Key message
Epigenetic combined with genetic background of immune-related genetic
loci, mainly HLA-G promoter region and CpG41 island ofHLA-DRB1 highlighted their potential to FA appearance.HLA-G hypomethylation and consequent generation of HLA-G
positive/FOXP3 negative Tregs emerge as an immediate modulator of the
immune cells’ phenotype urging an early desensitization process. Also,
rs1233333 residing withinHLA-G gene’s promoter
region, shows significant results in safeguarding the area from DNA
methylation spreading. Methylation levels of HLA-DRB1 CpG island
41 and co-occurrence of SNPs pronounce their cooperation and their
modulatory role towards FA development. Finally, aberrant background
methylation patterns at HLA-G gene’s promoter region andFOXP3 TSDR are attributed to parents’ smoking habit.
Introduction
IgE-mediated food allergy (FA) development during childhood appears as a
complex disorder, implicating immune dysfunction and influenced by
genetic variants, epigenetic modifications, parental habits and
environmental contributors or combinations thereof1-5. Among factors
mediating gene-environment interactions is the epigenetic remodelling of
genome, a critical mechanism for immune system adaptation to
environmental exposures6.
FOXP3-expressing Tregs hold a leading role in the immune system
homeostasis and effectively protect against allergies7. High levels ofFOXP3 methylation inhibiting gene’s expression, have been
attributed to extensive exposure to air pollutants, an effect pronounced
in asthmatic compared to non-asthmatic children8.
Other immune related genes, encompassed in the major histocompatibility
complex (MHC) system, modulate adaptive immune responses. The human
leukocyte antigen-G (HLA-G ) is a MHC class I gene, epigenetically
regulated by methylation9 and has been
recognized as an important mediator of immune tolerance at the
fetal–maternal interface of human placenta10,11.
In healthy adults, thymus generates a proportion of 1-3%
HLA-G-positive/FOXP3-negative CD4+ and
CD8+ T-cells,12 with regulatory
properties (Tregs) 1314 and increased
frequency at sites of inflammation.
MHC class II cluster includes HLA-DQ and HLA -DRgenes, whose expression is limited to the professional
antigen-presenting cells. Cell-processed antigens’ presentation by MHC
class II to CD4+ T lymphocytes, stimulates the
antigen-specific hypersensitivity type I allergic reaction. GWAS studies
and review analysis have provided convincing evidence that HLA-DRand HLA-DQ genes’ polymorphic regions harbor significant genetic
and epigenetic risk for FA15,16.
The present study aimed to accomplish deeper insights for the
genetic/epigenetic and environmental associations influencing the
predisposition to FA development.
Methods