The neonatal period represents a critical time period in the development of the
immune system. Adaptive human immune responses are generally viewed as
immature at birth. However little is known about innate immune capacity at birth.
The TLR system plays an integral role as pattern recognition receptors in the
innate immune response. It is also critical in initiating and regulating the adaptive
immune response. Preterm birth is associated with increased risk of developing
infections in early life and has been associated with increased risk of development
of other chronic disorders in later life; however the underlying mechanisms are
not at all well understood. Recently, late preterm neonates (34-36 weeks gestation
vs full term, 37+ weeks) have been identified as having significantly greater risks
of morbidity and mortality in the perinatal period than their full term counterparts.
Hence, we focus on examination of TLR responses in late preterm and full term
neonates to better understand immune potential and function in these populations.
We examined cord blood cytokine and chemokine responses following
stimulation with a broad range of TLR agonists. Our results show for the first
time that late preterm neonates have reduced capacity to produce both pro- and
anti-inflammatory cytokines following stimulation with a panel of TLR agonists.
This reduced responsiveness was not due to a reduction in the number of
responding cells, but instead appears to be mediated by a reduction in the intrinsic
levels of expression of TLRs and associated adaptor proteins.
Because little is known about how the innate immune system develops
throughout life, we next compared TLR responses in full term neonates to
7 children, adolescents and adults. We found that neonates had selective
impairments in TLR responses, most notably in anti-inflammatory cytokine
production and anti-viral immune responses compared to the other age groups.
Epigenetic modifications, such as the addition or removal of acetyl groups
to histone proteins by histone acetyl transferase (HAT) and histone deactylase
(HDAC) respectively, are able to modify the expression of genes. Hence,
environmental stimuli have been shown to influence gene expression in part by
modifying the level or activity of these epigenetic regulators. Currently there are
no studies which have examined how epigenetic modifications may influence
neonatal innate immune responses. Hence, we sought to determine how
modulation of endogenous HDAC activity would affect neonatal innate immune
responses. We found that inhibition of HDAC had both inhibitory and enhancing
effects on cytokine expression depending on the TLR pathway activated,
indicating that the endogenous HDAC expression does not have a global
inhibitory impact on all TLR-dependent responses.
In summary, this body of work demonstrates that neonatal innate immune
responses vary depending on gestational age, indicating that the final few weeks
of gestation are crucial for maturation of responses to both bacteria and viruses.
Neonates respond differently to TLR stimuli than do older individuals, further
highlighting a maturation process of the innate immune system which continues
throughout life. Finally, we have shown that environmental exposures may have
powerful effects on immune responses in early life.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:MWU.1993/3189 |
| Date | 03 September 2009 |
| Creators | Macpherson, Stephanie |
| Contributors | Dr. Kent T HayGlass (Immunology), Dr. Ganesh Srinivasan (Pediatrics) Dr. Oleg Krokhin (Physics) Dr. John Wilkins (Immunology) |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | en_US |
| Detected Language | English |
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