Module 6: Immunology
AnS 536
Spring 2015
Innate and Adaptive Immunity
in the Newborn
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Fetus exists in a sterile environment
prior to birth
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Neonates require an efficient host defense
Types of Immunity
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Innate
Adaptive
Humoral
Cell-Mediated
Active
Passive
Innate and Adaptive Immunity in
the Newborn
Body Defenses
Innate
Adaptive
Inflammation
Interferon
Natural Killer cells
Complement System
Humoral
B Lymphocytes
Cell mediated
T Lymphocytes
Innate Immunity
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Basic, immediate defense against
invading pathogens
Doesn’t attack singular pathogen
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Defends against all antigens
Cellular and bodily defenses
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Phagocytosis of invading pathogens
Inflammation
Physical barriers
Innate Immunity in the
Newborn
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Innate
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Non-specific defense mechanisms that respond
immediately to antigens present in the body
Include:
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Physical barriers (skin, mucous membranes)
Inflammation (reaction of the body to tissue damage)
Phagocytosis (neutrophils, monocytes, and tissue
macrophages)
NK cells
Interferon
Complement
Generalized response not specific to a particular
antigen
Innate Immune System
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Without adaptive immunity, neonate
relies on complement and effector cells
of innate immune system
Phagocytic ability of cells is
normal/increased, but less responsive
to activation by lymphokines
Innate Immune System
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Decreased/normal IL-1 production by
neonatal macrophages
Lower expression of Class II molecules,
thus decreased antigen presentation
Possibly due to decreased IFN
production by neonatal lymphoid cells
Complement
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Does not cross the placenta
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Lower serum complement levels leads to
decreased ability to activate the complement
cascade
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Concentrated in colostrum
Due to decreased hepatic synthesis rates
Cord blood monocytes fail to produce
complement in response to (LPS) in vitro
Innate and Adaptive Immunity
in the Newborn
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Adaptive
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Antigen-specific immune response
More complex than innate
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Antigen must be processed and recognized
Immune cells designed to attack specific
antigens
Develops a “memory” for future attacks
Adaptive Immunity
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Increased level of defense
Attacks specific pathogen
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Memorizes that pathogen in case of future
need
Mostly cellular responses
Divided into humoral and cell mediated
immunity
Adaptive Immunity
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B cell development
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Pluripotent stem cells within blood islands
of yolk sac give rise to progenitor cells
Progenitor cells migrate to the fetal liver
where B cell development begins
Later in fetal development, bone marrow
assumes this function
Humoral Immunity
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Immunity using macromolecules
B cells
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Antibodies/Immunoglobulins
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Type of lymphocyte that is formed in bone marrow
Possesses a protein on outer surface called B cell
receptor
Produced by B cells
Takes out bacteria and viruses
Complement System
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Helps phagocytic cells clear pathogens
Causes cytolysis of target cell
Passive Immunity
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Antibodies passed from one individual to
another
Natural
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Transfer of antibodies through placenta or
colostrum
Artificial
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Taking antibodies for a specific pathogen
from immune individual to non-immune
Short duration
Active Immunity
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Antibodies are produced when immune
system is exposed to an antigen
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Artificially acquired
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Vaccines
Naturally acquired
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Memory T cells
Newborn Lymphocyte
Function
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Capable of producing restricted antibody
repertoire following antigenic challenge with
mainly IgM being produced
Suppression of lymphocyte proliferation
attributed to factor present in newborn serum
factors
Lymphocytes from colostrum fed calves
respond to a lesser extent to mitogenic
stimuli than colostrum deprived calves
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Suggests colostrum ingestion directly contributes
to suppression of lymphocyte function
Newborn Lymphocyte
Function
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At birth ungulates are essentially
agammaglobulinemic
Dependent on ingestion of immunoglobulins
and other humoral and cellular factors from
colostrum
De novo synthesis of antibodies is negatively
correlated with peak concentration of
maternally derived antibodies
Immunoglobulins
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Mark cells for attack or destroy cells
themselves
Five types
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IgM
IgE
IgD
IgG
IgA
Immunoglobulins
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Properties of Ig Classes and Subclasses
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IgM
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Pentameric structure in serum
Does not readily move out of vascular system
Does not cross the placenta
First Ig produced during immune response
Potent complement activator
IgM
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Basic antibody produced by B cells
First antibody on site when host
attacked by pathogen
“Precursor” to IgG
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Defends host until IgG has attained high
enough levels
Immunoglobulins
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IgA
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Limited quantity in serum
IgA in serum is predominantly in monomeric form
Most produced is associated with mucosal surfaces
& is in dimer form (called secretory SIgA)
Present in various body fluids (saliva, nasal,
colostrum, etc.)
IgD
IgE
IgE
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Found in lungs, skin and mucous
membranes
Main purpose is defense against
parasites such as worms and
protozoans
Cause body to respond against pollen,
dander
Primary immunoglobulin used for
allergic reactions
IgD
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Role isn’t fully understood
Signals the activation of B cells
Plays part in allergic reactions
Assists with respiratory immune defense
Immunoglobulins
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IgG
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Monomeric structure in serum
Predominant Ig in serum
4 subclasses
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IgG1 have Fc region that effectively bind to macrophage
Fc receptors
IgG2 does not cross the human placenta
IgG3 most effective activator of complement and also has
Fc regions like IgG1
IgG4
IgG
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Major immunoglobulin of defense
Part of secondary immune response
This is the only antibody that can cross
through the placenta
Causes agglutination of pathogens
Coats surface of foreign bodies for
ingestion by phagocytes
Activates complement system
IgG in Human Fetus
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Level of IgG in fetus are correlated to the level in mother
IgG must be bound to neonatal Fc receptor (FcRn) or face
degradation by lysosomal enzymes
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Fetus starts to acquire maternal antibodies beginning at
the 13th week of gestation
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Certain regions of Africa showed limited transfer of IgG
because FcRn was saturated with IgG (Palmeira, et al. 2012)
Largest amount of transfer happens in third trimester
At full term, fetal IgG concentrations surpass the mothers by
20-30%
Maternal age, parity, weight and delivery type have no
effect on IgG concentration
Adaptive Immunity
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Antibody Response
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Following antigenic stimulation in the adult,
initial antibody response consists mainly of
the production of IgM
Maturation of the humoral immune
response involves “class switching”
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Rearrangement of genes within DNA to
produce IgG
Rearrangements are delayed during fetal life
Adaptive Immunity
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Normal numbers of B & T cells are
present at birth
Humoral immune responses are
functionally immature
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Due to regulatory imbalance between T
cell mediated help & suppression
Also due to B cell immaturity
Adaptive Immunity
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Newborns are better able to respond to
protein antigens then capsular
polysaccharide antigens
Demonstrate delayed ability to switch
from IgM to IgG
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Results in developmental lag prior to
attainment of adult levels of serum IgM,
IgG, and IgA
Adaptive Immunity
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Human neonate has adult levels of B
cells at birth
Most domestic species only show 1/3
adult B cell levels at birth
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Foal and calf reach adult levels at 20 d
Pig reach adult levels at 30 d
Adaptive Immunity
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T-Suppressor Cells
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Possess Fc receptors for IgM and occur in
cord blood as early as 26 weeks
Capable of inhibiting proliferation of Ab
secretion by maternal lymphocytes
Found in peripheral blood of neonates and
older infants
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Decrease to near adult levels by 3 months of
age
Adaptive Immunity
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Summary
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Regulatory imbalance between T cell
mediated help and suppression, as well as
B cell immaturity
Gap between development of lymphocytes
and their ability to effectively generate a
normal antibody response
Antimicrobial Sources in
Neonatal Immunity
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Antimicrobial peptides classification:
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Defensins
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α-defensins
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β-defensins
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Human neutrophil peptide 1 to 4 (HNP1-4)
Human defensins 5 to 6 (HD5-6)
HBD1-4
 Expressed primarily by epithelial cells
Cathelicidins
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Have been thought to only be expressed in mammals
LL-37 only one found in humans
Highly variant antimicrobial peptides
Antimicrobial Sources in
Neonatal Immunity
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Antimicrobial peptides are cationic
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Have an affinity to negatively charged microbial
membranes
Have been shown to kill Gram+ and Grambacteria, fungi, parasites, certain enveloped
viruses, and cancer cells in vitro
Expressed in many organs in the body
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Neutrophils, paneth cells, epithelial cells of skin,
respiratory & gastrointestinal tracts, urogenital
system, kidney pancreas, and placenta
Expression is continual (α-defensins and HBD1) or
induced (HBD2-4)
Antimicrobial Sources in
Neonatal Immunity
Table 1. Human Antimicrobial Peptides
Peptides
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α-Defensins
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HBD1
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HBD2
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granulocytes, lymphocytes, spleen, cornea, thymus, vernix, amniotic fluid
granulocytes
paneth cells of the intestine
HBD3
HBD4
kidney, pancreas, salivary gland, lung, skin, placenta, thymus, gut, testis, small
intestine, mammary gland, breast milk
skin, lung, kidney, small intestine, colon, stomach, pancreas, thymus, uterus, testis,
liver
skin, tonsil, lung, thymus, uterus, kidney
testis, gastric antrum
LL-37
granulocytes, lymphocytes, lung, skin, colon, saliva, vernix, amniotic fluid
Histatin
Hepcidin
saliva
liver
Cathelicidin
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HNP1-3
HNP4
HD5,6
β-defensins
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Distribution
Others
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Maternal Recognition of
Fetus
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Some embryonic proteins are recognized as
foreign due to paternal origin
Maternal immune response is impaired during
pregnancy
Fetal trophoblast
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Maternal blood circulation contacts
Anatomic barrier between dam and fetus
Syncytiotrophoblastic layer of cells has been found
to be lacking in transplacental antigens
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Most likely reason why maternal immune system doesn’t
reject the fetus
Maternal Recognition of
Fetus
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Fetus creates its own protection
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Idoleamine 2,3-dioxygenase (IDO)
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Destroys tryptophan (TRP)
TRP fuels I-cells, that then attack foreign tissue
Active vs. Passive Immunity
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Active
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The production of antibodies as a result of
exposure to an antigen
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Natural exposure
Artificially acquired
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Vaccines contain modified antigens that initiate an
immune response without causing the disease
Initial response produces memory T lymphocytes or
B lymphocytes
Active vs. Passive Immunity
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Passive
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Direct transfer of antibodies actively formed by
another person or animal
“Borrowed” immunity
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Transfer of IgG from the mother to fetus across the
placenta during gestation
Ingestion of colostrum transfers IgA
Antibodies are usually broken down before one
month of age
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Antibody-synthesizing ability does not develop before
one month of age
Colostrum and its Role
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First time neonate will receive antibodies from
mother
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Stomach is porous at birth to allow absorption
Absorption at max for first six hours post birth
Can acquire antibodies for up to 24 hours, but
transfer hindered
Without adequate intake of colostrum, newborn
will have less productive life
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Higher risk of morbidity, mortality, decreased
growth rates and first lactation milk production in
dairy calves (Fidler, et al. 2007)
Colostrum Components
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Immune factors
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Growth factors
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IGF-1, IGF-2, epithelial growth factor
Nutritional components
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Immunoglobulins, cytokines, lysozymes, glycoproteins
Vitamins, minerals, amino acids
Antibodies
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IgG
IgA
IgM
Changing Absorption of IgG
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Difructose anhydride III
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Indigestible disaccharide which promotes
absorption of calcium and magnesium in
intestines
Improves absorption of IgG in newborns
Feed colostrum in one feeding
Heat treated colostrum
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Decreases microbial count while
maintaining IgG levels
Changing Absorption of IgG
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Use of colostrum replacers
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Colostrum replacers (CR) had less transfer
of passive immunity when compared to
colostrum (Fidler, et al. 2011)
However, the more CR the calves received,
the better the transfer
Feeding sodium bicarbonate
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NaHCO3 can increase IgG concentration up
to a point (Cabral, et al. 2011)
Ig Deficiencies
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Hypogammaglobulinemia
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Lack or decrease of one or more types of
antibodies
Fetuses that don’t receive antibodies
through the placenta fall into this category
IgG deficiencies
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More susceptible to infections such as
pneumonia, bronchitis and others
Often occurs when there’s also a deficiency
in IgA or IgM