Basis of Neonatal Immunity Flashcards
What is the major cause of death in under 5s
Infection
Malnutrition is underlying cotributor to these deaths
What are the major pathogens that causes infection in young children (?that cause death)
Respiratory
- Repiratory Syncytial Virus (RSV)
- Bordetella pertussis
- Streptococcus pneumoniae
- Haemohpiul Influenzae B
Other
- Measles Virus
- Rotavirus
- Malaria
- HIV
What is the most common type of URTI? What are the agents that usually cause these
Common cold
- Rhinovirus (all year)
- Influenzae (epidemics)
- RSV (epidemics)
75% viral, 25% bacterial
RSV is a negative sense _____-stranded RNA virus. It causes severe airway inflammation in the very young (_____) and the elderly. RSV infection in early life is associated with the development of _____. It reinfects throughout life as we have poor immunological _____ to natural infection. Monoclonal antibody therapy is available but is _____. There is no effective vaccine against RSV
RSV is a negative sense single-stranded RNA virus. It causes severe airway inflammation in the very young (bronchiolitis) and the elderly. RSV infection in early life is associated with the development of asthma. It reinfects throughout life as we have poor immunological memory to natural infection. Monoclonal antibody therapy is available but is expensive. There is no effective vaccine against RSV
What immune cell bias do neonates have
Th2 and Th17
Why are RSV (respiratory) infections important to study
- Children get more viral infections more frequently
- They get infected with higher viral loads
- Very severe in the very young - lots of hospitalisations
- Are Vectors of disease
- Early infection association with respiratory health development (asthma and allergies)
Neonates have a Th2 and Th17 bias. How is this advantageous?
- Foetus an allograft of mother and ∴risk of rejection
- Neonate goes from sterile to microbe-rich environment
- Allows for development of tolerance
- Otherwise may lead to harmful reactions
- Bias regulates immune response (i.e. away from Th1 inflammation) - anti-inflammatory
- Dangerous to developing lung tissue
- Neonate goes from sterile to microbe-rich environment
How is neonatal immunology studied
- Murine Models
- One week old pups considered similar to neonates
- Human Studies
- Ehtically difficult
- Carried out on cord blood
When studying cord blood, what implications does this give rise to and how is it approached?
- Implication
- Cord blood is mix of neonate and maternal blood
- Approach
- Compare to adult PBMCs
Describe the role of alveolar macrophage in the first breath of a baby
First breath causes mechanical damage to epithelial cells in alveoli
release of IL-33 (alarmin)
Acts on ST2 receptor on ILC2
ILC2 rleases IL-13 which favours M2-activated macrophage (homeostatic/repair)
But also means there is decreased anti-bacterial responses
Saluzzo S et al Cell ReP 2017
How are neonatal dendritic cells different to adult dendritic cells
- Low numbers
- Low IL-12
- Poor TLR response
- Similar response to adult DC if inflammatory signal is strong (i.e. IFN-g and LPS)
- Poor APC function
- Goriely et al J Immunol 2001*
- Ruckwardt T J et al Mucosal Immunol 2018*
What is causing the poor response and maturation of neonatal DC cells
IL-12p35 deficiency
How are Neonatal CD8+ T cells different to adult CD8+ cells
- Less acttivity - more reliant on innate iimmunity
- Homeostatic proliferation
- Different transcription factors
T cell responses are different in neonates. Under what circumstances can neonates produce adult-like responses
Dose
- Leukamia Virus Infection
- High dose = Th2 cell response
- Poor CTL response
- No protection from disease
- Low dose = Th1 response
- Adult-like response
- Mature Th1
- Protective CTL response
- High dose = Th2 cell response
Adjuvant
- Immunisation with antigen
- Antigen in IFA = Th2 adult-response
- Antigen in CFA = Th1 adult response
CFA = Complete Freund’s Adjuvant (has heat-killed mycobacerial components) IFA does not
Is the defect in T cell response at the level of the environment or the cells themselves
Environment
- Neonatal T cell able to resolve P. carinii infection when transferred into adults
- Neonatal T cells can not resolve infection in neonatal environment
T cells
- T cells are Th1 deficient even in adults when transferred
- IFN-γ promoter methylated differently in neonatal T cells
Compare the features and function of CD8+ T cells in neonates and adults
- ↓Cytotoxic
- ↓TCR signalling
- ↑Cell cycle gene expression
- ↑Anti-microbial peptide
- ↑ROS
Compare the neonatal antibody response to adult antibody response
- Delayed and weaker IgG response
- Poor Affinity maturation
- Rapid decline of Ab production
- Has preferntial memory cell production but short-lived
- Lower responses to polysaccharides
Many commonly used vaccines are ineffective or poorly effective if administered at birth. They do not protect and they generate weak, short-lived or inappropriate immune response. What are three maternal mechanisms as to why this happens?
- Neutralisation of vaccine
- Dependent on maternal/neonatal Ab ratio
- MatAb binds to immunogenic epitopes
- Masks immunogenic epitopes so neonatal T/B cells either don’t react or respond to non-immunogenic epitopes
- MatAB forms complexes with Ag
- Processed by APC
- Presented to non-functioning T cells
- No response
What is the window of susceptibility
Time period where the maternal antibodies are not sufficient (in numbers) to induce an immune response and when the baby is not yet making antibodies
3-12 months
What could be a possible mechanism for the tolerogenic effects of breast milk
Allergen and TGF-B from breastmilk activates CD4+ cells to differentiate into Treg cells
Regulates tolerance to that allergen
