Module 6: Immunology AnS 536 Spring 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

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

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 IgG 1 have F c region that effectively bind to macrophage F c receptors IgG 2 does not cross the human placenta IgG 3 most effective activator of complement and also has F c regions like IgG 1 IgG 4

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 13 th 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 F c 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 Peptides Peptides 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 NaHCO 3 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