Cytokines, natural molecules that facilitate communication within the immune system and facilitate immune reactions, have been known to cause mood symptoms in humans. Some studies suggest that cytokines may be the intermediate step linking allergy and suicidal behaviors (see What Accounts for Link Between Allergy and Suicide?).

The nose and prefrontal cortex are not only physically close in proximity, but also intimately connected. Although most outside molecules are kept out of the brain by the blood-brain barrier, the nasal mucosa is connected with the brain through nerves and vascular pathways. For example, large molecules such as oxytocin and insulin have been shown to pass through the blood-brain barrier and enter the brain through intranasal administration in clinical trials. It is conceivable, Teodor Postolache, M.D., said, that either the increased cytokines in the nose of a patient with allergy enter the brain directly or the allergy triggers the expression of cytokines by glial cells and neurons in the brain. The increased cytokines in certain brain regions in turn may affect the functions involved in mood and behavioral regulation.

Postolache and colleagues published a study in the March Acta Psychiatrica Scandinavica showing that the RNA expression of cytokines released by the type 2 T-helper lymphocytes, such as interleukins 4 and 13, was significantly higher in the orbitofrontal cortex in victims of suicide compared with controls who died primarily of cardiac events. The type 2 cytokines have a significant role in initiating and perpetuating allergic reactions.

However, "are we simply observing nonspecific sickness behavior induced by cytokines, rather than affective and behavioral effects?" Postolache wondered. His answer is that it's "unlikely." He pointed to a study by Abraham Reichenberg, Ph.D., and colleagues published in the May 2001 Archives of General Psychiatry, which showed that a small dose of endotoxin injected into healthy volunteers induced a transient lower mood, increased anxiety, and cognitive-function impairment. The endotoxin dose injected was minimal, so that the volunteers felt no physical sickness symptoms but had signs of an immune response. Although the cytokines triggered by endotoxin are generally of type 1 T-helper lymphocytes, the study suggested a possible cause-and-effect link between immune factors and mood.▪