Module 6: Immunology

AnS 536Spring 2015

Innate and Adaptive Immunity in the Newborn

Fetus exists in a sterile environment prior to birth Neonates require an efficient host

defense

Types of Immunity

Innate Adaptive Humoral Cell-Mediated Active Passive

Body Defenses

Innate Adaptive

Inflammation

Interferon

Natural Killer cells

Complement System

Humoral Cell mediated

B Lymphocytes T Lymphocytes

Innate and Adaptive Immunity in the Newborn

Innate Immunity

Basic, immediate defense against invading pathogens

Doesn’t attack singular pathogen Defends against all antigens

Cellular and bodily defenses Phagocytosis of invading pathogens Inflammation Physical barriers

Innate Immunity in the Newborn Innate

Non-specific defense mechanisms that respond immediately to antigens present in the body

Include: 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

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

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 Does not cross the placenta

Concentrated in colostrum Lower serum complement levels leads

to decreased ability to activate the complement cascade 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

Adaptive Antigen-specific immune response More complex than innate

Antigen must be processed and recognized

Immune cells designed to attack specific antigens

Develops a “memory” for future attacks

Adaptive Immunity

Increased level of defense Attacks specific pathogen

Memorizes that pathogen in case of future need

Mostly cellular responses Divided into humoral and cell

mediated immunity

Adaptive Immunity

B cell development 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 Immunity using macromolecules B cells

Type of lymphocyte that is formed in bone marrow

Possesses a protein on outer surface called B cell receptor

Antibodies/Immunoglobulins Produced by B cells Takes out bacteria and viruses

Complement System Helps phagocytic cells clear pathogens Causes cytolysis of target cell

Passive Immunity

Antibodies passed from one individual to another

Natural Transfer of antibodies through placenta or colostrum

Artificial Taking antibodies for a specific pathogen from

immune individual to non-immune Short duration

Active Immunity

Antibodies are produced when immune system is exposed to an antigen Artificially acquired

Vaccines Naturally acquired

Memory T cells

Newborn Lymphocyte Function 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 Suggests colostrum ingestion directly

contributes to suppression of lymphocyte function

Newborn Lymphocyte Function 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

Mark cells for attack or destroy cells themselves

Five types IgM IgE IgD IgG IgA

Immunoglobulins

Properties of Ig Classes and Subclasses IgM

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

Basic antibody produced by B cells First antibody on site when host

attacked by pathogen “Precursor” to IgG

Defends host until IgG has attained high enough levels

Immunoglobulins IgA

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 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

Role isn’t fully understood Signals the activation of B cells Plays part in allergic reactions Assists with respiratory immune

defense

Immunoglobulins IgG

Monomeric structure in serum Predominant Ig in serum 4 subclasses

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

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 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 Certain regions of Africa showed limited transfer of

IgG because FcRn was saturated with IgG (Palmeira, et al. 2012)

Fetus starts to acquire maternal antibodies beginning at the 13th week of gestation

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 Antibody Response

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”

Rearrangement of genes within DNA to produce IgG

Rearrangements are delayed during fetal life

Adaptive Immunity

Normal numbers of B & T cells are present at birth

Humoral immune responses are functionally immature Due to regulatory imbalance between

T cell mediated help & suppression Also due to B cell immaturity

Adaptive Immunity

Newborns are better able to respond to protein antigens then capsular polysaccharide antigens

Demonstrate delayed ability to switch from IgM to IgG Results in developmental lag prior to

attainment of adult levels of serum IgM, IgG, and IgA

Adaptive Immunity

Human neonate has adult levels of B cells at birth

Most domestic species only show 1/3 adult B cell levels at birth Foal and calf reach adult levels at 20

d Pig reach adult levels at 30 d

Adaptive Immunity T-Suppressor Cells

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

Decrease to near adult levels by 3 months of age

Adaptive Immunity

Summary 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

Antimicrobial peptides classification: Defensins

α-defensins Human neutrophil peptide 1 to 4 (HNP1-4) Human defensins 5 to 6 (HD5-6)

β-defensins HBD1-4

Expressed primarily by epithelial cells

Cathelicidins 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

Antimicrobial peptides are cationic Have an affinity to negatively charged

microbial membranes Have been shown to kill Gram+ and Gram-

bacteria, fungi, parasites, certain enveloped viruses, and cancer cells in vitro

Expressed in many organs in the body 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 PeptidesPeptides Distribution

α-Defensins HNP1-3 granulocytes, lymphocytes, spleen, cornea, thymus, vernix, amniotic fluid HNP4 granulocytes HD5,6 paneth cells of the intestine

β-defensins HBD1 kidney, pancreas, salivary gland, lung, skin, placenta, thymus, gut, testis,

small intestine, mammary gland, breast milk HBD2 skin, lung, kidney, small intestine, colon, stomach, pancreas, thymus,

uterus, testis, liver HBD3 skin, tonsil, lung, thymus, uterus, kidney HBD4 testis, gastric antrum

Cathelicidin LL-37 granulocytes, lymphocytes, lung, skin, colon, saliva, vernix, amniotic fluid

Others Histatin saliva Hepcidin liver

Maternal Recognition of Fetus Some embryonic proteins are recognized

as foreign due to paternal origin Maternal immune response is impaired

during pregnancy Fetal trophoblast

Maternal blood circulation contacts Anatomic barrier between dam and fetus Syncytiotrophoblastic layer of cells has been

found to be lacking in transplacental antigens Most likely reason why maternal immune system

doesn’t reject the fetus

Maternal Recognition of Fetus

Fetus creates its own protection Idoleamine 2,3-dioxygenase (IDO)

Destroys tryptophan (TRP) TRP fuels I-cells, that then attack foreign

tissue

Active vs. Passive Immunity

Active The production of antibodies as a

result of exposure to an antigen Natural exposure Artificially acquired

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 Passive

Direct transfer of antibodies actively formed by another person or animal

“Borrowed” immunity 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

Antibody-synthesizing ability does not develop before one month of age

Colostrum and its Role First time neonate will receive antibodies

from mother 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 Higher risk of morbidity, mortality, decreased

growth rates and first lactation milk production in dairy calves (Fidler, et al. 2007)

Colostrum Components Immune factors

Immunoglobulins, cytokines, lysozymes, glycoproteins

Growth factors IGF-1, IGF-2, epithelial growth factor

Nutritional components Vitamins, minerals, amino acids

Antibodies IgG IgA IgM

Changing Absorption of IgG

Difructose anhydride III 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

Decreases microbial count while maintaining IgG levels

Changing Absorption of IgG Use of colostrum replacers

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 NaHCO3 can increase IgG concentration up to a

point (Cabral, et al. 2011) Feed colostrum in two feedings

Ig Deficiencies Hypogammaglobulinemia

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 More susceptible to infections such as pneumonia,

bronchitis and others Often occurs when there’s also a deficiency in IgA

or IgM Cause unknown but has possible genetic ties