Gut immunity – What are the keys to protection?

Gut immunity – What are the keys to protection?

Gut immunity – What are the keys to
­protection?
Christopher Chase, DVM, PhD, Diplomate ACVM
South Dakota State University, Brookings, ­South Dakota
Introduction
The mucosal immune system provides the first immune
defense barrier for over 90% of potential pathogens in
the gastrointestinal tract. It must not only protect against
harmful pathogens but also tolerize the immune system
to dietary antigens and normal microbial flora (Figure 1).
The mucosal immune system is very rudimentary in the
newborn pig and gradually develops in four stages over
the first 6 weeks of life1 (Table ­1).
Secretory IgA plays an important role in immunity at
mucosal surfaces by making infectious agents stick together, preventing attachment of infectious agents to
epithelial cells, and neutralizing toxins. Other components of the immune response may also be important in
protection against various types of infection at mucosal
surfaces. For example, neutrophils in the pig can migrate
into the intestinal lumen in large numbers in response to
antigen-antibody ­complexes.
Gut associated lymphoid t­ issue
Mucosal immunity, particularly the gut associated lymphoid tissue (GALT), is greatly influenced by environmental factors on the surface of the mucosal (Figure 1).3
The GALT of the pig is poorly developed and undergoes
a rapid period of development and expansion that is not
completed when pigs are weaned commercially at 14-24
days. The two most important critical control points for
environmental influences are immediately after birth and
at weaning. Colostrum is important for gut development
and growth and non-antigen specific immune development. Colostrum is also important for providing pathogen
specific immunoglobulin (Ig). Colostrum contains high
levels of transforming growth factor β (TGF-β that has
anti-inflammatory effects and accelerates the switch to
IgA antibody along with preventing expression of active
immune responses and promoting the development of tolerance against nutrient antigens (Bailey et al 2005a). The
presence of commensal microbial flora is absolutely essential for the development of GALT in the neonatal ­pig.
The second major environmental control point for
GALT is weaning. At weaning, the pig can make active
immune responses. The weaning period is characterized
by diet change, low feed intake, poor growth and development, diarrhea and increased risk for disease from
enteric pathogens. Unfortunately the maternal milk factors that modulate the immune response (TGF-β and
provide specific immunity in the newborn (Ig) are no
longer available and the balance between tolerance and
active immunity at weaning is disturbed. The magnitude
and severity of this “weaning” GALT crisis is dependent
Table 1: The development of the mucosal immune response in the neonatal pig.†
Stage
Pig age
Immune status
1
The newborn pig
Rudimentary Peyers patches
Small numbers of mucosal APCs and T-cells
2
1 Day - 2 weeks
Non-specific expansion of Peyer’s patches and B-cells
Appearance of some conventional, activated, helper T-cells
Influx of MHCII+ cells in lamina propria
3
2 weeks-4 weeks
Appearance of mature helper T-cells in lamina propria;
IgM+ B cells in intestinal crypt areas
4
4 weeks-6 weeks
Expansion of B-cell repertoire to IgA+ B cells in intestinal crypt area
Appearance of memory cytotoxic T-cells in the epithelium
(intraepithelial T cells) and in lamina propria
† Adapted from Veterinary Immunology and Immunopathology, Bailey M, Haverson K, Inman C, Harris C, Jones P, Corfield G,
Miller B, Stokes C, The influence of environment on development of the mucosal immune system, 108:189-198, 2005, with
permission from Elsevier.
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2015 AASV Annual Meeting: Beyond Our Oath: Integrity, Intensity, Professionalism
on how much the immune system was expanded during
the preweaning period. Unfortunately the point where
the production system determines the weaning age and
the point where the immune system is ready for “weaning” are not the same and managing the immune system
for optimal disease prevention at early weaning ages will
continue to be ­problematic.
Stress, immunosuppression, and
­immunity
There is ample evidence that both physical and psychological distress can suppress immune function in animals,
leading to an increased incidence of infectious disease.
Excess heat or cold, crowding, mixing, weaning, limitfeeding, shipping, noise, and restraint are stressors that
are often associated with intensive animal production
and have been shown to influence immune function in
various species. Also social status, genetics, age and the
duration of stress (chronic vs. acute) have been shown to
be important in the pig’s response to ­stress.
Weaning is stressful event for the young pig. Research
indicating that weaning before 3 weeks results in long
term negative effects on immune system and mucosal development. Weaning at 2, 3, or 4 wk of age (but not at 5
wk of age) has been shown to decrease response of piglets
to initiate an immune response. Early weaning results
in increases in mast cells resulting in intestinal mucosa
dysfunction. However, successful vaccination strategies at
the time of weaning are frequently reported in the ­field.
Nutritional influences on i­ mmunity
The immune system does not get a free ride when it
comes to nutrition. The immune requires energy, protein,
vitamins and trace minerals. Both malnutrition and overfeeding may result in impairment of immune function
and increased susceptibility to disease due to a deficiency
or excess of proteins or calories, or a relative imbalance in
vitamin or trace mineral content. Animals under intensive production conditions typically have a completely
controlled diet. Therefore, it is very important that the
diet, especially the vitamin and trace mineral content, be
optimally formulated. Key vitamins and minerals for optimal immune function include vitamins A, C, E, and the
B complex vitamins, copper (Cu), zinc (Zn), magnesium
(Mg), manganese (Mn), iron (Fe), and selenium (Se). The
balance of these constituents is especially important since
excess or deficiency in one component may influence the
availability or requirement for ­another.
The route of ­vaccination
The route of vaccine administration can be important
when attempting to induce mucosal immunity. To induce
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secretory IgA production at mucosal surfaces, it is best
for the vaccine to enter the body via a mucosal surface.
This can be accomplished by feeding the vaccine to the
animal, aerosolizing the vaccine so the animal will inhale
it, or by intramammary exposure. If a sow is exposed to
an infectious agent in her intestinal tract, she may respond by producing secretory IgA not only in her own
intestinal tract, but also in her mammary gland. The sow
passes the IgA against the infectious agent to the piglet
when it suckles, thus protecting the piglet from infectious
agents present in the sow’s intestine. This protection will
only last as long as the piglet continues to suckle. Enteric
infections by many organisms are not controlled by the
presence of IgG and IgM in the bloodstream or by a
systemic cell-mediated immune response. If a modified
live vaccine is given by injection, but goes to a mucosal
surface to replicate, it may also induce a secretory IgA
response. In addition, killed vaccines for some respiratory pathogens, such as M. hyopneumoniae and SIV are
capable of stimulating an IgA response to c­ hallenge.
The common mucosal ­system
The acquired immune response is the target of vaccination.2 Its myriad of B cells, T cells, cytokines, and
antibodies provides the pathogen-specific memory with
continued duration of protective immunity (Figure 1).
The acquired response is the target for vaccines to generate memory and protection. In the mucosal lymphoid
tissues (Figure 2), mature T cells and B cells that have
been stimulated by antigen and produce IgA will leave
the submucosal lymphoid tissue and reenter the bloodstream. These lymphocytes will exit the bloodstream into
the submucosa of other mucosal associated lymphoid
tissue (MALT), many that are associated with the respiratory tract (Figure 2). Many of these cells will return to
the same mucosal surface from which they originated
but others will be found at different mucosal surfaces
throughout the body. This homing of lymphocytes to
other MALT sites throughout the body is referred to as
the “common immune system” (Figure 2). The predominant Ig secreted by the mucosal immune system is IgA.
IgA is secreted by plasma cells in the submucosa and is
transported to the mucosal surface of the epithelial cell.
The epithelial cell add a secretory component to IgA
that is important for protecting the IgA molecule from
proteolytic enzymes and also serves to anchor the IgA
into the mucous layer forming a protective coating on the
mucosal surface (Figure 1). IgA plays an important role
in immunity by making infectious agents clump together,
preventing attachment of infectious agents to epithelial
cells, and neutralizing toxins. Intraepithelial T lymphocytes are important mediators of immunity at mucosal
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Figure 1: Mucosa immune system of the gut epithelium. The lamina propria (LP) contains scattered T-cells
and epithelium contains intraepithelial lymphocytes (IELs). B-cells are scattered in the LP but more often in
the crypt regions along with plasma cells that produce IgA that is transported and secreted into the lumen.
M cells facilitate antigen uptake and delivery to the organized lymphoid tissues. T-cells activated in the
Peyer’s patch and medistinal LN express the integrin α4β7 interacts with cell-adhesion molecule MADCAM1, on the high endothelial vessels (HEVs). This homes these T-cells to the mucosal LP. The chemokine
ligand CCL25 produced by epithelial cells recruits lymphocytes with CCR9 receptor to the LP.
Adapted by permission from Macmillan Publishers Ltd: Nature Reviews Immunology, Cheroutre H, Madakamutil L. Acquired
and natural memory T cells join forces at the mucosal front line ­4:290-300,2004.
surfaces (Figure 1). This is especially true for respiratory
infections. Pigs have high numbers of intraepithelial
lymphocytes that are predominantly T cells (many are
cytotoxic T cells that kill virus-infected cells).
Summary
Management of the pig’s mucosal immune system is not a
simple process. Stressors and nutrition often compromise
immunity. It is important that vaccinations be given at
optimal times and that vaccination is not overused. Vaccination can never overcome poor ­management.
References
1. Bailey M, Haverson K, Inman C, Harris C, Jones P, Corfield G, Miller
B, Stokes C. 2005. The influence of environment on development of the
mucosal immune system. Veterinary Immunology and Immunopathology,
­108:189–198.
2. Chase CCL, JK Lunney. 2012. Chapter 16 Immune System. In Diseases
of Swine, 10th edition. Eds Karriker L, KJ Schwartz, A Ramirez, GW Stevenson, JJ Zimmerman. Wiley-Blackwell, Ames IA, p­ p.227–250.
3. Cheroutre H, Madakamutil L. 2004. Acquired and natural memory T
cells join forces at the mucosal front line. Nature Reviews Immunology
­4:290–300.
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2015 AASV Annual Meeting: Beyond Our Oath: Integrity, Intensity, Professionalism
Figure 2: Lymphocyte circulation and common mucosal immune system of the pig. As illustrated on the
left side of the figure, the pig has unique lymphocyte circulation with lymphocytes entering the lymph
nodes by afferent lymphatics but exiting via blood vessels rather than efferent lymphatics. The common
mucosal system involves the circulation of B- and T-cells between lymphoid tissues on mucosal s­ urfaces.
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