THE IMMUNE SYSTEM The cells of the immune system and their responses to infection are obviously complex, but can be partitioned into two separate but interacting components those that pr
Trang 1Immune System: Nutrition Effects
The National Research Council (NRC) nutrient
require-ments for animals can be defined as nutrient levels
adequate to permit the maintenance of normal health and
productivity Failure to provide a diet that fulfills the
minimal requirements established by the NRC for any
nutrient will ultimately immunocompromise the animal
and render it more susceptible to infectious disease
Because nutrient requirements to support optimal
produc-tivity are well defined, marked deficiencies in protein,
amino acids, or trace nutrients are not likely to occur in
animals reared in commercial situations However, the
nutrient requirements for optimal productivity may not
equal those for optimal immunity because the NRC
requirements have been determined from experiments
conducted in laboratory situations where infectious
disease is minimal Thus, an important issue that has
been the focus of nutritional immunology research is
whether specific nutrients fed at or above
NRC-recom-mended levels could be used to modulate the animal’s
immune system in a beneficial manner
THE IMMUNE SYSTEM
The cells of the immune system and their responses to
infection are obviously complex, but can be partitioned
into two separate but interacting components those that
provide innate immunity and those that provide acquired
(or adaptive) immunity (Fig 1) Both components are
influenced by nutrition (Table 1)
The component of the immune system that protects the
host animal but does not distinguish one pathogen from
another provides innate immunity For example,
macro-phages recognize pathogens using relatively
indiscrimi-nant receptors They ingest and degrade microorganisms,
and provide important signals (e.g., cytokines) that
orchestrate other aspects of the immune response The
innate immune system is inherent and the capacity of it to
respond does not change or improve from the first
encounter with a particular pathogen to the second
encounter Neutrophils and natural killer (NK) cells arealso important for innate immunity
Acquired immunity is a highly specific response to aspecific pathogen that is acquired over time due to previousexposure to that same pathogen or through vaccination.Fully differentiated B lymphocytes (i.e., plasma cells) se-crete pathogen-specific antibodies, whereas T lymphocytesuse discrete receptors to recognize and kill infected cells oractivate other cells of the immune system The initialexposure to a pathogen produces lymphocytes with immu-nological memory so that if the pathogen is encountered asecond time, a rapid response is initiated and the pathogen
is eliminated before visible signs of infection appear
Arginine is considered a semiessential amino acid forhumans and other mammals because it is synthesized fromother amino acids via the urea cycle However, exogenousarginine is required for growth in young animals and invarious stress situations (e.g., sepsis, trauma) to optimizegrowth and minimize nitrogen excretion Arginine is adirect precursor of nitric oxide (NO), a potent cytotoxicagent produced by macrophages and neutrophils tokill bacteria
Although glutamine is not an indispensable amino acidfor growth of animals, it may be conditionally essential
DOI: 10.1081/E EAS 120019687
Copyright D 2005 by Marcel Dekker, Inc All rights reserved.
Trang 2in times of immune system activation Glutamine is
essential for the normal functioning of macrophages and
lymphocytes during an immune response The requirement
for glutamine in these cells is due to the increased
metabolic activity following stimulation by an infectious
pathogen Accelerated metabolism is necessary to
facil-itate cell division and the secretion of antibodies and
cytokines all processes that require amino acids and
energy Glutamine is a primary carrier of nitrogen in the
blood, and its concentration is generally maintained
within a relatively small range However, during catabolic
states like sepsis, there is an increased demand for
glutamine as a substrate for cells of the immune system
Lipids
High-fat diets reduce lymphocyte proliferation compared
to low-fat diets, but the precise effects depend on the
amount and type of fat There are two major classes of
polyunsaturated fatty acids (PUFAs) the n-6 and the n-3
families Linoleic acid is the precursor of the n-6 family,
and is found in plant oils, including corn and soybean oil
In animals, linoleic acid is converted to arachidonic acid,
which can account for 25% of the total fatty acids in the
plasma membranes of immune cells The amount of
arachidonic acid in the plasma membrane of immune cells
is important because it is the precursor of several
prostaglandins and leukotrienes that have potent
inflam-matory effects The precursor of the n-3 PUFAs
is a-linolenic acid, which in animal tissues is converted
to eicosapentaenoic and docosahexaenoic acids As
op-posed to n-6 PUFAs, which are inflammatory, n-3 PUFAsare anti-inflammatory
Diets rich in n-3 PUFAs decrease inflammation in
at least two ways First, diets rich in n-3 PUFAs increasemembrane levels of eicosapentaenoic and docosahexa-enoic acids at the expense of arachidonic acid Thus,when immune cells are stimulated, there is less arachi-donic acid available to generate prostaglandins andleukotrienes, which are inflammatory in nature Second,eicosapentaenoic acid is a substrate for the same enzymesthat metabolize arachidonic acid However, the products
of eicosapentaenoic acid metabolism are less tory than those derived from arachidonic acid
inflamma-Although it may be useful to consume high levels ofn-3 PUFAs to decrease inflammation associated withautoimmune and neoplastic disease, or to reduce the risk
of heart disease, these conditions are not especiallyrelevant to food-animal production, and the immunosup-pression may render animals more susceptible to infec-tious disease Thus, inclusion of fish or other n-3 PUFA-rich oils in animal diets should be approached withcaution to avoid increased incidence of infections
Zinc
Zinc (Zn) is a component of at least 300 enzymes,and inadequate intake of Zn renders animals severelyimmunodeficient and highly susceptible to infection Bothinnate and acquired immunity are inhibited by Zn de-ficiency Some studies suggest that the Zn required foroptimum immunity is higher than that for optimumproductivity For example, in humans daily Zn supple-mentation reduced the incidence and duration of diarrheaand reduced the incidence of acute and lower respiratoryinfections Furthermore, strains of mice that are geneticallysusceptible to infection by a certain pathogen can be maderesistant by consuming a Zn-enriched diet However,adverse effects of Zn excess on lymphocyte proliferationand chemotaxis and phagocytosis of neutrophils are
Fig 1 The immune system can be partitioned into two separate
but interacting components that which provides innate immu
nity and that which provides acquired immunity Both innate and
acquired immunity can be modulated by nutrition
Table 1 Several nutrients with well documentedimmunomodulatory effects
Primary immunologicalfunction
in blood
Vitamin Eand Selenium
[3] Enhance humoral and
cell mediated immunity andinhibit inflammatorycytokine production
Trang 3possible, and beneficial immunological effects of excess
Zn have not been clearly demonstrated in livestock
Iron and Copper
The effect of iron (Fe) on immunocompetence is not as
clear as that of Zn; however, generally speaking, an
imbalance in Fe intake either too much or too little
decreases immunity One of the acute responses induced
by infection is hypoferremia The inflammatory cytokines
released by activated macrophages cause Fe to be
se-questered Because Fe is a rate-limiting nutrient for the
growth of several pathogenic microorganisms, its removal
from blood and temporary storage in compartments that
are not accessible to pathogens is considered part of the
host defense Iron-binding proteins chelate the most Fe;
however, supplementation can saturate these proteins,
leaving excess Fe available to pathogens
Copper (Cu) status is determined primarily by the plasma
concentration of the acute-phase protein ceruloplasmin
The inflammatory cytokines induce synthesis of
cerulo-plasmin Therefore, whereas infection decreases circulating
Fe, it increases circulating Cu The increase in plasma Cu
may be to enhance lymphocyte responses because Cu
deficiency reduces production of IL-2 a cytokine that acts
in an autocrine manner to promote T-cell proliferation To
our best knowledge, there have been no studies clearly
demonstrating that the Cu required for optimum immunity
is higher than that for optimum production
Vitamin E and Selenium
The primary role of vitamin E in nutrition is to protect cell
membranes from peroxidative damage, whereas Se is an
integral component of glutathione peroxidase Vitamin E
and Se also play an active role in the host’s response to
infection Vitamin-E and Se supplementation in excess of
minimal requirements may increase both innate and
acquired immunity and offer protection against certain
pathogens such as influenza However, feeding a vitamin
E level 50 times the NRC requirement did not afford pigs
protection from the effects of porcine reproductive and
respiratory syndrome virus infection on growth
perform-ance, cytokine production, or certain hematological traits
(e.g., white blood cell counts) Nonetheless, vitamin E
reduces the production of certain inflammatory
cy-tokines and inhibits some behavioral signs of sickness
Thus, in certain instances vitamin-E supplementation may
be beneficial
Vitamin A
Vitamin-A deficiency severely compromises the integrity
of mucosal epithelial cells in the respiratory,
gastrointes-tinal, and uterine tracts In the respiratory tract, ciliated
columnar epithelium with mucus and goblet cells traps
and removes inhaled microorganisms In animals deficient
in vitamin A, ciliated epithelial cells are replaced bystratified, keratinized epithelium, and there is a decrease
in mucin Similarly, in the small intestine, vitamin-Adeficiency results in a loss of microvilli, goblet cells, andmucin Other effects of vitamin-A deficiency on innateimmunity include changes in epidermal keratins thatdisrupt skin barrier function; defects in chemotaxis,adhesion, phagocytosis, and the ability to produce reactiveoxygen species in neutrophils; decreased number of NKcells and cytotoxicity; and a decrease in the expression ofthe receptor that recognizes Gram-negative bacteria aswell as the secretion of inflammatory cytokines bymacrophages and monocytes
An adequate level of vitamin A is also necessary tosupport acquired immunity The growth and activation of
B cells require retinol Pigs deficient in vitamin Asynthesize less than one-tenth of the amount of antibodyproduced by pigs fed vitamin A fortified diets Infectionwith Trichinella spiralisa normally induces a strong Thelper type 2-like response (i.e., high levels of parasite-specific IgG and production of IL-4, IL-5, and IL-10), but
in vitamin-A deficiency an inappropriately strong T helpertype 1 like response (i.e., production of interferon-g andIL-12) is induced
CONCLUSION
The nutrient requirements determined to support optimalproductivity of healthy animals may fall short of thoseneeded to promote optimal immune responses in animalschallenged by infectious disease It may be possible todevelop diets that promote optimal immune responses.What is considered optimal may change from oneproduction system to another, or even within a system,depending on the disease environment at a given time.The goal should not always be to minimize the immuneresponse, for in certain environments this would result inincreased incidence of infection Similarly, the goalshould not always be to maximize the immune responsebecause an overzealous response to nonpathogenic stimulican be counterproductive
REFERENCES
1 Johnson, R.W.; Escobar, J.; Webel, D.M Nutrition andImmunology of Swine In Swine Nutrition, 2nd Ed.; Lewis,A.J., Southern, L.L., Eds.; CRC Press LLC: Boca Raton,2001; 545 562
2 Calder, P.C.; Grimble, R.F Polyunsaturated fatty acids,inflammation and immunity Eur J Clin Nutr 2002, 56(Suppl 3), S14 S19
3 Meydani, S.N.; Beharka, A.A Recent developments in vitamin E and immune response Nutr Rev 1998, 56, S49 S58
Trang 4Immune System: Stress Effects
Stress has been difficult to define because of its dual
function in life It can be a positive influence that satisfies
a need for excitement (environmental enrichment) or a
negative influence that interferes with homeostasis and
life functions The latter is referred to as a state of distress
Our use of stress will refer to this darker side of stress The
interaction between stress and the immune system is a
conundrum because of the negative impact that stress can
have on immune functions, and because active immune
responses can be stressors in and of themselves Stress can
also activate or suppress immune responses depending on
the degree and persistence of the stressor; the species, age,
sex, and genetics of the subject; and the immune cells that
are the targets of the stress Not all stressors result in the
same immune response, such as isolation compared to
restraint stress But, in general, most psychological and
environmental stressors lead to impaired immune
func-tions, especially those that regulate inflammatory and
cytotoxic responses The deleterious effects of stress are
readily observed at an early gene expression level in cells
of the innate (not requiring prior exposure to foreign
antigen) and adaptive (requiring prior exposure to foreign
antigen) immune systems Thus, stress-immune
interac-tions usually have significant physiological consequences
even before behavioral or gross pathogenic changes are
observed
TWO MAJOR PATHWAYS OF
THE STRESS RESPONSE
The degree to which homeostasis becomes unbalanced
and leads to distress[1]is largely influenced by the impact
of stress hormones on target cells Glucocorticoids
(primarily cortisol in farm animals) are the main effector
endpoints of the neuroendocrine response to stressors,[2]
and result from activation of the
hypothalamus-pituitary-adrenal (HPA) axis (Fig 1) Systemic cortisol
concen-trations increase several minutes after a perceived threat
and can last for a number of hours and recur in waves if
the threat (stressor) is not removed The well-known inflammatory and immunosuppressive effects of cortisolmay serve as physiological downregulators of initiatedimmune responses following infection or tissue damage.[3]However, contemporary management stressors that sig-nificantly and repeatedly activate the HPA axis inotherwise healthy animals cause pronounced changes inimmune cell physiology, leading to disease susceptibilityand clinical pathology
anti-Another pathway that mediates stress responses inanimals is the sympatho-adrenal axis (Fig 1) Activation
of this neurotransmitter axis results in release of renergic hormones (mainly the catecholamines, adrena-line, and noradrenaline) from the medullae of the adrenalglands and from nerves that innervate lymphoid tissuesand blood vessels Catecholamine secretion occurs sec-onds following perceived threats, enabling rapid increases
ad-in heart and respiration rate and constriction of smallblood vessels in peripheral tissues to increase blood flow
to the brain, liver, and muscles, and enhancing awarenessand athletic prowess to facilitate the fight-or-flightresponse.[4]However, like HPA axis activation, catechol-amine responses may be inappropriate and harmful toimmunity and health in the context of exposure torecurring or chronic stressors
TWO ARMS OF THE IMMUNE SYSTEMAFFECTED BY STRESS
Molecules such as cytokines, chemokines, adhesionmolecules, major histocompatability complexes (MHC),and antibodies link the innate and adaptive arms of theimmune system (Fig 2) The innate immune systemprovides the first line of immune defense and is composedprimarily of neutrophils, macrophages, and dendriticcells Under nonstress conditions, these professionalphagocytes gain rapid entry into infected tissues to clearpathogens by receptor-mediated phagocytosis, leading tothe production of free radicals and the release of enzymesthat kill the ingested microorganisms The adaptiveimmune system is primarily composed of B and T
DOI: 10.1081/E EAS 120019688 Copyright D 2005 by Marcel Dekker, Inc All rights reserved.
Trang 5lymphocytes, which require prior exposure to pathogens
for immune activation The B lymphocytes (B cells)
produce and secrete antibodies, which are particularly
effective in protecting animals against extracellular
pathogens The T lymphocytes are made up of several
subpopulations Helper T cells of the type I class (THI)
participate in inflammatory, cytotoxic, and some antibody
responses Helper T cells of the type II class (THII)
facilitate primarily antibody-mediated responses
Cyto-toxic T cells (TC) and their innate counterparts, the natural
killer (NK) cells, lyse and kill host cells infected withintracellular viruses and bacteria Less well-definedgamma delta-T cells (gd T cells) appear to have tissuehealing and immune-modulating roles that vary insignificance across species
STRESS AFFECTS GENE EXPRESSION
IN IMMUNE CELLS
Glucocorticoids (GC) such as cortisol act by regulatingexpression of multiple GC-sensitive genes and thus theexpression of proteins that determine the phenotype andfunction of cells responsible for coordinating the body’sresponse to stress Gene expression regulation results fromthe binding of GC to its receptor (GR), found primarily inthe cytoplasm of target cells, with subsequent transloca-tion of the hormone-activated GR into the nucleus It ishere that GR has its major effects on gene expression, byinteracting either directly (GR-DNA binding, as shown inFig 3) or indirectly (GR-other protein-DNA binding; notshown) with regulatory DNA in and around GC-sensitivegenes Glucocorticoids both induce and inhibit theexpression of sensitive target genes, depending on thegene and the target cell affected Thus, blood cortisolconcentrations resulting from a stress response can havepronounced effects on immunity through altered expres-sion of hundreds of immune cell genes
Phagocytic cells, THI cells, and gd T cells seem to beparticularly sensitive to the potent anti-inflammatory andimmunosuppressive properties of stress cortisol, which:
Fig 1 Environmental and psychological stressors activate the
hypothalamus pituitary adrenal (HPA) axis and sympatho adre
nal axis
Fig 2 Two arms of the immune system are affected by stress
Trang 61) downregulates the expression of multiple chemokines
responsible for recruitment of innate immune cells into
infected tissue; 2) inhibits expression of leukocyte
adhesion molecules responsible for migration of
circulat-ing innate immune cells into infected tissues and adaptive
immune cells into inflamed lymph nodes; 3) alters the
expression of apoptosis genes in most immune cells,
thereby changing their numbers in primary and secondary
lymphoid tissues and blood; 4) inhibits expression of key
pro-inflammatory cytokines, upsetting the balance of TH
I-based inflammatory/cytotoxic responses in favor of TH
II-based antibody responses; and 5) downregulates MHC II
expression on key antigen presenting cells (macrophages,
dendritic cells) normally responsible for alerting THI cells
to an infection.[5]
More immediate immune regulation is induced by
stress through the actions of catacholamines In addition to
circulating catacholamines secreted by the adrenal
medullae in response to stress (Fig 1), sympathetic nerve
fibers from the central nervous system innervate primary
and secondary lymphoid tissues providing direct ‘‘hits’’
of these neurotransmitters to developing B and T cells
Blood vessels are also innervated, so stress
catachol-amines influence the trafficking of leukocytes between
lymphoid compartments and peripheral tissues by
influ-encing gene expression in vascular endothelial cells The
most common of these in stressed farm animals are
increased circulating neutrophil numbers, which drive
similar increases in blood neutrophil:lymphocyte ratios.Variable decreases in blood TH:TC cell ratios are alsoobserved in stressed animals, but these ratios may bemore responsive to cortisol than to catacholamines.Adrenoreceptors for the catacholamines are expressed
by each of these immune cells and may be partlyresponsible for the acute alterations in lymphoid tissuecellularity, leukocyte trafficking patterns, and cytokineand antibody networks observed in some stressedanimals.[4–7] Compared to glucocorticoids, however,relatively little information is available on molecularmechanisms used by catacholamines to change leukocytebiology and immune responses
STRESS EFFECTS ON THEIMMUNE RESPONSE
Given that stress hormones modify expression patterns ofhundreds of immune genes, it is reasonable to speculatethat stress also has complex and pleiotropic effects ondisease resistance through its effects on innate and adapt-ive immune responses Several examples can be cited tosubstantiate this speculation One is that glucocorticoidsinterfere with activation of adaptive immune responses,including those to vaccinations,[8] via their negative ef-fects on MHC expression, cytokine expression, and the
T :T ratio in blood In addition, the combined actions of
Fig 3 Immune cells respond to stress by expressing cytoplasmic receptors (GR) for glucocorticoids (GC) such as cortisol Cortisolreadily crosses the plasma membrane of cells (step 1) and binds tightly with GR (step 2) This activates GRs to dimerize with anotherhormone bound receptor (step 3), enabling them to translocate into the cell’s nucleus (step 4), where they interact directly (shown in step5) or indirectly (through interaction with other transcription factors; not shown) with promoters of GC responsive genes This interactionwith promoter DNA enables GR to influence transcription of the target gene, either inducing (step 6) or suppressing (not shown)expression of mRNA for the gene When mRNA abundance is increased or decreased by GR, increased abundance or reducedavailability of protein encoded by the affected gene (steps 7 and 8) can alter the phenotype and thus the function of the cell (step 9)
Trang 7catacholamines and glucocorticoids on adhesion molecule
expression by vascular endothelial cells and circulating
neutrophils prevents this first line of immune defense
from gaining access to infected tissues, leaving animals
susceptible to diseases caused by opportunistic pathogens
The macrophage barrier to infection in peripheral tissues
is also compromised during stress because glucocorticoids
inhibit expression of key inflammatory molecules,
in-cluding prostaglandins, chemokines, cytokines, and free
radicals, which normally clear pathogens, initiate
neut-rophil recruitment to the site, and activate appropriate
adaptive immune responses Glucocorticoids also
dramat-ically reduce circulating numbers of gd T cells in
rumi-nants and alter the expression of key apoptosis genes to
induce death in developing T cells and longevity in
cir-culating neutrophils This partly accounts for the altered
tissue and circulating cell numbers during stress Some
degree of species specificity is evident in responses of the
immune system to stress.[9] However, these changes in
leukocyte numbers and their altered ability to
communi-cate with each other through chemokines, cytokines,
ad-hesion molecules, MHC complexes, and other
inflamma-tory mediators occur in most farm animals when blood
glucocorticoids and catacholamine concentrations
in-crease, leaving stressed animals at risk for diseases caused
by bacteria, virus, and parasites
CONCLUSION
Whereas endocrine factors that link the stress and immune
systems are beginning to be elucidated, phenotypic
responses of the whole immune system to stress are not
well understood and are often unpredictable.[10] Past
studies in the animal sciences have mostly focused on
measuring altered proportions of blood leukocytes as
potential biological indicators of physiological stress and
disease susceptibility However, most of the indicators
studied have been used with little biological justification
Rather, indicators such as the ratios of TH:TClymphocytes
or neutrophil:lympocyte in blood have been used because
researchers have the technology to perform such
measure-ments and can show impressive changes in them due to
imposed stressors Whereas these measurements may
indicate that changes are occurring in the animals, they are
incomplete and not diagnostic of the overall
immunophys-iological response to stress Part of the current lack of
ability to prevent stress-related disease in farm animals is
our lack of basic knowledge about what stress hormones
do to leukocytes at the molecular level Future prevention
and treatment of stress-related infectious diseases will
undoubtedly require that animal science researchers move
beyond the study of isolated cellular phenomena to more
holistic studies of genome-level changes that occur in
specific leukocytes in response to glucocorticoids, cholamines, and other stress mediators and explain thecells’ dysfunctions
cata-ACKNOWLEDGMENTS
The authors extend thanks to Sally Madsen and JenniferJacob for contributing to the development of Figs 2 and 3
ARTICLES OF FURTHER INTEREST
Environment: Effects on Animal Health, p 335Molecular Biology: Animal, p 653
REFERENCES
1 Moberg, G.P Biological Response to Stress: Implicationsfor Animal Welfare In The Biology of Animal Stress BasicPrinciples and Implications for Animal Welfare; Moberg,G.P., Mench, J.A., Eds.; CABI Publishing: New York,2000; 1 21
2 Eskandari, F.; Sternberg, E.M Neural immune interactions
in health and disease Ann N Y Acad Sci 2002, 966,
20 27
3 O’Connor, T.M.; O’Halloran, D.J.; Shanahan, F The stressresponse and the hypothalamic pituitary adrenal axis:From molecule to melancholia Q J Med 2000, 93,
323 333
4 Kohm, A.P.; Sanders, V.M Norepinephrine and beta
2 adrenergic receptor stimulation regulate CD4 + T and Blymphocyte function in vitro and in vivo Pharmacol Rev
2001, 53 (4), 487 525
5 Burton, J.L.; Erskine, R.J Mastitis and immunity: Somenew ideas for an old disease Veterinary Clinics of NorthAmerica Food Anim Pract 2003, 19, 1 45
6 Elenkov, I.J.; Wilder, R.L.; Chrousos, G.P.; Vizi, E.S Thesympathetic nerve An integrative interface between twosupersystems: The brain and the immune system Pharmacol Rev 2000, 52 (4), 595 638
7 Bergmann, M.; Sautner, T Immunomodulatory effects
of vasoactive catecholamines Wien Klin Wochenschr
2002, 114 (17 18), 752 761
8 Kehrli, M.E.; Burton, J.L.; Nonnecke, B.J.; Lee, E.K.Effects of stress on leukocyte trafficking and immuneresponses: Implications for vaccination Adv Vet Med
Trang 8Higher species have the evolutionary benefit of an
immune system that comprises both innate and acquired
components Whereas the innate immune system confers
initial protection, the acquired immune system provides a
second line of defense against infectious organisms.[1,2]
The acquired immune system is activated once
macro-phages, dendritic cells, and other antigen-presenting cells
(APCs) process foreign antigens (i.e., the products derived
from infectious organisms, tumors, vaccines, etc.) Many
APCs also transport the foreign antigen into regional
immune lymph nodes.[3] APCs initiate adaptive immune
responses by interacting with different populations of T
and B cells
IMMUNE CELL SUBSETS AND MARKERS
Table 1 outlines the differences between the innate and the
adaptive, or acquired, immune response Figure 1 shows
some of the blood cell subsets involved in immune
responses Immune cell subsets are designated by their
cluster of differentiation (CD) antigen markers,
recog-nized by monoclonal antibodies (e.g., CD4 + T helper
cells, CD25 + activation antigen, CD1 + dendritic cells,
CD172 + macrophages).aT cells express the CD3 antigen
and the T cell receptor (TCR) B cells produce
immunoglobulins (Igs); some express them on their
surface as part of the B cell receptor (BCR) The variant
antigen-binding T and B cell receptors the TCR and
Ig are complex; in the genome they are encoded as sets
of gene segments coding for variable and constant
regions.[2,3] To have an active TCR or Ig expressed,
multiple gene rearrangements must take place in eachindividual cell Each TCR has two antigen-bindingpolypeptides the TCR alpha and beta or gamma anddelta gene complexes The gdTCR + T cells and abTCR +
T cells are active in innate and adaptive immuneresponses, respectively Each Ig also has four antigen-binding polypeptides, two heavy and two light chains.[4]bThere are different Ig isotypes defined by their heavychains (e.g., IgA, IgM, IgD, IgE, and multiple IgGisotypes) on B cells or in blood and mucosal secretions.The diversity of TCR and Ig expression adds to immunediversity, enabling the acquired immune system torespond to a broad array of immune molecules
IMMUNE SYSTEM DEVELOPMENT
As it matures, the fetus develops its immune organs.Lymphocytes are generated in the primary lymphoidorgans: the bone marrow, thymus, and intestinal Peyer’spatches.[2,3]T and B lymphocytes from these tissues thenstart circulating and eventually localize in peripheral orsecondary immune tissues, where adaptive, or acquired,immune responses take place Effective immune re-sponses require immune cells to be localized in secondarylymphoid organs The neonate requires time for itsimmune tissues to become mature Because of their lack
of immune system development, neonates are typicallymore susceptible than older animals to respiratory orintestinal infections Probiotics have been developed toassist in maturing the intestinal immune tissues Cytokinesand chemokines serve as lymphoid tissue hormones andhelp to regulate immune system development anddifferentiation.[5]
Once a foreign antigen (i.e., an antigen produced frominfectious microbes or vaccine preparations) enters thebody, it is encountered by an APC a dendritic cell ormacrophage and is transported to the local lymphoid
b The VIC IUIS Comparative Immunoglobulin Workshop [CIgW] Committee maintains a website on immunoglobulins, Fc receptors and their genes for veterinary species (http://www.medicine.uiowa.edu/cigw/).
a The Veterinary Immunology Committee of International Union of
Immunological Societies (VIC IUIS) maintains a series of websites for
immune reagent information (Pig website: http://eis.bris.ac.uk/~lvkh/
welpig.htm; cattle: www.iah.bbsrc.ac.uk/leucocyte/bovsite.html; horses:
www.vetmed.wisc.edu/research/eirh; other websites are under develop
ment.) The Human Leucocyte Differentiation Antigens (HLDA8)
Animal Homologues Workshop (www.hlda8.org) is underway to expand
the CD markers and species tested for cross reaction of anti human CD
markers on other species cells.
DOI: 10.1081/E EAS 120019689 Published 2005 by Marcel Dekker, Inc All rights reserved.
Trang 9organ, the lymph node, spleen, or specialized lymphoid
tissues in the gut or respiratory sites In these secondary
lymphoid sites the foreign antigen is presented by APCs to
T and B cells and an acquired immune response is
initiated Many immune cells excrete a broad range of
cytokines and chemokines, such as the interferons (IFNs)
and interleukins (ILs), that activate the immune system
and encourage cells to migrate and localize to the area of
infection or tumor growth.[5]
MAJOR HISTOCOMPATIBILITY
COMPLEX (MHC) ANTIGENS
The major histocompatibility complex (MHC) antigens
or the swine, dog or bovine leukocyte antigens (SLA,
DLA or BoLA) are highly polymorphic, cell-surface
antigens involved in antigen presentation.[4]cClass I MHC
antigens are expressed on most cells, whereas class II
MHC antigens are preferentially expressed on APC The
MHC genes are localized close together in the genome
Animals are usually MHC heterozygous, having two
alleles at each of the multiple classes I and II genes.[3,4]
Each animal expresses several class I MHC molecules,
each of which is highly polymorphic Class II genes are
encoded by several linked loci, the DR and DQ alpha and
beta genes This wide diversity of MHC antigens is
thought to be needed to handle the enormous number of
foreign antigens that an animal encounters
INITIATION OF ADAPTIVE T CELL IMMUNITY
Innate immune responses help to control and eliminateinfectious organisms, yet they are not always completelyeffective However, even if the innate response is not fullyprotective, it results in the activation of the adaptive im-mune response Numerous innate signals (e.g., Toll-like re-ceptor (TLR) signaling, chemokines, and cytokines) attractimmune cells to the local tissues where they are activated,causing the more complex, adaptive immune response Tostimulate adaptive immunity, foreign antigens must first beprocessed into peptide fragments by APC; the resultingfragments associate with MHC class I or II antigens and arepresented to the TCR In most cases, class I MHC binds in-ternally processed foreign antigens, such as cell-processedviral or parasite peptides, whereas MHC class II presentsexternally generated peptides, such as vaccine peptides(Table 2) CD8 + T cells respond to class I MHC presentedforeign antigens; CD4+ T cells respond to class II MHC.[2,3]The way in which the animal’s immune system initiallyreacts to an infectious pathogen is critical; it determineswhether a protective, or an ineffective, or even a path-ogenic, immune response will be mounted The intensity
of the response to foreign antigen peptides is dependent
on the strength of immunostimulation This is determined
by the immunogenicity of the foreign peptide and thestrength of the MHC-antigen complex, as well as on thefrequency of TCRs that recognize that complex.[2,3]
POLARIZATION OF T CELLCYTOKINE RESPONSES
Cytokines are secreted by immune cells and can eitherstimulate or suppress the activity of immune cells andalter each cell’s pattern of cytokine expression.[5] They
Table 1 Comparison of innate immunity to acquired, or adaptive, immunity
Antigen independent
Narrow antigen specificityAntigen dependent
Enhanced recall responses
Effector proteins Antimicrobial peptides
Acute phase proteins, complementCytokines, chemokines
Cytokines, chemokinesImmunoglobulin (Ig) antibodiesPerforins, granzymes
Granulocytes, neutrophilsNatural killer (NK) cells
APC: dendritic cells, macrophages
T and B cellsRegulatory cell subsets
c The international ImMunoGeneTics project (IMGT) maintains the HLA
website and its IMGT/HLA Sequence Database A related IPD/MHC
sequence database website (http://www.ebi.ac.uk/ipd/mhc/index.html)
will be used for MHC sequences of veterinary species.
Trang 10regulate a broad range of actions resulting in
antigen-specific immune responses, alterations in levels of other
cytokines, chemokine secretion, Ig production and isotype
maturation, eosinophil and mast cell recruitment and
activation, and cytotoxic T cell generation.[3]To
counter-act these mediators of host defense, certain infectious
organisms actually encode their own cytokine modulators
or receptor-blocking proteins
Once activated, CD4 + T cells produce specific sets of
cytokine signals CD4 + T helper 1 (Th1) cells express
the cytokine IFN-g, which is essential for effective
antiviral and bacterial responses (Table 2) In many
species Th1 responses are amplified by the release of
IL-12 Th1 cytokines activate macrophages and naturalkiller cells in response to internally processed antigens.CD4 + Th2 cells stimulate a different set of cytokines,including IL-4, IL-5, and IL-13 in response to externalpeptides These Th2 cytokines increase mast cell andeosinophil numbers and activities and stimulate B cells
to switch to IgA and IgE production, thus enhancinginflammatory and allergic responses
Cytotoxic CD8 + T cells interact with infected cells ortumor cells via antigen presented by class I MHC Cellconjugates stimulate TCR-encoded recognition processes
Fig 1 Cells regulating immune responses Blood immune cells Immune cells that circulate in blood are shown All immune cells inthe blood, the hematopoietic cells, are derived from bone marrow stem cells These hematopoietic stem cells give rise to two mainlineages: one for lymphoid cells (lymphoid progenitor) and one for myeloid cells (myeloid progenitor) The common lymphoidprogenitor will differentiate into either T cells or B cells depending on the tissue to which it travels (homes) In mammals, T cellsdevelop in the thymus while B cells develop in the fetal liver and bone marrow Pigs use special areas of their intestines, termed thePeyer’s patches, for B cell maturation B cells produce the antibodies so crucial to immune and vaccine responses To produceantibodies, B cells must become antibody forming cells (AFC), or plasma cells Innate immune responses are carried out by naturalkiller (NK) cells that also derive from the common lymphoid progenitor cell The myeloid cells differentiate into the committed cells onthe left The platelets help blood to clot and thus heal injured tissue Three other myeloid derived cell types, the monocyte, macrophageand dendritic cells are critical in helping the immune system recognize what is foreign, and thus stimulating specific immune systemresponses Finally, the ‘‘granulocytes’’, a term used for eosinophils, neutrophils and basophils, have specialized functions, e.g.,neutrophils will use antibodies to trap and kill invading bacteria (Picture used with permission of National Hog Farmer.) Adapted fromhttp://www.ed.sc.edu:85/book/immunol sta.htm Courtesy of Department of Pathology & Microbiology, University of South CarolinaSchool of Medicine, Columbia, SC (View this art in color at www.dekker.com.)