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Mechanisms underlying migraine precipitation are largely unknown. A role of the immune system in migraine precipitation is a matter of debate because of the association of atopic disorders and migraine. Recently, it was demonstrated that migraineurs benefit from eradication of a Helicobacter pylori infection, which substantiates a possible role for (sub-clinical) infections in precipitation of migraine. Since 1966, about 45 clinical investigations have reported on alterations of immune function in migraine patients, which we present in this review. Changes of serum levels of complement and immunoglobulins, histamine, cytokines and immune cells were found in some of these studies but in most cases not corroborated by others. Migraineurs suffering from comorbid atopic disorders show elevated plasma IgE levels but not patients without a type I hypersensitivity. Histamine plasma levels are chronically elevated in migraineurs, and interictally decreased lymphocyte phagocytotic function and increased plasma tumor necrosis factor alpha (TNFalpha) levels were found, and may be related to increased infection susceptibility. The cause of this increased susceptibility is unclear but most likely is a result of chronic stress, a well-known suppressor of the immune system. Stress relief enhances immune activity and triggers a burst of circulating vasoactive compounds that function as mediators of inflammation and potential precipitators of a migraine attack in vulnerable subjects. In conclusion, in the clinical literature of the past decades, there is no clear-cut evidence of an immune dysfunction in migraineurs, but we cannot totally exclude the possibility of an altered immune function in migraineurs. Discrepancies in the literature most likely are caused by the divergent patterns of sample collection relative to the time of the attack. We propose stringent definition of sample collection times for future studies of immune function in migraine patients.

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Stress has been shown to affect brain structural plasticity, promote long-term changes in multiple neurotransmitter systems and cause neuronal atrophy. However, the mechanisms involved in these stress-related neural alterations are still poorly understood. Mitogen-activated protein kinase (MAPK) cascades play a crucial role in the transduction of neurotrophic signal from the cell surface to the nucleus and are implicated in the modulation of synaptic plasticity and neuronal survival. An intriguing possibility is that stress might influence brain plasticity through its effects on selective members of such intracellular signalling cascades responsible for the transduction of neurotrophin signals. Here, we have investigated the effects of stress on the expression of three members of the MAPK/extracellular-regulated kinase (ERK) pathway such as phospho-ERK1, phospho-ERK2 and phospho-cAMP/calcium-responsive element-binding protein (CREB) in the adult rat brain. Male rats were subjected to mild footshocks and the patterns of protein expression were analysed after 21 consecutive days of stress. We found that chronic stress induced a pronounced and persistent ERK1/2 hyperphosphorylation in dendrites of the higher prefrontocortical layers (II and III) and a reduction of phospho-CREB expression in several cortical and subcortical regions. We hypothesized that defects in ERK signalling regulation combined with a reduced phospho-CREB activity may be a crucial mechanism by which sustained stress may induce atrophy of selective subpopulations of vulnerable cortical neurons and/or distal dendrites. Thus, ERK-mediated cortical abnormalities may represent a specific path by which chronic stress affects the functioning of cortical structures and causes selective neural network defects.