//Background//---
Early life from gestational-age/neonatal to pediatric stage
experiences significant physiological development and change, both neurological
and non-neurological cells/tissues/organs. In the immune system, the period
from 1 to 20 years old is transient(2). Therefore, the longitudinal
understanding of immune system in both a neonate and a child in line with their
development is crucial. In these immune developments, not
congenital(heritable), but epigenetic regulation of immune response is
included. Furthermore, the environmental factor like lifestyle, significantly
affects this epigenetic immune responses related to the pathogenesis of a wide
variety diseases.
Jennifer
Bermick & Matthew Schaller review epigenetic regulation of pediatric and
neonatal immune response longitudinally(1). I hope to share a small part of
these contents with the global important readers.
//Epigenetics definition(1)//---
*There are at least three components in
epigenetics as following.
1: DNA methylation:
DNA
methylation involves methylation (decoration) of 5-methlylcytosine, which are
located in CpG dinucleotides(3). This regulates transcriptional state
(expression switch).
2: Histone tail modification:
Histone
tail modification alters conformation(steric structure) of the proteins, which
alters DNA accessibility into nucleus. DNA wraps around histones, so histone
modification makes DNA mobility in the chromatin structure change.
3: MicroRNA:
MicroRNA are small non-cording RNAs (not
production of designed proteins by itself) from 19 to 25 nucleotides(4). This
microRNA binds to its specific mRNA in the post-transcriptional manner, in
which the mRNA expression is altered in a both enhanced and attenuated
way(5,6).
//Special brief note//---
*When we consider about immune health of
premature neonates, it is important to differentiate umbilical cord blood from
normal blood. Umbilical cord blood has the distinctive feature in placenta
transport. For example, it is rich in blood stem cells, therefore, this cell is
utilized to cancers, immune deficiencies and genetic disorder.
*Generally, the degree of DNA methylation
in whole blood is prone to decrease as age advances((1) See Fig.3).
*Immune responses and infection risk differ
across the developmental stage (lifespan). Neonates and infants have
distinctive inflammatory responses and an increase risk of invasive bacterial
infection compared to older children and adult(15). Therefore, vaccine program
in each nation and its compliance are crucial for health of neonates and
infants.
//Premature neonates//---
In
perinatology, health and medical care of premature birth and the premature
neonate are one of crucial issues. In such region, immunity on premature
neonates is considered(1). We need to scrutinize the hallmarks of immune
function including the epigenetic status in umbilical cord blood cells which
corresponds well to gestational age, that is, the life period in placenta. The
immune cells in umbilical cord blood cells have distinctive methylated sites
such as T cells, monocytes, granulocytes, that induces fetal development and
immune response(7-14). Therefore, the physiological effects by DNA methylation
from gestational-age to premature neonate persist during early childhood, but
at least a part of this alteration is resolved by adolescence(8,11,12). During
this lifespan, umbilical cord blood cell tends to be hypermethylated compared
to peripheral blood from infants, children and adolescent(8,16-19),
subsequently demethylated as age advances(19). On the other hand, histone tail
modification and mRNA alteration has not yet well-known.
#: DNA methylation
*DNA methylation states may affect
gestational period. Low birth weight term neonates have differential umbilical
cord blood DNA methylation compared to normal birth weight term neonates(20).
#: MicroRNA
*MicroRNA of neonatal mononuclear cells (T
cells, monocytes etc.) are downregulated in neonatal mononuclear cells as
following genes.
(let-7e-5p, miR-19a-3p, miR-200a,
miR-142-5p, miR-146a-5p, let-7c-5p, miR-301a-3p,and let-7d-5p)(21).
#: Histone modification
*Over the first 6 weeks of life in neonatal
mononuclear cells, H3K4me3 histone modification and H3K9me3 repressive histone
modification at the pro-inflammatory cytokine (IL1B, IL6, TNF) inducing site
are activated(22). Therefore, immune activation of T cells, monocytes,
dendritic cells, NK cells is prone to be emerged through virus infection.
//Prenatal risk factors(1)//---
(Tobacco)
*Maternal smoking during pregnancy is
associated with low birth weight infants, childhood adiposity, neuropsychiatric
disorders, persistent wheezing/asthma in her child(23-25). Differential DNA
methylation(#following genes) in neonatal umbilical cord blood was
found(26-30).
#Hypomethylation: AHRR, GFl1, *CNTNAP2
/Hypermethylation: *MYO1G, CYP1A1
*MYO1G: Hematopoiesis, *CNTNAP2: Nervous
system development(31-33)
(Heavy metals)
Mercury and arsenic in utero exposure are
known as developmental toxicants which is associated with poor cognitive
development in their child(34-36). Methylated site map shows the involvement in
antigen processing and presentation, TGF-beta signaling, leukocyte migration
and NK cell cytotoxicity (associated with auto-immune response)(37).
(Organic compounds)
Per-
and polyfluoroalkyl substances in utero exposure is related to altered vaccine
response, lipid profile, increased adiposity in offspring(38,39). This material
is defined as use limitation subject in EU (27/June/2008: PFOS restriction).
Other risk material is Polybrominated diphenyl ether (PBDE).
(Air pollution)
Air
pollution(Surrogate makers: NOx) is associated with persistent asthma(40).
Affected genes are CAT and TPO in umbilical cord blood(41). Maternal exposure
to traffic-derived air pollutant polycyclic aromatic hydrocarbon during pregnancy
leads to methylation of offspring mononuclear immune cell and developed asthma
symptom prior to age 5(42,43). Affected genes is IFNG and ACSL3.
(Obesity)
The
maternal pre-pregnancy obesity (defined as BMI>30) is associated with
abnormal umbilical cord blood immune cell DNA methylation(52-54). The
differential methylation in the offspring persists at least until age 3(55).
This DNA methylation contributes to maternal obesity-related neonatal monocyte
hypo-responsiveness(56).
(Infection)
#: HIV
Human
immunodeficiency virus (HIV) has persistent effects on long-term health
outcomes including cognitive deficits, metabolic abnormalities, renal
complications, even when antiretroviral therapy is started early(57-59).
Peripheral blood from 4-9 years old children with perinatally acquired HIV have
differential DNA methylation compared to uninfected control groups(60).
#: Zika virus
Congenital Zika virus infection is associated
with severe microcephaly and poor neurocognitive outcomes(61). Affected DNA in
offspring is following#. Zika virus is spreading in some low latitude
countries. Therefore, when we go to these countries, we need to avoid the
infection especially in the persons assuming birthing. The clinical trial of
Zika virus vaccine, such as DNA vaccine, attenuated/inactivated vaccine, mRNA
vaccine, is underway.
#Hypomethylation of RABGAP1L, MX1 and ISG15(62)
//Maternal nutrition (tends to be lack)//---
(Vitamin D)
Vitamin D deficiency in pregnant mother is associated with increased
serum DNA methyltransferase activity, increased methylation of the IFNG locus
and decreased IFN-gamma expression(44). Therefore, controlling ability of
lymphocytes(T cells, B cells, NK cells etc.) decreases.
(Folate)
Sufficient folate levels are necessary for DNA methylation to
occur(45). In mouse model (#not human model), folate supplementation during
pregnancy shows decreased methylation of the PPARA locus, and affect the immune
function of CD4+T cells, myeloid cells, allergic response in her neonate(46,47).
PPAR locus is associated with diabetes, arteriosclerosis, bone metabolism,
cancer and immune inflammation.
(Fatty acids.)
The
child born to mothers with high fatty fish intake during pregnancy (rick in
omega-3-polyunsaturated fatty acids) have a decreased risk of developing
allergic diseases during childhood(48,49). This influences DNA methylation(50).
According to epigenetic trait, Th1 phenotype may be dominant, which may
associated with allergy risk(51). However, the relation of allergy and Th1/Th2
balance in CD4 Tcell is controversial.
//Discussion//---
Immuno-sensitivity such as virus infection, food,
drink and air molecules may be partly associated with epigenetic status of
(immature) immune cells. For example, DNA methylation is an important indicator
of gene-environmental interaction in food allergy(63). In mononuclear immune
cell, immune activation of T cells, monocytes, dendritic cells, NK cells is
prone to be emerged through extrinsic factors due to epigenetic decoration
against these immune cells. Therefore, step by step or/and little by little dietary
uptake the food of which tends to become allergy may be recommended in the
pediatric period. On the other hand, for immune stability and immune
compensation/help, breastfeeding is crucial. Especially, the smaller the
children are, the more careful we need to be against their immune dysfunction.
//Contributions(1)//---
Drafting the article or revising it
critically for important intellectual content: J.B., M.S. Final approval of the
version to be published: J.B., M.S.
(Reference)
(1)
Jennifer Bermick & Matthew Schaller
Epigenetic regulation of pediatric and
neonatal immune responses
Pediatric Research (2021)
---
Author information
Affiliations
Department of Pediatrics, Division of
Neonatology, University of Iowa, Iowa City, IA, USA
Jennifer Bermick
Iowa Inflammation Program, University of
Iowa, Iowa City, IA, USA
Jennifer Bermick
Department of Pulmonary, Critical Care
& Sleep Medicine, University of Florida, Gainesville, FL, USA
Matthew Schaller
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