**1. Introduction**

246 Biomarker

Yu, Z., Westerlund, D. and Boos, K.S. (1997). Determination of methotrexate and its

metabolite 7-hydroxymethotrexate by direct injection of human plasma into a column-switching liquid chromatographic system using post-column photochemical reaction with fluorimetric detection. *J. Chromatogr. B*, 689, 379-386

> In the modern society, the issues on mental health have always been pressing and global problem, and unfortunately it remains today unsolved. It does not apply only to a personal matter, but also having a huge impact on economics as it has estimated a decade ago of that the social cost concerning mental health problem in European Union was 3 to 4% of GNP (Gabriel, 2000). However generally speaking, the mental stress is quite difficult to be aware of personally. It is hard for anyone to manage mental stress by on his/her own. Therefore it is an urgent task to figure out a "practical" methodology to evaluate, manage and control the mental stresses.

> On the other hand, recent developments of the molecular analysis techniques has been revealed that particular hormones and immune substances secreted within human body change its level in responding to human mental state. For an instance, salivary Immunoglobulin-A shows a transient increase against short-term psychological stressors such as mental arithmetic task, stroop task, academic presentation (Valdimarsdottir, 1994). "All illnesses come from the mind" is no longer a folk story. These particular hormones and immune substances can potentially be a practical biomarker for human mental stress. Number of hormones and other substances in our body has been studied as a possible stress biomarker (Izawa, 2004; Wakida, 2004), and the number of academic research has been increasing as well, as shown in Figure 1. Currently it forms an interdisciplinary research field called psychoneuroendocrinology (PNE) and/or psychoneuroimmunology (PNI) (Ader, 2001) (hereafter, we use the term psychoneuroendocrine-immunology (PNEI) to indicate both PNE and PNI).

> PNEI must be a contributory research field which should possibly establish "practical" criteria for objectively evaluating human mental state. However it is a relatively new field of study still developing, there are a lot of stuffs to be investigated, e.g. the precise stress response of these biomarkers in the time series, the sensitivity of the response against other than acute stressors, physiological mechanism dynamically regulating the release of these biomarkers in responding to stress.

> In this chapter, PNEI research of its background, method, experiments, and mathematical modelling approach are introduced.

Salivary Hormones, Immunes and Other Secretory Substances as Possible Stress Biomarker 249

Serum Saliva Urine Sweat

Breast milk

**2.1 Salivary Immunoglobulin A (IgA)** 

caries or periodontitis (Gregory, 1992).

Fig. 2. Stress reaction physiological pathways: HPA and SAM system

An antibody, Immunoglobulin A (IgA), is one of the most important substances in human immune system (Tsujita, 1999). It is present in almost all human secretory fluids, such as saliva, serum, urine, breast milk etc. IgA works non-specifically and therefore plays a very important role on our health, e.g. preventing bacteria from forming colonies, neutralizing toxins and enzymes produced by bacteria, and inhibiting pathogenic viruses from penetrating into the epithelial cell. Especially the salivary IgA called as "the first line of defense" since it functions in the mouse to prevent from contracting influenza or other respiratory tract infection (URTI) illnesses. In fact, clinical studies have suggested the negative correlation between the level of salivary IgA and the incidence of an acute URTI (Jemmott III, 1989). It was also reported the relevance between the level of salivary IgA and

On the other hand, it has been reported that salivary IgA changes its level in response to various psychological factors (Bosh, 2002), such as desirable or undesirable daily events (Stone, 1994), daily hassles (Martin, 1988), negative or positive moods (Martin, 1993), academic stresses such as examination (Jemmott III, 1983) and presentation (Evans, 1994), a short-term stressful cognitive task (Jemmott III, 1989), and relaxation (Green, 1987; Knight, 2001). These stress responses of IgA can be classified into two types: 1) a transient increase of IgA secretion immediately after an exposure of short-term laboratory stressor and subsequent recovering to the basal lever after the removal of the stressor, and 2) decline of basal IgA level several days after or during a long-term stressful situation or under chronic stress. The transient increase of IgA is considered to be regulated by autonomous nervous system (Valdimarsdottir, 1997). Thus it can be taken as a biomarker for SAM system activitiy. The decline of basal IgA level over longer period of time, by contrast, is considered to indicate chronic wear and tear of production capability. Thus it is assumed to represents

**Hypothalamus Cerebral Cortex**

Stressor

**Autonomic Nuclei**

HPA

SAM

**Pituitary**

**Adrenal Cortex Adrenal Medulla**

Fig. 1. Number of salivary biomarker researches: Retrieved by "PubMed" with queries "saliva", "stress" and "X (one of each substance)"
