Cent. Eur. J. Med. • 7(1) • 2012 • 1-8 DOI: 10.2478/s11536-011-0121-2 Central European Journal of Medicine Brain asymmetry, immunity, handedness Review article Zlatislav Stoyanov*, Lyoubka Decheva, Irina Pashalieva, Piareta Nikolova Department of Physiology and Pathophysiology Medical University “Prof. Paraskev Stoyanov” 55 Marin Drinov Str., 9002 Varna, Bulgaria Received 17 December 2010; Accepted 3 October 2011 Abstract: The principle of symmetry-asymmetry is widely presented in the structural and functional organization of the nonliving and living nature. One of the most complex manifestations of this principle is the left-right asymmetry of the human brain. The present review summarizes previous and contemporary literary data regarding the role of brain asymmetry in neuroimmunomodulation. Some handedness-related peculiarities are outlined additionally. Brain asymmetry is considered to be imprinted in the formation and regulation of the individual’s responses and relationships at an immunological level with the external and internal environment. The assumptions that the hemispheres modulate immune response in an asymmetric manner have been confirmed in experiments on animals. Some authors assume that the right hemisphere plays an indirect role in neuroimmunomodulation, controlling and suppressing the left hemispheric inductive signals. Keywords: Brain asymmetry • Hemispheric control • Immunity • Handedness. © Versita Sp. z o.o 1. Introduction 2. Hemispheric lateralization in neuroimmunomodulation The principle of symmetry-asymmetry is widely pre- sented in the structural and functional organization of The fact that structural and functional asymmetry is a the nonliving and living nature. One of the most complex fundamental trait of the brain generated expectations manifestations of this principle is the left–right asym- that brain asymmetry is implicated in the neural control metry of the human brain [1]. The term “brain asym- of immune functions. In 1975 Semenov and Chuprikov metry” summarizes the anatomical, neurochemical, postulated that brain asymmetry is imprinted in the for- physiological and behavioral differences between the mation and regulation of the individual’s reactivity and two halves of the brain [2,3]. The psychophysiology of relationships at an immunological level with the external sensory functions and perception, cognitive processes, and internal environment [11]. attention, learning and memory, and emotions are com- The assumptions that the hemispheres modulate mon objects of interests to the investigators of cerebral immune response in an asymmetric manner have been lateralization [1,4]. Since the end of the 20th century, confirmed in experiments on animals. In one of the first the asymmetries in autonomic-physiologic functions studies Bardos et al. [12] found out that NK-cell (natural have been included in the realm of scientists, and in killers) activity was significantly impaired following left particular the neural control of cardiac activity, endo- cortical lesions, whereas right cortical lesions exerted crine functions and immunity [5,6]. The present review no observable influence on NK-cell activity, as com- summarizes previous and contemporary literary data pared with normal control animals. Renoux et al. [13] regarding the role of brain asymmetry in neuroimmu- observed weight reduction in lymphoid organs (spleen nomodulation. Some handedness-related peculiarities and thymus), and a decreased number of splenic T-cells are additionally outlined because it is well known that (Thy-1+) also in left cortical lesioned mice. The study left-handers show some specificity in the patterns of of lymphocyte proliferation in response to mitogen cerebral lateralization [7-10]. stimulation provided evidence that left cortical ablation * E-mail: [email protected] 1 Brain asymmetry, immunity, handedness significantly suppresses the response of splenic lym- stimulate the HPA axis to increase the plasma levels of phocytes to T-cell specific mitogens such as phytohe- corticosterone, and (b) the cortical regulation of cortisol magglutinin and concanavalin [5]. An opinion exists secretion is under the primary control of the right hemi- that left hemispheric influences enhance the reactivity sphere [5,15]. Our previous investigations (although on of different T-cell dependent immune mechanisms and, different physiological functions) also provided evidence in general, immune functions under physiological con- that hypothalamic-pituitary-glandular axes operate in ditions, whereas right hemispheric influences have a a dependent relationship with individual differences in predominantly immunosuppressive effect [14,15]. Some brain asymmetry [23,24]. authors assumed that the right hemisphere plays an Hori et al. [25] focused their attention on the roles indirect role in neuroimmunomodulation, controlling and and mechanisms of neural communication between the suppressing the left hemispheric inductive signals [16]. brain and the immune system, and summarized: (a) pri- The data from studies in humans parallel those mary and secondary lymphoid organs are sympatheti- involving observations in animals. Kang et al. [17] found cally innervated; (b) different types of immunocompetent significantly higher levels of NK-cell activity in subjects cells possess alpha- and beta-adrenergic receptors; with pronounced left frontal electroencephalographic (c) the exposure of lymphocytes and macrophages to (EEG) activation, as compared to subjects with right adrenergic agonists in vitro modulates their functions; frontal activation. According to Davidson [18], individu- (d) a surgical or chemical sympathectomy alters the als with predominant right frontal activation are immu- immune responses in rodents; (e) the altered activities nosupressed. Gruzelier et al. [19] reported a significant of the splenic sympathetic nerves is causally related to positive correlation between higher left-sided activation the alteration in immunological responses (for instance (lower EEG amplitude) and CD8+ T-lymphocytes count, NK cytotoxicity). Regarding the roles and mechanisms and, conversely, relatively higher right-sided activation of the parasympathetic control of lymphoid organs, associated with lower CD8+ count. Meador et al. [20] some data suggest that the thymic vagal efferent nerve compared postoperative to preoperative T-lymphocyte may be involved in the central modulation of immunity indices in epileptic patients who had undergone neu- [25]. In the context of functional brain asymmetry and its rosurgical treatment. The researchers found that the links with immunity, it is a noteworthy fact that the right absolute lymphocyte count, total T-cells (CD3+), helper hemisphere predominantly modulates the sympathetic T-cells (CD3+4+), cytotoxic/suppressor cells (CD3+8+), nervous system, and the left hemisphere predominantly and total suppressor cells (CD8+) were reduced follow- modulates parasympathetic activity (according to exper- ing surgical interventions on the language-dominant imental data and clinical observations) [26-30]. Abramov hemisphere, however, they increased after non-domi- et al. [31], discussing their own results on differences nant hemisphere resections. In the study of Clow and in the functional properties of thymocytes from left and colleagues, the influence of lateralized transcranial right thymus lobes, also considered the differences in magnetic stimulation on secretory immunoglobulin A the sympathetic and parasympathetic innervation of the (sIgA) concentrations in the saliva was examined [19]. contralateral lobes of the thymus, and stressed the dif- The main finding, according to the authors, was an ferentiated hemispheric control of the two branches of increase in sIgA following left-sided cortical stimulation. the autonomic nervous system. The molecular basis of brain–immune interac- tions remains insufficiently understood, but in sev- 3. Brain–immune system eral publications the role of cytokines has been outlined interactions [15,22,32,33]. Cytokines, besides regulating immune responses, function as mediators of an afferent path- What are the channels through which the brain and the way to the brain, and probably are a part of a neuro- immune system communicate? The exact mechanisms endocrine-immune signalling system [32]. An important of this interaction are not fully understood. Betancur et al. role in asymmetrical brain immunomodulation has been [21] searched for, an engagement of the hypothalamic- ascribed to brain IL-1β and interleukin-6 (IL-6). Both pituitary-adrenal (HPA) axis in the relationships between interleukins can regulate the neuro-endocrine-immune brain asymmetry and immune response. Later on Shen network by invoking autonomic, neuro-endocrine, and et al. [22] argued that cytokines (such as interleukins) behavioural action [32,33]. The publications of Fu et regulate immune responses, possibly through activation al. [15] and Shen et al. [22] presented intriguing data of the HPA axis, and HPA axis activities are related to about an asymmetrical distribution of IL-1β and IL-6 in brain lateralization. There are two supporting facts in this the mouse brain: the basal levels of IL-1β and IL-6 are context: (a) it is known that interleukin-1β (IL-1β) can higher in the right cortex than in the left. The authors 2 Z. Stoyanov et al. proposed that the rightward asymmetry in IL-1β and IL-6 Geschwind and Behan [37] revealed that the incidence is probably related to the differences between the right of diseases associated