101

Brain Research Reviews, 17 (1992) 101-107

Q 1992 Elsevier Science Publishers B.V. All rights reserved 0165-0173/92/$05.~

BRESR 90145

Asymmetrical brain modulation of the immune response P.J. Neveu Laboratoire de Fsycho~iolog~e des Com~~rteme~ts Adaptatifs, INSERM U. 259 - Uniuersitk de Bordeaux iI, Bordeaux (France)

(Accepted 5 May 1992)

Key words: Brain asymmetry; Cortical ablation; Lateralized behavior; Immune reactivity

CONTIZNTS l.lntroduction ........................................................................................ 1.1. Brain lateralization ................................................................................

101 101

2. Lateraiized brain immunomodulat~on . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Neuroanatomicaf approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.1. Opposite effects of left and right cortical ablations on immune parameters . 2.1.2. Brain structures involved in neocortex mediated immunomodulation ... 2.1.3. Limits of the lesion approach ................................ 2.2. Functional approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . _. . . . . . . . . . . . 2.2.1. Association between handedness and immune disorders in humans . . . . . , 2.2.2. Association between paw preference and immune reactivity in mice . , , . . 3.Conclusion

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..~.........................................................

105

4. Summary ...........................................................................................

105

Acknowledgements

10.5

References

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1. INTRODUCTION

1.1. Brain lateralization Functional and neuroanatomical studies have demonstrated that the brain is lateralized. There is widespread agreement that the two cerebral hemispheres contribute differentially to the regulation of human behaviour 46. In right handers, the left hemisphere is considered to be specialized for speech and handedness and the right hemisphere for spatial abilities and the expression of affect *7~23,28,33,34,35,42~69. Individual cerebral organization depends on various pa-

105

rameters including sex and familial h~dedness~ suggesting that it depends on hormonal and genetic factors during brain development. The right and left hemispheres, as demonstrated by electroencephalographic studies, develop at different rates and with different post-natal onset times”. Sex hormones may be involved in such differential development of the hemispheres. Testosterone has been postulated to be able to slow down the development of the left hemisphere and this has been related to an increased frequency of Ieft-handedness in males and to an enhanced number of learning disorders in boys38. This hypothesis

Correspondence to: P.J. Neveu, Laboratoire de Psychobiologie des Comportements Adaptatifs, INSERM U. 259 - Universite de Bordeaux II, Domaine de Carreire - Rue Camille Saint-SaBns, 33077 Bordeaux Cedex, France. Fax: (33) 56.96.68.93.

102 is in agreement with the enhanced left-handedness observed in female congenital hyperplasia patients exhibiting high plasma levels of testosterones2. Functional brain asymetries are not restricted to humans and have also been extensivily studied in animals27~“0~s1. The two hemispheres appear to be differentially involved in psychiatric and neurological diseases. The right hemisphere has been hypothesized, in contrast to the left, to become activated by and to preferentially process negative emotional stimuli64. In agreement with this hypothesis, patients with right hemisphere lesions have been reported to tolerate pain longer than those with left hemisphere lesions25,5’. Dysfunction of the right hemisphere may be responsible for the alterations of perceptual asymmetry observed in patients with melancholia or bipolar depression’x. In comparison, the left hemisphere appears to be mainly affected in schizophrenia3’. Increased left-hemisphere arousal has been demonstrated by cognitive and perceptual measures in chronic schizophrenics4’. Furthermore, the schizophrenics were inclined to use the left hemisphere when initiating thought on material that normally requires right-hemisphere processing72. Morphological brain asymmetries have been described in man for some long time. These asymmetries mainly involve the cortical areas located around the posterior end of the Sylvian fissure, essentially the planum temporale as well as other regions including the parietal operculum, inferior parietal lobule and inferior frontal gyrus. In most instances, cortical asymmetries favour the left hemisphere (for review see 41). However, the functional significance of these asymmetries is not well known. Likewise, the relationship between callosal size and cerebral dominance remains controversa14”~‘s. It was shown that in the human brain40 as well as in the Sprague-Dawley rat and the C3H mouse brain”.““T6”,the asymmetry in neurotransmitter distribution is correlated with the functional heterogeneity of the two hemispheres. For example, the observed asymmetry in cholinergic parameters from the temporal lobe may be related to differences in memory and cognitive functions between the two hemispheres’. In C3H female mice, paw preference has been demonstrated to be related to neurotransmitter asymmetries”. Furthermore, asymmetries in brain neurotransmitter distribution may be affected in pathological situations. Brain ischemic events induced changes in transmitter turnover depending on the side of the lesion30. Likewise, in C3H female mice, lesions of left or right neocortex differentially modified amine metabolism4. Conversely, unilateral cortical injection of a noradrenergic neurotoxin induced an asymmetrical locomotor response in Sprague-Dawley male rat44. Neuropsycho-

logical and neurochemical differences between patients with idiopathic Parkinson’s disease showing predominant left or right impairments suggested a possible relationship between functional lateralization (motor symptoms and neuropsychological deficits) and anatomical asymmetries of dopaminergic systems2Y. This asymmetry in neurotransmitter distribution could explain the fact that some drugs act predominantly on one hemisphere. For example, in man the typical effects of administered LSD diminished after right, but not left, temporal lobectomy74. The average difference in serotonin content between the two hemispheres is reduced after the administration of lithium4x. In schizophrenic patients, chlorpromazine reduced functional brain asymmetry possibly by lowering arousal of the left hemisphere4’. These functional, anatomical, neurochemical and pharmacological studies demonstrate than human and animal brains are lateralized and that each hemisphere can be functionally linked to the other. 2. LATERALIZED BRAIN IMMUNOMODULATION As it is now well known that the central nervous system modulates the activity of the immune system and that number of brain functions are lateralized, the question arises whether the brain regulates immune responses in an asymmetrical way. In the early 1980’s, two different paradigms were used to demonstrate that indeed the CNS may asymmetrically modulate immune functions. First, left or right cortical ablations in mice were shown to have opposite effects on several immunological parameters. Left cortical lesions depressed T-lymphocyte functions whereas symmetrical right ablations had no or even enhancing effect@‘. Secondly, Geschwind and Behan described an association between left-handedness and the incidence of immune disorders. 2.1. Neuroanatomical approach 2.1.1. Opposite effects of left and right cortical ablations on immune parameters. In C3H female mice tested six

to ten weeks after ablation of the left fronto-parietooccipital cortex (grL) mitogen-induced T-cell proliferation was decreased. After a similar lesion of the right neocortex (grR) mitogenesis was enhanced6*v6’. Differences were statistically significant only when left hemisphere- and right hemisphere-lesioned groups were compared. Usually, neither of these groups differed from the unoperated control group. These modifications in T-cell proliferation have been shown to parallel interleukin-2 production5”. Additionally, natural killer cell activity was impaired after left cortical abla-

103 tions2. Cortical lesions also modified, but only slightly and non si~ificantly, mitogen-educed proliferation Of B cells62. Production of antibodies of the IgG isotype (T-dependent) but not IgM antibody synthesis (T-independent) was depressed after left lesions67. In further studies, we have observed that the brain asymmetrically modulates macrophage activation57. The intrape~toneal injection of Calmette-Gu~rin bacillus is known to induce an accumulation of activated macrophages in the peritoneum. A similar accumulation was not observed after cortical lesions, mainly after the left ablations. Moreover, oxidative metabolism was decreased in animals of group L as compared to group R or controls. The function of non-activated resident macrophages was not affected by damaging the cortex. We have extended this experimental model of unilateral cortical lesions for studying lateral~ation of brain modulation of the immune system in rodents. The results obtained in female C3EI mice have been partially replicated male mice for NK cell activity14 and for lymphocyte proliferation in female SpragueDawley and in male Wistar rats8*45.The results suggest two conclusions. First, findings in mice may be applied to other species and thus, may be expected to be a general phenomenon. Second, similar results were observed for both sexes in rat and in mouse experiments suggesting that the phenomenon can be generalized across sex. This indicates that the results are robust despite differences in sex hormones of the adult animals studied. Furthermore, our results may be generalizable to humans, but the evidence for this is more indirect. The modifications of mitogenesis observed in mice 2 weeks after brain cortex ablation” are in agreement with the perturbations of blood lymphocyte subsets observed 3 weeks after stroke in humans26. This suggests that this model could be useful for studying the mechanisms involved in immune disorders following stroke in humans. Although we have shown that the neocortex modulates the activity of both lymphocytes (T and B) and macrophages, the cellular target of brain cortex immunomodulation is not yet known. In addition, the physiopathological effects of immunological perturbations induced by cortical lesions remain to be clarified. Until now, the effects of cortical ablation on infection have been studied in only one experiment in which mice were infected with Tiypatwsoma musculi. Even though, parasitemia was slightly enhanced in the brain damaged mice, as~metrical effects were not observed5’. Similar experiments, using other infectious diseases or tumor grafts, have yet to be conducted. Cortical lesions do not induce a lymphocyte redistri-

bution similar to that observed during stres?. Furthermore, cortical lesions modulate concanavalin A-induced proliferation of both lymph node and spleen lymphocytes in a similar way6. The cortex, therefore appears to modulate the immune system above the secondary lymphoid organs. Given that it does so, the neocortical damage may affect immune function in one of two ways. As the cortex affects both lymphocyte and macrophage functions, it is possible that it acts on a hematopoietic stem cell at the bone marrow level as previously postulated 57. Alternatively, the neocortex may first act on T-lymphocytes and only secondarily modulate B-cell and macrophage functions through the lymphokines produced by T-lymphocytes. In fact, it has been shown that left cortical lesions decreased production and/or release of serum factor(s) involved in T-cell maturation6’. Experiments are currently being performed to address these issues. 2.1.2. Brain structures involved in neocortex mediated immunomodulation. The respective role of each hemisphere in neocortex mediated immunomodulation is still controversal. Renoux and Biziere6’ have postulated that the right hemicortex modulates the activity of the left, which in turn controls the immune system. According to this hypothesis, the effects of bilateral cortical ablation should be similar to that of left lesion alone. Indeed, they have shown that both bilateral and left lesions depressed natural killer cell activity to the same extent. However, in our experiments, bilateral lesions (two unilateral lesions performed within a time interval of 3 weeks to avoid mortality observed after one stage bilateral damage) did not modify mitogen-induced l~phoproliferation “. Suppression of the asymmetrical immunoregulato~ effects by bilateral cortical ablation suggested that each hemicortex may be active on the immune system in an opposing fashion. The right hemisphere may increase while the left depresses T-cell functions. Furthermore, each hemicortex appears to be heterogeneous concerning its immunoregulatory functions. The effects of unilateral lesions restricted to the parieto-occipital areas are different from those observed after lesions involving all of the frontoparieto-occipital cortex 5,54.That different immunological parameters may be modulated in various ways depending on the size and location of the lesions suggests that each hemicortex may contain both activating and suppressing areas which may interact both within a hemisphere and between hemispheres. Subcortical structures implicated in cortical immunomodulat~on are not yet known. Preliminary experiments using bilateral lesions of the nucleus basalis magnocellularis, whose cholinergic neurons are known to project to the cortex, strongly increased mitogen-in-

104 duced lymphoproliferation and natural killer cell activity ” . However, the conclusion that cholinergic systems are involved in neuroimmunomodulation must he considered with caution because neurotransmitters other than acetylcholine may be affected by lesion of the nucleus basalis. Other experimental data suggest that catecholaminergic pathways may be involved in immunomodulation. The immune-enhancing activity of sodium diethyldithiocarbamate has been suggested to depend on the presence of the intact cortex and to be related to the inhibition of dopamine P-hydroxylase68. In the same vein, there is evidence to suggest that unilateral cortical lesions as~metrically modify the concentration of catecholamines in various subcortical structures“. This might suggest that catecholamines are modified by cortical lesions and that they, in turn, modulate the immune system. Even though these suggestions are speculative, we were recently able to demonstrate that unilateral lesions of the right or left substancia nigra, had opposite effects on T-cell mitogenesis’“. 2.1.3. Limits of the lesion approach. The lesion model demonstrating asymmetry in brain immunomodulation contains some inbuilt methodological problems. After cortex damage, there are many secondary functional changes involving neuronal plasticity as well as alterations in several subcortical structures4a6. These secondary modifications may mask the respective role of each hemisphere in neuroimmunomodulation. Additionally, the immune system is known to send information to the central nervous system. For example, interleukin-1 produced by macrophages stimulates corticoid production by acting at the hypothalamic’” or/and pituitary level ” . During antibody production, the firing rate increased and norepinephrine turnover decreased in the hypothalamus *2,‘3. In mice, after stimulation of the immune system induced by bacillus CalmetteGuerin, norepinephrine levels increased in both hemispheres, but only significantly in the right one. This increase has been correlated with lymphoproiiferation9. These results suggest that the communication pathways from the immune system towards the brain may also be lateralized. Feed-back mechanisms could modify the immunological effects of cortical lesions and therefore make analysis of these effects difficult. 2.2. Functional approach 2.2.1. Association between handedness and immune disorders in humans. An association between left-handedness and Geschwind of immune left-handed

immune disorders has been described by and Behan3” who found a higher incidence disorders, such as auto immune diseases, in people.

Similar, but also contradictory results have been reported by other authors24,“5.7”,7”.For allergic diseases. for which ethiopathogenesis is well known, the association with handedeness seems controversial. Strong associations have been found in some studies. Geschwind and Behan” reported a significant increase of allergies in strongly left-handed individuals. Similar results were found by Smith7” but not by Bishopi6. In a similar study I”‘, we found only a slight tendancy towards left-handedness in patients whose allergic symptoms started before puberty. It may be hypothesized that left-handers should have an increased predisposition to allergic diseases that is manifested during early life. The discrepancies in the different human studies probably result from differences between patient populations. Furthermore, in these studies only the clinical signs of immune disorders were taken into account; the immune status of patients was not studied, These contradictions in the human studies are difficult to resolve because of both theoretical and methodological problems71,79and will require further research. 2.2.2. Association between paw preference and immune react&y in mice. in order to overcome the difficulties encountered in human studies for demonstrating a possible association between asymmetrical brain and immune responses, we recently started an experimental approach in labotary animals, Mice may be selected for right- or left- handedness using a paw preference test described by Collins 21. In female C3H/He mice, lefthanded mice exhibited higher mitogen-induced Tlymphocyte proliferation than right-handed animals. B-lymphocyte mitogenesis was not, however, affe ted by handednessso. Such an association between haniedness and T-cell mitogenesis was not found In C3H/OuJIco male mice but in these animals natural killer cell activity appeared to be associated with handedness. Left-handed male mice exhibited lower natural killer cell activity in comparison to right-handed animals14. These results showed that the association between paw preference and immune reactivity depends on the immunological parameters studied and the sex of animals. In a second series of experiments, the possible association between handedness and autoimmunity was studied in a murine systematic lupus e~hematosus mode15’. New Zealand black mice are known to spontaneously develop auto-immune disease such as lupus like glomerulonephritis and hemolytic anemia related to anti-DNA and anti-erythrocyte antibodies. Both anti-erythrocyte and anti-DNA antibodies of the IgG isotype appeared earlier in left-handed female animals. IgM anti-DNA antibody production were not correlated with paw preference. Assuming that IgG, but not

105 IgM production

is dependent on T-cells, handedness may be associated mainly with T-cell functions. NO such correlation between handedness and auto-antibody production was observed in males. As sex hormones are known to be involved in auto-immune processus75, in immune reactivity22, and in brain development49, these results suggest that they may also be important factors in the association between brain asymmetry and antibody production. The possible differences in brain organization as well as in neuroendocrine pathways which may be responsible for differences in immune reactivity between left- and righ-handed mice is now under study. In recent work, we reported that left- and right-handers differed in the asymmetric distribution of brain monoamines especially in cortical and bulbospinal norepinephrine contents as well as in dopamine turnover of the tuberofundibular system3. 3. CONCLUSION Brain immunomodulation may be lateralized as evidenced by two experimental approaches. Using a cortical lesion paradigm we have shown that each hemicortex modulated in opposite directions the activity of lymphocytes (T and B) and macrophages in mice as well as in male and female rats. The cellular immune target(s) susceptible to brain modulation are currently under investigation. Although lateralized brain modulation of immune function is well accepted, the specific neural structures involved are not well known but preliminary data are available.Interpretations of ablation studies is also complicated by various inherent consequences of this type of manipulation such as separating the effects of damage to structures from compensation by remaining tissue and disruption of feed-back relationships. This animal model, useful to elucidate the mechanisms whereby the brain and the immune system can communicate, appears to be suitable for studying the immune perturbations observed during stroke in humans. Using a behavioral paradigm, we have looked for a possible association between asymmetrical brain function and immune responses in mice selected for right- or left-handedness using a paw preference test. Left-handed mice, in comparison to right-handed may be characterized by (1) higher mitogen-induced T-lymphocyte proliferation in C3H/He females but not in C3H/OuJIco males, (2) lower NK cell activity in C3H/OuJIco males and (3) earlier auto-antibody production in females but not in males of the NZB strain. Sex hormones may be involved in the association between paw preference and immune reactivity. Furthermore, some recent studies32,61 should

indicate that this association may be under some genetic control. The experimental models for investigating asymmetrical brain modulation of the immune system should be useful for studying several physiological, pathological and genetic aspects of neuroimmunomodulation. 4. SUMMARY It is now well known that the central nervous system can regulate the immune system. Interestingly the two sides of the brain have been demonstrated to be differently involved in the modulation of immune responses. In rodents, lesions of right or left neocortex induced opposite effects on various immune paramaters including mitogen-induced lymphoproliferation, interleukin-2 production, macrophage activation or natural killer cell activity. Furthermore in humans, left-handedness has been reported to be associated with a high incidence of immune disorders. Likewise in mice, the direction of a lateralized motor behavior, i.e., paw preference in a food reaching task, correlated with an asymmetrical pattern of brain organization, was shown to be associated with lymphocyte reactivity, natural killer cell activity and auto-antibody production. Conversely the immune system could send to the brain information that may be asymetrically expressed. The experimental models for investigating asymmetrical brain modulation of the immune system may be useful for studying physiological, pathological and genetic aspects of neuroimmunomodulation. Acknowledgements. I would like to thank Prof. Guy Mittleman for his critical review of the manuscript. This work was supported by INSERM, University of Bordeaux II and the Conseil General d’Aquitaine.

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Asymmetrical brain modulation of the immune response.

It is now well known that the central nervous system can regulate the immune system. Interestingly the two sides of the brain have been demonstrated t...
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