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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 31 October 2016

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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)
S
epsis 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
Full transcript