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CELLULAR AND MOLECULAR BASIS OF THE IMMUNE RESPONSE IN NEWBORNS

INTERNATIONAL SYMPOSIUM NEONATAL INFECTIONS AND IMMUNE RESPONSE IN NEWBORNS
by

Gregor Nosan

on 15 March 2013

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Transcript of CELLULAR AND MOLECULAR BASIS OF THE IMMUNE RESPONSE IN NEWBORNS

Cellular and molecular basis of the immune response in newborns Gregor Nosan
Department of Neonatology
Division of Paediatrics
University Medical Centre Ljubljana
Slovenia T lymphocytes Lymphocytes Small mononuclear
non-phagocytic leukocytes Cellular immunity
Intracellular pathogens, vaccines Reduced Newborn Complement activity Functionally immature immune competence Extracellular fiber-like networks Neutrophil extracellular traps Activity Maternal T lymphocytes
Weak responsiveness to fetal HLA molecules Protective & germ free
intra-uterine conditions Newborn
term, preterm Anatomical barriers Thinner skin Factor H: 60% Natural killer cells Complement Natural killing
Antibody-dependent killing Activity
Lethal toxins (perforines and granzymes)
IFN-γgamma Targets
virus-infected and cancer cells Normal NK activation
Normal IFN-gamma production
No functional immaturity Newborn NK Antigen presenting cells Monocytes
Macrophages
Dendritic cells Newborn Cytokine
secretion Immune response in newborn Th2 immune response
Anti-inflammatory cytokines Placenta
Complement down-regulation Trophoblast specific HLA-G molecules
Down-regulation of maternal NK and macrophages Innate immunity Smaller production of antimicrobial proteins and peptides Higher stomach pH Less active sebaceous glands Weaker intracellular contacts % of adult values CH50: 60% C1: 60% C2: 60% C3: 50% C4: 50% C5: 50% C6: 45% C7: 60% C8: 30% C9: 10% Properdin: 60% Factor B: 50% Factor I: 55% Innate immunity ‹1000 g: 26 per 1000 live births 1000-2000 g (8 per 1000 live births) term (2 per 1000 live births) Sepsis incidence HSV
HIV Formation of neutrophil extracellular traps Degranulation of antimicrobial proteins Phagocytosis Neutrophils Antimicrobial proteins
and peptides (myeloperoxidase, serine protease, lactoferrin…) Neutrophils’ DNA
chromatin Newborn neutrophils Reduced neutrophil storage pool in bone marrow Decreased deformability, adhesion, transepithelial migration Depressed oxidative metabolism Reduced neutrophil extracellular trap formation Granulopoiesis Granulocyte Colony Stimulating Factor (G-CSF)
Steady state: 120 billion granulocytes per day
Infection: 20-fold increase
Imobilization from bone marrow
De novo production Phagocytosis
Antigen processing and presentation
Pathogen killing Macrophages Dendritic cells Activity
detection of pathogens
presentation of their epitopes
to naïve T lymphocytes Activity
Phagocytosis
Antigen presentation
Production of cytokines and chemokines Alveolar macrophages
Histiocytes
Kupffer cells
Microglia Eythema toxicum
neonatorum Invasion of commensal skin bacteria into hair follicles
Intercepted by local macrophages
Production of high amounts of IL-1 and IL-6 Newborn APC Diminished
antigen presentation
phagocytic and chemotactic function
cytokine production (IL-12, IL-18, IFN-gamma)
response to stimulatory mediators (e.g. IFN-gamma)
response to pathogen-derived products (e.g. LPS) Fully functional
adhesion
undirected migration
bactericidal capacity Pattern Recognition Receptors
Toll-like receptors Fetomaternal
immunotolerance Innate immunity TLR expression
APCs
Epithelial cells (respiratory, intestinal, urogenital, vascular)
Endothelial cells Newborn TLR Reduced
TLRs mediated production of pro-inflammatory cytokines TNF-alpha, IFN-alpha, IFN-beta

Similar
APC TLRs expression as adult cells

Enhanced
production of IL-6, IL-10, IL-23 lipopolysaccharide
peptidoglycan
flagellin
atypical bacteria
fungal components
viral RNA and DNA fragments Adaptive immunity “ Cytotoxic T lymphocytes - Tc (CD8+)
lysis of virus-infected and tumor cells Regulatory T lymphocytes - Treg
balance between Tc and Th
limitation of effector responses
immunological tolerance Helper T lymphocytes - Th (CD4+)
cytokine secretion Maturation in Bursa equivalent
fetal liver, spleen, bone marrow
B lymphocytes Thymus
T lymphocytes Newborn
T lymphocytes equivalent to adult response
BCG vaccine

reduced to adult response
polio
hepatitis B
measles vaccine Adult cytokine response
IL-12: 12 months
IFN-gammaγ, TNF-αalpha:
12 to 18 months Lower incidence of GVHD Newborn
Graft Versus Host Disease Newborn
Cellular immune response to Vaccines Predominance of Th2 cytokine response
Due to low IL-12 secretion
from DC and macrophages Suppressed
Synthesis of IFN-gamma Higher levels of IL-10? Higher tolerance of graft acceptance Gradual cytotoxic response maturation
achieved at 9 to 12 months Th predominance Low Tc lymphocyte counts Newborn
B lymphocytes Reduced
activation, Ig production IgM production
adult levels at 12 to 24 months IgG production
adult levels at 4 to 6 years Maternal immunoglobulins Transplacental transfer of maternal Igs Maternal Igs, transferred by human milk Weak IgGs opsonic activity
Very low IgM concentration
Higher frequency of gram-negative infections? Important adaptation to newborn immunological immaturity Finely regulated composition
Adjusted to infant’s gestational & chronologic age and its specific needs Components of innate and adaptive immunity Human milk Immunoglobulins (IgA, IgG, IgM, IgE, IgD)
Cytokines
Complement factors
Colony Stimulating Factors
Chemotactic factors
Lactoferrin Important adaptation to
newborn deficit in humoral immunity Active immunological and antiinfective function Human milk Conclusion Reduced neutrophil and NK counts, complement and APC activity,
TLR mediated cytokine production Reduced cytotoxic response cytokine synthesis
antibody production Deficit in innate immunity Deficit in adaptive immunity Quantitative and qualitative decline of numerous immune components Full competence of
immune functions
in about one year period Cellular and molecular basis of the immunological immaturity of a newborn Conclusion Represents a risk factor for
various infections
& reduced clearance of pathogens adult 0.5 per 1000 No stimulus for
immune system Cytotoxic lymphocytes
No immunological memory Reduced number of mature NK cells
Diminished cytotoxic function Full capability of NK cells: 9 to 12 months of life Decreased granulopoiesis
Reduced G-CSF gene expression
Reduced G-CSF protein syntesis Humoral immunity Precursors of plasma cells B Lymphocytes Initiation of cellular
immunity TLR location
Cell surface
Cytoplasm
Phagosoms GBS
E. coli
CN. staphylococcus
H. influenzae
S. aureus
Klebsiella
Enterobacter
Serratia Candida Pathogen - Associated Molecular Patterns
(PAMPs) But normal cytotoxic response to viral infections. Exception: HIV and HSV expression of TCR
activation
cytokine secretion Production of immunoglobulins IgA production
adult levels in puberty Cells:
Macrophages: ~ 60 %
Neutrophils: ~ 25 %
Lymphocytes: ~ 10 % Functionally immature
immune competence
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