**3. Acquired neuroimmune responses and GAD**

Of interest to the argument that the diaeventome drives an epigenetically modifiable immune-based regulation of global physiological and pathophysiological consequence is that the ablation of NK cells prevents trophoblasts from obtaining endometrial vascularity. This results in spontaneous abortion. Whether this phenomenon is associated with controlled cell destruction or chemokine/cytokine-mediated signaling, leading to reprogramming of gene expression, is not yet clear, but it does suggest that NK cells may be necessary for in utero trophoblast invasion. Since dendritic cells play a key role in communication between the constitutive and adaptive immune response, it is of further note that loss of uterine Dendritic Cell

Stress can induce epigenetic changes to loci that control the expression of RNAi production. RNAi epigenetics involves the production of interfering RNA species and thus prevents target mRNA expression. This removal of target mRNA can have global or specific effects on

Even though chronic psychological and social stress has been implicated in anxiety disorders, the mechanism for how social defeat and worrying can be linked to genomic or epigenomic

Recently, it was reported that chronic stress in a murine model was targeting an RNASE II enzyme complex (DROSHA subunit) via differential hypomethylation at that locus. A decrease in methylation suggests there is a concomitant increase in the non-specific expression of the target gene, and in this case, it would mean an increase in RNAi-mediated epigenetic ablation

In a rat model, pro-inflammatory CNS-localized M1 type microglia are induced by cumulative unpredictable mild stress (CUMS) within the Hypothalamic Pituitary Adrenal (HPA) axis [6]. This resulted in the expression of pro-inflammatory tumor necrosis factor (TNF)-α, interferon (INF)-γ, interleukin (IL)-1β, and IL-17 cytokines while simultaneously reducing the production of the anti-inflammatory IL-4, IL-10, and IL-13 cytokines typically associated with

Macrophages are classified into inflammatory or anti-inflammatory. Inflammatory macrophages differentiate in response to microbial and tumor antigens and interferon γ by producing pro-inflammatory cytokines at the site of nascent infection and cancerous lesions while anti-inflammatory macrophages differentiate via signaling by glucocorticoids or anti-inflammatory (type II) cytokines like IL-4, IL-13, and IL-10 where they promote TH2 immunity and

The cytokines IL-4 and IL-13 drive anti-inflammatory macrophage polarization through the IL-4 receptor alpha chain (IL-4Rα), and anti-inflammatory polarization is also promoted by activation of several master regulators, including signal transducer and activator of transcription 6 (STAT6), Krüppel-like factor 4 (KLF4), and interferon regulatory factor 4 (IRF4) [7].

Diet and nutritional life style choices likely modulate macrophage polarization and, by inference, the inflammatory response associated with anxiety disorder. Bioenergetic reprogramming is associated with this mechanism wherein the inflammatory macrophage cell type is fueled by

mediate tissue remodeling, wound healing, and immune modulation [7].

gene expression including those involved in psychiatric and mood disorders [4].

(DCs) blocks decidual maturation and blastocyst implantation [3].

phenomena has been difficult to track.

16 Anxiety Disorders - From Childhood to Adulthood

the regulatory M2 microglial lineage [6].

of gene expression [5].

The serotonin transporter (HTTPLPR) has been linked to depression and GAD in human populations. The short allele of the HTTPLPR gene was associated with these neuropsychiatric disorders although whether there was a hypo- or hyper-HPA axis effect depended upon the cohort population under study including parameters age, race, and gender [12]. However, this is not necessarily ambiguous, since the downstream processing of serotonin binding to its receptor is complicated by the level of allele-specific HTTPLPR-mediated translocation, availability of serotonin, plus the receptor subtype, and ultimate release of glucocorticoid via the HPA axis [12].

There are serotonin receptors on macrophages, monocytes, and lymphocytes, and these subpopulations interact to mediate inflammatory responses leading to HPA axis activity [13].

Serotonin has been associated with a blockade of the antigenic determinate capacity of macrophages via IFN-γ, thus diminishing the suppression of NK cells and therefore enhancing their potential cytotoxic function on host cells [13].

For their part, NK cells contribute to inflammation via their frank cytotoxicity, thus releasing potential activating antigens of pathogenic origin. NK cells also establish and maintain the "cytokine storm" which lays out the persistence and maturation of the local inflammatory response [14]. Certain non-cytotoxic clones of NK cells over-express high IFN-γ while others, that are manifestly cytotoxic, produce negligible amounts of IFN-γ. A third sub-population of NKs weighs in with intermediate characteristics [14].

ubiquination, and phosphorylation of cohering histones and the processing of doublestranded RNA in the generation of siRNA are epigenetic phenomena involved in the modulation of gene expression. The mechanisms of these epigenetic phenomena have been described and they include the activities of methyltransferases, acetyltransferases, kinases, phosphatases, demethylases, deacetylases, E3 ubiquitin ligases, and RNase enzymes [16]. The substrates for these reactions are either chromatin or in the case of the RNase activities, double-stranded mRNA. S-adenosyl methionine (SAM or AdoMET) is the recognized nuclear methylation agent, deriving the methyl group from folic acid derivatives. Acetyl CoA is used in acetylation of chromatin-associated histones in the process of chromatin remodeling which generally enhances gene expression downstream from ligand/receptormediated activation of the complex which may be in association with the nuclear ubiquitin/ proteasomal pathways. Nuclear-associated posttranslational modifications (such as acetylation) of histone carboxyl termini clearly alter chromatin structure and function [16]. The major effect is a pronounced change in the physical-chemical accessibility of DNA-binding proteins to unwind the double helix and potentiate the transcription to RNA. These covalent modifications are at least conceptually reversible, but often, they can lead to a complete removal of histones from the chromatin complex, thus inducing for a time in the cell cycle, uncontrolled constitutive gene expression. Indeed, while methylation tends to dissociate histones from the chromatin complex, demethylation tends to favor non-transcribable chromatin rearrangement although this leaves open the potential for acetylation which

The Diaeventology of Anxiety Disorders http://dx.doi.org/10.5772/intechopen.82176 19

Besides the specificity of the methyltransferases and acetyl transferases on certain histone residues (typically LYS), there is also a specificity at the amino acid sequence level. To generate changes in reactivity of chromatin to remodeling, only certain covalently modified histone amino acid residues play a role. The discrete biochemistry of these epigenetic modifications are lysine methylation, acetylation and ubiquination, serine phosphorylation, and arginine methylation. All of these modifications have been observed by superimposition of the diet (see below). The point is that, these covalent modifications effect DNA accessibility to various proteins and they alter protein:protein interactions among chromatin-bound histones and

The "histone code" hypothesis asserts that covalent modification of chromatin-bound histones is communicated to a host of nuclear proteins to provide a directive for discrete chromatin molecular dynamics and gene expression control. The theory suggests that other proteins and protein complexes can distinguish and indeed interpret histone modifications. Communication of the histone code to the nuclear machinery of transcription ultimately controls gene expression or silencing, heterochromatin formation, DNA replication, and even chromosome segregation [16]. All of these mechanisms play a diaeventological role in neuropsychiatric states such as anxiety.

Most if not all of these epigenetic modifications are heritable changes in gene expression. Even though DNA sequence modification does not generally occur, there are reports where amplification of nucleotide repeats can be proximal to DNA methylation. Whether or not this is a common phenomenon in acquired epigenesis may be significant in neuropsychiatric disease. What is clear is that many developmental disorders as well as cancer, age-related illnesses,

often promotes chromatin remodeling and gene expression [16].

other polypeptides [16].

Upon signaling-based activation, NKs kill their target via direct cellular contact involving either secretory lysosomal cytotoxic perforin and granzymes or deployment of the "death receptors and ligands" such as FasL and TRAIL, which mediate target cell apoptosis [14]. This shift to NK cell plenary function can mediate effects in the HPA that could result in either attenuation or enhancement of glucocorticoid signaling that would impact GAD and Major Depressive Disorder (MDD).

While these interacting immune responses maintain a metastable inter-uterine environment, the successful development of the fetus requires a perpetual modification of the mechanism that must deliver a balance between surveillance of potential toxic stress metabolites and pathogens on one hand, and the tolerance of the developing baby on the other.

Consequently, the presence of immune cells at the implantation site is not associated with a response to the "foreign" fetus but to facilitate and protect the pregnancy. Therefore, it should be theorized that the immune system at the implantation site is not suppressed; on the contrary, it is active and functional and is carefully controlled via real-time procession of gene expression—controlled by the developmental program between mother and fetus and the epigenetic modifications that are necessary for signal response (including stress) from the entire biological system including the external environment.
