The immune system can recognize, assimilate or reject self and non-self components. Indeed, immunological activities vary in a spectrum that goes from total tolerance (assimilation of self and non-self) to intolerance (rejection of self and non-self). Immunologists are aware of the power of immunologic rejection of histo-incompatible transplanted organs or tissues as well as the mother`s tolerance towards fetal alloantigens. In the same vein, the host responses to virus, bacteria, fungi, and helminthes can vary from tolerance, partial tolerance[1, 2] to extreme intolerance that might be deleterious to the host, exemplified by the septic shock syndrome .
Infection is one of the primary stimuli for bidirectional interaction of the immune system and central nervous system [4, 5]. Upon infection, cells of the immune system release type 1 pro-inflammatory cytokines such as interleukin (IL)-1, tumor necrosis factor (TNF) and IL-6 that are endogenous pyrogens, triggering the febrile response via hypothalamus . Febrile temperatures attenuate IL-1 production and favor type 2 cytokines that counterbalance pro-inflammatory cytokines . Notably, the neural response to infection involves a complex network of interactions between neurotransmitters, cytokines and endocrine hormones that, in turn, might down and up-modulate diverse immune activities .
The same scenario can be found in autoimmune diseases where the targets of the immune system are self-components. In infectious diseases or autoimmune disorders CD4+ T helper 1 (Th1) or Th17 cells trigger the release of a variety of inflammatory mediators, mainly cytokines that are responsible for adaptive behavioral changes in humans and animals referred as sickness behavior. The symptoms such as fatigue and malaise, loss of appetitive, anxiety, sleepiness, hyperalgesia in conjunction with the febrile response and neuroendocrine changes represent an archetypal response of the organism to infection . These archetypical neuroimmunoendocrine responses to infection, that ultimately aid the organism to cope with the insulting stimuli has been extensively studied [7, 8].
In contrast to Th1/Th17 dominated responses, CD4+ Th2 cells orchestrate another well-characterized and highly coordinated immune response. Th2 or type 2 immunity is usually induced by helminthes, insect bites and environmental irritants or allergens . It has been suggested that reciprocal co-evolution between vertebrate immune system and helminthic infections have shaped the characteristics of both . In general, type 2 immunity aids the organism to cope with parasite worms by inducing diverse immune-mediated mechanisms such as mucus production, increased peristalsis, bronchoconstriction, eosinophilic inflammation and IgE-mediated release of pleiotropic inflammatory mediators from mast cells and basophils . Much of these responses are influenced by neuronal mechanisms.
Several studies have evidenced the influence of atopic disorders on mental health, such as higher prevalence of anxiety and/or depression in allergic patients[10, 11] and even an association between asthma and suicide-related behavior [12, 13]. Nevertheless, other studies have failed to find these associations [14, 15] arguing that the diagnosis of psychological symptoms may undergo biased interpretation . The lack of scientific evidence for the direct effect of allergy on nervous system used to be the main argument against allergy-induced psychological symptoms.
Indeed, some drawbacks limit important advances in neuroimmune studies with humans, such as challenge on achieving a precise allergy diagnosis, implication of putatively unrelated psychological factors, psychosomatic aspects of the disease, ethical issues involved in submitting allergic patients to experimental contact with the allergen, and others. Here we review recent work on the interaction of immune and central nervous systems observed during allergic reactions, showing clear evidences on the direct influence of allergy on behavior and neural activity.
Allergy elicits in the organism, via the central nervous system (CNS), a state that induces rejection of allergens when present in the food or in the air and is referred to as avoidance behavior [1, 16]. The pioneering work of the Nelson Vaz group published the first evidence of behavioral changes as a consequence of allergic reactions, showing that ovalbumin (OVA)-allergic mice avoided drinking an otherwise preferred artificially sweetened solution containing OVA . This aversion is specific, since peanut- or cashew nut-sensitized mice, when offered with a mixture of the grains in natura avoided only the grains containing the allergen they were sensitized to . Figure 1 shows a free interpretation of Vaz group main findings.
Figure 1. Illustration of the specificity of food avoidance behavior (Drawing by Katia Haipek).
In addition, avoidance behavior was observed in an experimental model of allergic lung disease. OVA-sensitized mice, different from control animals, avoided entering an environment that had been previously nebulized with OVA . Consistent with the expression of avoidance behavior, allergic mice also exhibited an increased level of anxiety upon exposure to the allergen . By evaluating the c-fos expression in the brain, the neural areas found activated after nasal or oral contact with the allergen were the nucleus paraventricular nucleus of the hypothalamus (PVN), central nucleus of amygdala (CeA), and nucleus of the solitary tract [19, 20]. These brain areas are part of the limbic system, and are related to emotional and affective behaviors.
The activation of PVN and CeA has also been observed in models of conditioned taste aversion, in which animals avoid the consumption of saccharin (conditioned stimulus) after it had been paired with an intraperitoneal injection of lithium chloride (unconditioned, noxious stimulus) [22, 23]. Further, to test a conflicting situation, the aversive stimulus (allergen) was offered to mice associated with highly palatable solutions. Since high concentrations of artificial sweeteners are associated with bitterness, a palatable natural sweetener (sucrose) was usedas the attractive stimuli. Therefore, OVA-sensitized mice received a solution containing OVA and increasing concentrations of sucrose and the avoidance behavior was positively correlated with the levels of OVA-specific IgE and inversely correlated with the animal preference for sucrose (Figure 2).
Figure 2. BALB/c mice present higher levels of IgE and a lower preference for sweet flavors when compared to C57BL/6 mice (Drawing by Katia Haipek).
This evidence highlights the complexity and fine control of such adaptive behavioral response.Furthermore, the aversion behavior was abolished when high concentrationsof sucrose (higher palatability) were present in the allergen-solution . In a broader scenario, this animal model evidenced a complex crosstalk, in which the very sensorial response triggered by a taste preference could be modulated by an immune response. Figure 3 shows a cartoon representing an animal’s choice when the allergen is associated with a palatable flavor.
Figure 3. Illustration of the avoidance behavior being abolished when the aversive stimulus (allergen) was offered associated with an attractive sweet taste (sucrose) (Drawing by Katia Haipek).
The underlying mechanisms by which the immunological information generated during allergic responses reaches the brain are still unknown. However, recent findings show the importance of the allergic early-phase in this scenario. Depletion of IgE using non-anaphylactic anti-IgE antibodies, or inhibition of mast cell degranulation using sodium cromoglicate (a well-established mast cell stabilizer), were equally effective in preventing neuronal activation and avoidance behavior in allergic mice [24, 19, 20].
Differently, the pre-treatment of allergic mice with a mixture containing antagonists of mast cell mediators, such as methysergide (of serotonin) and mepyramine (of histamine), inhibited local edema but the aversive behavior was maintained [25, 26]. It was abrogated with a pre-treatment with glucocorticoid (dexamethasone), but it is known that corticosteroids have general anti-inflammatory  and psychological effects . The avoidance behavior was also dissociated of local inflammation, since allergic C3H/HeJ mice, which did not present overt pulmonary inflammatory infiltrate, exhibited brain and behavioral changes similar to BALB/c animals .
Consistent data demonstrate the proximity of mast cells and nerve endings [29, 30], giving anatomical support for the role of mast cells in the interaction between immune system and CNS. Neural pathways most likely to mediate this interaction are the autonomic nervous system: vagus nerve and sympathetic nerve fibers to the main sites of the immune system, and afferent nerves conveying sensory information to the CNS [31, 32]. Studies using capsaicin, a neurotoxin that promotes a selective dysfunction of sensory fibers such as C-fibers , showed complete abrogation of c-fos expression in the PVN and diminished avoidance behavior in OVA-sensitized mice . The implications of the direct CNS activation via IgE-antigen interactions should also be considered in the investigations of the role of neural pathways in allergy.
In summary, this review showed a direct evidence of allergic reactions conveying information to the CNS and inducing brain activation and behavioral changes associated with avoidance behavior towards allergen exposure. The early phase of allergic hypersensitivity and the sensory function of the vagus nerve play a fundamental role in this scenario. The typical features observed in allergy, such as smooth muscle contraction (bronchoconstriction or peristaltism) and increased mucus secretion, which are usually considered as pathologic processes, can be viewed as an attempt of the organism to eliminate the irritant stimulus. Furthermore, the highly sensitivity response to IgE-based recognition of allergens and its association with avoidance behavior may indicate that allergic reactions evolved to elicit anticipatory responses and to promote avoidance of hostile environments . Finally, the interaction between immune and nervous systems strongly supports the robust homeostatic status of an organism.
The authors would like to thank FAPESP, Luciana Mirotti’s postdoctoral fellowship 2010/11071-8 and Projeto Temático 2009/07208-0, CNPq grants to Prof. Momtchilo Russo.
Luciana Mirotti, Momtchilo Russo – Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
Corresponding author: Mirotti L (LMIROTTI@GMAIL.COM)
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