lymphocytes
iii. By this route, activated lymphocytes enter lamina propria – B cells
develop into plasma cells making secretory IgA and T cells activate
intestinal macrophages
ii. Only lymphocytes that first encounter antigen in GALT are induced to express gut-specific homing
receptors and integrins
1. Induction is under control of intestinal dendritic cells and is mediated by retinoic acid, a
derivative of vitamin A made by these cells
2. Analogous tissue specificity are acquired by effector T cells activated in non-mucosal
tissues
Effector lymphocytes activated in any one mucosal tissue recirculate through all mucosal tissues
a. MAdCAM-1 is not restricted to intestinal blood vessels but is also present on the vasculature serving other
mucosal tissues
i. As a result, B and T cells first activated in GALT can recirculate as effector cells to the respiratory
tract and vice versa. Thus, secondary lymphoid tissues of mucosal surfaces form a unified and
exclusive network of recirculation of effector cells
b. Naïve B cells activated in Peyer’s patches and mesenteric lymph nodes preferentially undergo isotype
switching to IgA, the dominant antibody in mucosal secretions
i. Process is directed by cytokine transforming growth factor (TGF-β) abd occurs in the organized
lymphoid tissues of the gut
ii. After B cell activation and differentiation, cells express α4:β7 and CCR9. Effector B cells leave
secondary lymphoid tissue in efferent lymph and travel to the blood – some will then return to
lamina propria close to where they were activated and others will go to lamina propria in the
same, as well as different, tissue
iii. In lamina propria, B cells differentiate into plasma cells and synthesize intact J-chain-linked IgA
dimers which are secreted into the sub-epithelial space, from where they are transcytosed by
poly-Ig and delivered to mucosal surface
c. In nursing mothers, activated B cells will home from the mucosal tissues to the lactating mammary gland
and contribute their dimeric IgA to the breast milk – will represent all antibody response the mother has
recently made to microorganisms, food and infections ; passed to infant – provide comprehensive
protective mucosal immunity directed toward normal gut flora and endemic pathogens
Dimeric IgA binds pathogens at various sites in mucosal tissues
a.
Dimeric IgA is secreted in mucosal tissues by plasma cells that derive from B cells activated in the mucosal
immune system
i. Dimeric IgA can bind antigens and pathogens at several different locations
1.
VIII.
IX.
X.
XI.
In the lamina propria IgA can bind pathogens and antigens and carry them to intestinal
lumen on transcytosis.
2. During transcytosis, free IgA can bind pathogens and antigens that have been
internalized into endosomes
3. IgA that has been secreted and is present at mucosal surface can bind pathogens and
toxins in the gut lumen
4. Secreted IgA can bind pathogens on an M cell surface and by passing through the M cell
can take them into the secondary lymphoid tissue
5. As free IgA passes through an M cell, it can bind pathogens in the endosomes and take
them into secondary lymphoid tissue
Two subclasses of IgA have complementary properties for controlling microbial populations
a. The two IgA subclasses differ mainly in the hinge region, which is twice as long in IgA1 than in IgA2
i. The drawback to the longer hinge region is the increased susceptibility to proteolytic cleavage
1. Major bacterial pathogens have evolved specific proteases that cleave the IgA1 hinge
and separate the Fc and Fab regions, preventing antibody from targeting the bacteria –
bacteria coated with Fab fragments of IgA1 can become more able to adhere to mucosal
epithelium, penetrate physical barrier, and gain access to lamina propria
ii. In the case where IgA1 is cleaved by proteases, IgA2 synthesis helps control the infection –
bacteria have yet to evolve a protease that can cleave IgA2
b. Normally the switch to IgA secretion goes from IgM to IgA1, but in the presence of TNF-family cytokine
APRIL, isotype switches from IgM to IgA2
Humans with selective deficiency of IgA do not succumb to infection
a. Selective IgA deficiency – little to no IgA, but makes all other immunoglobulin isotypes
b. Most people are healthy, and are often oblivious to their lack of antibody – lack of IgA is compensated for
by increased production of other isotypes
i. Most importantly IgM because it can be secreted by mucosal tissues by the same mechanism as
dimeric IgA because it contains the J chain necessary for binding to the poly-Ig receptor
c. Chronic lung disease is more common in people with IgA deficiency in industrialized countries
Intestinal epithelial cells contribute to innate defense of the gut
a. To detect the presence of bacteria in their cytoplasm, epithelial cells have intracellular sensors called
nucleotide-binding oligomerization domain proteins NOD proteins – structurally related to the toll-like
receptors
i. NOD1 recognizes a muramyl tripeptide that contains diaminopimelic acid, which is present only in
the cell walls of G- bacteria
ii. NOD2 recognizes a muramyl dipeptide present in the peptidoglycans of most bacterial cell walls
b. Binding to its ligand causes NOD protein form oligomers that activate the protein kinase RICK which turns
on NFκB signaling pathway in the epithelial cell. This causes the cell to make and release cytokines,
chemokines and antibacterial defensins
Intestinal helminth infections provoke strong TH2 mediated immune responses
a. Parasites cause disease by competing with the host for nutrients or by causing local damage to epithelial
cells or blood vessels
b. Characteristic of immunity to almost all helminth infections is that a response dominated by TH2 CD4 T cells
is protective, whereas a TH1 biased response fails to eliminate the pathogen and produces inflammatory
response that damages mucosal surfaces of human host
i. Bias toward TH2 is cause by worm products that influence the dendritic cells presenting worm
antigens
ii. Major antibody – IgE –binding releases major basic protein and other cytotoxic molecules that
damage and kill the worms
iii. Mast cells activated by worm antigens bound to IgE release mediators such as histamine that
cause the smooth muscle to contract, helping to expel the worm
Immunological memory and the secondary immune response
XII.
The antibodies formed during a primary immune response prevent reinfection for several months after disease
a. After successful termination of infection by the primary immune response, elevated levels of high-affinity
pathogen-specific antibody will be present in the blood and lymph or at mucosal surfaces