| The association between atopic disorders and depression: The Northern Finland 1966 Birth Cohort Study | ||
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The findings of this thesis can be explained according to the following biological and psychosocial hypotheses, which might serve as a psycho-neuro-biological link between atopic disorders and depression. In the paragraphs below, each hypothesis, theory, or suggestion will be briefly and critically reviewed.
Cytokines play a crucial role in the pathogenesis of allergic diseases (Kronfol & Remick 2000, Kelley 2001). Besides acting as chemical messengers between immune cells, cytokines can serve as mediators between the immune system and the brain (Kronfol & Remick 2000, Dantzer 2001).
In atopic states, there exists a shift from Th1 to Th2 responses originating from Th lymphocyte precursors (Prescott et al. 1998, 1999). Of the anti-inflammatory cytokines produced by Th2 cells (Kronfol & Remick 2000, Kelley 2001), IL-4 is an essential mediator of immediate hypersensitivity, favouring the production of immunoglobulin E (Abbas et al. 2000). Very recently, however, a biphasic response of the Th1/Th2 cell subsets has been noted to exist among atopic patients: An initial Th2 response with elevated levels of IL-4 is shown to be followed by a second shift toward a Th1 secretion pattern as reviewed by Buske-Kirschbaum et al. (2002). Thus, it seems that the Th cell response pattern differs during different states of atopic disorders. Indeed, it has been proposed that the chronic inflammatory response in allergic dermatitis is dominated by a Th1 response with corresponding cytokine expression (Leung 2000). Furthermore, in asthmatic patients, bronchoalveolar lavage has been shown to contain large quantities of IL-1β (da Silva et al. 2002). After antigen challenge, increased levels of IL-1β and IL-6 have also been noted in nasal secretions of allergic patients (Sim et al. 1994, 1995, Marshall et al. 2002). On the other hand, depression was also shown to be associated with excessive secretion of proinflammatory cytokines such as IL-1 and IL-6 (Maes et al. 1998, Maddock & Pariante 2001).
During an immune response, the brain and the immune system communicate with each other in order to maintain homeostasis in the body (Elenkov et al. 2000, Kronfol & Remick 2000). Two major pathways, the HPA-axis and the SNS are involved in this bidirectional interaction (Mössner & Lesch 1998, Elenkov et al. 2000).
During the allergic hypersensitivity reaction (late phase reaction), proinflammatory cytokines such as IL-1β and IL-6 are released by the IgE-mediated stimulation of tissue mast cells and basophils (Abbas et al. 2000, Hagaman et al. 2001, Hurwitz & Morgenstern 2001). In addition, e.g., IL-1β has been shown to be released by structural cells, such as epithelial cells and fibroblasts as well as by eosinophils as reviewed recently by da Silva et al. (2002). These proinflammatory cytokines are capable of activating both the SNS and the HPA axis (Elenkov et al. 2000, Hurwitz & Morgenstern 2001). The end products of this “stress system” – glucocorticoids and catecholamines – cause a selective suppression of Th1 responses and a Th2 shift by inhibiting the production of IL-12 and favouring the production of IL-10 (Elenkov & Chrousos 1999, Elenkov et al. 2000). Proinflammatory cytokines themselves can cause dysfunction of corticosteroid receptors (Maes & Smith 1998, Musselman et al. 2001, Pariante et al. 1999), which together with hypercortisolism are usually present in depression (Holsboer 2001, Murphy 1997, Pariante & Miller 2001). In addition, both IL-1β and IL-6 have the capacity to induce a syndrome of “sickness behaviour” that shares many features with major depression, including anhedonia, fatigue, anorexia, reduced activity, and altered sleep patterns (Dantzer 2001, Musselman et al. 2001). On the other hand, there is also evidence that psychosocial stress suppresses cellular immunity but boosts humoral immunity, thus causing a Th2 shift via these same stress hormones, i.e., glucocorticoids and catecholamines (Elenkov & Chrousos 1999).
5-HT is an important mediator of bidirectional interactions between the nervous and the immune systems (Mössner & Lesch 1998, Mössner et al. 2001). As reviewed by Mössner and Lesch (1998), the CNS can, via the autonomic nervous system, induce the neural release of 5-HT to the immune system. 5-HT receptors and the 5-HTT are distributed widely in immune cells and 5-HT is known to have various immunological effects.
Recent evidence indicates that central serotonergic neurotransmission is altered by cytokines released during peripheral immune responses (Dantzer 2001, Mössner & Lesch 1998, Mössner et al. 2001). Furthermore, IL-4 has been shown to have an effect on 5-HT metabolism while having different regulatory effects on different 5-HTT genotypes (Mössner et al. 2001). Since 5-HT has both an essential role in the pathophysiology of depression and also functions as an important mediator between the nervous and immune systems (Mössner & Lesch 1998, Mössner et al. 2001), and because the genetic polymorphism in the 5-HTT gene promoter has been found to be associated with depression (Lesch 2001), the findings of this thesis might be explained by an altered 5-HT metabolism in the brain due to immunological reactions in atopy.
The histamine metabolism may also be drawn upon to explain at least some of the results of this thesis. During an immediate hypersensitivity reaction histamine is released from the cytoplasmic granules of activated mast cells. As a biogenic amine, histamine is mediating a variety of biological effects (Abbas et al. 2000). Via stimulation of H2-receptors, histamine has been shown to be capable of suppressing IL-12 and stimulating IL-10 secretion (Elenkov et al. 1998), thereby causing the shift of Th1/Th2 balance toward Th2-dominance (Elenkov et al. 1999, 2000). It is also known that histamine has various physiological roles as a neurotransmitter in the brain (Ito 2000). Histamine turnover in the diencephalon has been suggested to be related to the pathology of the depressive state (Ito et al. 1999), and it is known that histamine H3 receptor antagonists have antidepressive effects (Ito 2000). Furthermore, H1 receptor antagonists – commonly called antihistamines – have immunological effects by inhibiting the immediate wheal and flare response to intradermal allergens (Abbas et al. 2000), but they also have psychological effects by decreasing the anxiety state of a person (Ito 2000).
Changes in PUFA intake or metabolism can also be linked to the findings. Because PUFAs are either precursors of eicosanoids, such as prostaglandins, or affect eicosanoid and cytokine formation, they have important effects on immune and inflammatory processes (Maes & Smith 1998, Kelley 2001). An increased ratio of omega-6 to omega-3 PUFAs may lead to an overproduction of inflammatory cytokines and eicosanoids, which are responsible for the allergic inflammation, and which are also associated with major depression (Maes & Smith 1998, Kelley 2001). Evidence has been accumulating that diminished omega-3 fatty acid intake or concentrations are associated with depressive disorders (Hibbeln 1998, Maes et al. 1999, Peet et al. 1998, Tanskanen et al. 2001a, 2001b), and persons with atopic disorders have also been noted to have low levels of omega-3 fatty acids in their plasma and red cell membranes (Duchen 2001). On the other hand, fatty acids of the omega-3 type have anti-inflammatory effects by reducing the production of inflammatory cytokines/eicosanoids, which forms the basis for their use in the management of inflammatory diseases (Kelley 2001). Correspondingly, highly purified ethyl eicosapentaenoic acid, an omega-3 fatty acid, has also been shown to be effective in improving major depression even in two randomised, placebo-controlled studies (Peet & Horrobin 2002, Nemets et al. 2002).
There are some explanations for the gender difference, i.e., the fact that in females the association between the disorders is evident independently of the severity of the depression and that among males it is only seen in the presence of the most severe manifestations. It has been suggested that atopic disorders and depression share a common genetic etiology (Wamboldt et al. 1998, 2000). Since there is evidence that in women genetic factors play a greater role in the etiology of depression than in men (Bierut et al. 1999, Kendler et al. 2001a), it could be speculated that also the pathophysiology of the atopy-depression association would arise from different origins in females and males. For example, with respect to the serotonin metabolism, Enoch et al. (2001) have recently established that the 5-HT(2A) promoter polymorphism is associated with affective disorders in women but not in men. Because IL-4 has been shown to have an effect on the 5-HT metabolism (Mössner et al. 2001), it can be hypothesized that there might be an association between immediate hypersensitivity reactions with serotonin-related mental disorders and the female gender.
On the other hand, there is evidence that subtypes of depression may differ with respect to some immune parameters (Miller et al. 1999). Thus, it could be possible that in men minor depression could have different immuno-pathophysiological roots than those of major depression, which could explain the lack of the atopy-association among less depressive men.
In addition, it is also possible that men have underreported depression and/or were unable to recognize their symptoms correctly and this could have caused a bias in our results. In this same set of birth cohort data, it has previously been possible to show that the prevalence of alexithymia was higher in men (9.4%) than in women (5.2%) (Kokkonen et al. 2001). Further, since alcohol abuse and violent behaviour, for example, can be signs of psychosocial distress in men (Epperly & Moore 2000), it can be postulated that “masked depression” might be a manifestation of minor depression in predominantly men rather than in women.
Based on the findings of the original publication IV, it could be assumed that regarding heritability, it is specifically the maternal link, which is stronger than the paternal one. If true that atopic disorders and depression share a common genetic etiology (Wamboldt et al. 2000), the characteristic mode of inheritance for these disorders could be a gender-related pattern of inheritance, i.e., “parent-of-origin” effect. McMahon et al. (1995) first proposed that this “parent-of-origin” effect might involve mitochondrial inheritance. On the basis of recent genetic studies, Kato (2001) suggested that maternal inheritance could be one possible etiological factor in bipolar disorders via an association with mitochondrial DNA mutations. Since mitochondrial DNA mutations have also been found in persons with atopic and other skin-disorders (Karvonen et al. 1999), it could be hypothesised that mitochondrial DNA could have a role in the pathophysiology of unipolar depression as well. There exist also other possible explanatory genetic mechanisms for the “parent-of origin” effect, such as the phenomenon of genomic imprinting (Davies et al. 2001, Strauch et al. 2001).
Psychosocial explanations are also possible. The roots of atopic disorders exist already during pregnancy and in the first years of a person’s life (Björksten 1999). On the other hand, childhood psychosocial experiences (Veijola et al. 1998) together with genetic vulnerabilities (Kendler et al. 2001a) have been reported to be more highly predisposing factors to depression in women than in men. Psychosocial factors can have an effect on biochemical and metabolic functions, as well as on the immune system, due to the complex interactions between body and mind. Severe stress early in life can, for example, result in long-term alterations of the function of the HPA-axis (Heim et al. 2001). It could therefore be speculated that women may be more sensitive to changes in their body due to the symptoms of atopic disorders, which could at least partly explain the findings about the gender differences in this thesis.
For example, with regard to atopic dermatitis, psychosocial stress and skin condition appear to be bidirectionally related. Stressful situations are often accompanied by an exacerbation of symptoms of atopic dermatitis; however, worsening of skin condition may also lower the stress threshold as reviewed by Buske-Kirschbaum et al. (2001). Consequently, a vicious cycle of emotional stress and skin condition can be initiated (Buske-Kirschbaum et al. 2001). It has also been shown that preceding or concomitant stressful life-events may promote the manifestation of asthma and allergic rhino-conjunctivitis (Kilpeläinen et al. 2002).
There exist a growing body of evidence on stress-induced alterations in immune-mediated diseases and in the immune function (Olff 1999, Kilpeläinen et al. 2002). However, there seems to be considerable individual variability in the immune response to stress. Once the stressor has been perceived, interpreted and evaluated, the subsequent emotional and behavioural response is determined by the subject’s specific defense and coping strategies. Prolonged exposure to stressors may outweigh the person’s coping resources, ultimately leading to depression (Olff 1999). On the other hand, inadequate coping skills described in patients suffering from atopic disorders (Scheich et al. 1993), can make atopic patients liable to be stressed by the various normative life-cycle events and other stressful situations they have to face (Buske-Kirschbaum et al. 2001).