Maternal signals for progeny prevention against allergy and asthma

Abstract

Allergy and asthma are chronic inflammatory diseases which result from complex gene-environment interactions. Recent evidence indicates the importance of prenatal and postnatal developmental processes in terms of maturation of balanced immune responses. According to the current view, gene-environment interactions during a restricted time frame are responsible for programming of the immune system in favor of allergic immune mechanisms later in life. The interaction between genes and environment is complex and only partially understood; however, heritable epigenetic modifications including chemical additions in and alternative packaging of the DNA have been shown to play a crucial role in this context. Novel data indicate that epigenetic mechanisms contribute to the development of T-helper cell function. Environmental factors, including diesel exhaust particles (DEP), vitamins and tobacco smoke, operate through such mechanisms. Furthermore, the role of environmental microbes provides another and maybe even more important group of exogenous exposures which operates in this critical time frame.

Fig. 1

DNA methylation and histone modification during transcriptional processes. Methylation of CpG islands at promoter regions of target genes by DNA methyltransferases (DNMT) may contribute to gene silencing. Methylation of H3 residues at lysine 8 and 27 reduce the accessibility of the respective DNA segment, while methylation of lysine 4 at the same residue or acetylation of the H4 residue at lysine 4 increases the accessibility of the DNA

Fig. 2

Crosstalk between dendritic and T helper cells as a result of TLR activation by microbial stimuli. Dendritic cells are at frontline to different environmental exposures. TLR represent sensors for microorganisms and microbial components: TLR 1/6 and TLR 1/2 complexes are pattern recognition receptors for Gram-positive bacteria such as mycobacteria or lactic acid bacteria; TLR4 recognizes LPS from gram-negative bacteria, TLR5 serves as receptors for flagellin, the main protein in bacterial flagella; TLR3, 7 and 9 are endosome associated TLRs that detect foreign DNA: double-stranded (ds)DNA from bacteria and virus is recognized by TLR3 and 9, TLR9 is able to detect CpG domains in dsDNA while TLR7 detects bacterial and virus single-stranded (ss)DNA. TLR signaling results in a cytosolic cascade for transcription factors such as TNF-α. In parallel, antigen presentation via MHC II complexes (green–orange) and notch signaling (yellow) primes naïve Th-cells towards a Th1 or T-reg direction. T-regs moderate Th1 cell development and suppress generation of Th2 cells via TGF-β and IL-10 production. Inhibition of Th1 development is supported by release of IFNγ by Th1 cells

Fig. 3

Epigenetic pathways in fetal immune modulation—a model of prenatal modulation of the fetal immune system by exogenous maternal exposures. Exogenous exposures incorporated by the mother during pregnancy might activate the innate immune system. Thereby, maternal signals may be transferred through the feto–maternal interface. A long-lasting and early stimulus mediated by the mother may result in epigenetic changes that influence T cell lineage commitment in the progeny. The nature of the maternal exposure directs the developing fetal adaptive immune system to an allergy-favoring direction (Th2) or towards tolerance and protection against allergies (Th1/T-regulatory dominated)