169
Immunology Today, vol. 5, No. 6, 1984
Hormones, handedness, and autoimmunity It has been reported that left-handedness and autoimmune disease are associated ~. This was the conclusion from a three-part study. In the first part, subjects answered a questionnaire designed to test laterality and to establish personal and family medical histories. Left-handed subjects reported significantly more immune disorders and developmental learning disorders than right-handed subjects, but the two study groups were chosen from different populations. The diseases reported by the subjects that were classed as immune disorders were celiac disease, dermatomyositis, diabetes, Hashimoto's thyroiditis, myxedema, regional ileitis, rheumatoid arthritis, thyrotoxicosis, ulcerative colitis, and uveitis. In the second part of the study, all subjects were chosen from the same population and only immune diseases established in a hospital were counted. Left-handed subjects again reported an increased frequency of immune disorders and learning disorders in themselves and in family members. The third part of the study concentrated on patients with specific immune diseases. There was a slight increase in the frequency of left-handedness in patients with myasthenia gravis, but no increase in left-handedness among patients with multiple sclerosis, rheumatoid arthritis, or 'mixed-collagen vascular diseases'. These findings provide limited evidence for an association between left-handedness, learning disorders and diseases that may be autoimmune in origin. Geschwind and Behan postulate that this association reflects the prenatal influence of fetal testosterone on the developing immune and central nervous systems. They propose two hypotheses. The first is that during embryogenesis, testosterone slows neuronal development in the left hemisphere of the brain, predisposing to learning disorders, right cerebral dominance, and left-handedness; the second is that testosterone impairs development of the immune system, predisposing to autoimmunity. Although the role of male sex hormones is pivotal in these hypotheses, Geschwind and Behan did not report the effect of gender on either left-handedness or autoimmunity in their subjects, nor did they demonstrate concordance between immune disorders and learning disorders. Their hypotheses therefore are not based primarily on their own findings, but rather on their interpretation of other observations. They cite studies in rats demonstrating that part of the posterior cortex develops asymmetrically, the right side being thicker in males and the left side thicker in females 2. Sex-related functional asymmetry of the brain has also been reported in human beings3-5; left-handedness, for example, is more common in men than in women 5. These observations are consistent with the hypothesis that testosterone favors development of the right hemisphere relative to the left hemisphere. Several studies support the notion that androgen impairs prenatal development of the immune system. In mice, high androgen sensitivity correlates with low immune responses independent of postnatal androgen concentrations 6. In chickens, prenatal administration of androgen arrests development of the bursa and produces
cortical atrophy of the thymus 7'8. In the light of these findings, Geschwind and Behan propose two mechanisms that could explain an association between fetal androgen and subsequent autoimmune disease. First, by retarding. development of the fetal thymus, testosterone could impair recognition of self-antigens and thereby predispose to autoimmunity. While this is consistent with testosterone-induced thymic atrophy in chick embryos 8, it does not explain conflicting findings in mice where high androgen sensitivity and low immune responses correlate with large thymic size +. Alternatively, they propose that an association between fetal androgen and autoimmunity might reflect linkage between genes governing androgen sensitivity and immune response genes. They note that polygenic control of testosterone metabolism involves some genes that are linked to the major histocompatibility (H-2) complex of the mouse 9. However, these H-2-1inked genes do not account for the association between immune responsiveness and androgen sensitivity, which is controlled by genes that are not linked to the H - 2 region 6. One possible mechanism not considered by Geschwind and Behan involves direct effects of the CNS on the immune system. Several studies suggest that the CNS may influence immune regulation I°'11. For example, hypothalamic abnormalities can alter immune responses 11. Interestingly, testosterone may affect development of the hypothalamus ~2. Thus, androgen could conceivably influence the immune system, not through a direct effect on lymphoid tissue but indirectly, by altering the effects of the CNS on immunoregulation. If increased fetal androgen leads to autoimmune disease, then males should be at particular risk. On the contrary, females are more susceptible than males to most autoimmune diseases 19. Furthermore, in postnatal development, androgen exerts an immunosuppressive effect that may actually protect against autoimmunity 14-~7. It is difficult to reconcile these observations with any mechanism relating androgen sensitivity, left-handedness, and autoimmunity. Geschwind and Behan propose that prenatal androgen sensitivity predisposes to autoimmunity, but that high postnatal androgen concentrations protect men against autoimmunity. While it is possible that testosterone exerts diametrically opposing effects prenatally and postnatally, there is no evidence that prenatal androgen exposure predisposes to autoimmunity. Geschwind's theories have received added attention recently in conjunction with studies linking male gender, superior mathematical ability, and left handedness ~8.~9.A series of talent searches conducted at Johns Hopkins University and widely reported in the scientific and lay press have shown that boys consistently score higher than girls in tests of mathematical aptitude. The suggestion that this observation might reflect inherent genetic differences between boys and girls appropriately generated considerable controversy 2°. This controversy has been rekindled by a recent preliminary report suggesting an increased frequency of left-handedness and allergies among mathematically gifted children19+ Geschwind © 198'[, Elsevier Science Publishers B.V., Amsterdam
0167
4919/84/$02.00
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170
contends that his theories explain these findings 19. He proposes that increased testosterone in boys favors development of the right hemisphere of the brain, where mathematical ability is thought to reside, thus increasing the likelihood of both left-handedness and mathematical genius. Geschwind further speculates that real-development of the left cortex is responsible for an increased frequency of developmental verbal disorders (e. g., dyslexia, stuttering) in left-handed people in general and boys in particular 1. It is beyond the scope of this commentary to review each of the areas encompassed by Geschwind's hypotheses. From an immunological standpoint, however, they rest on a weak foundation. First, the data are not compelling. Some important information (e.g., the gender of their subjects) were not presented by Geschwind and Behan and not all of the data presented support an association between left-handedness and autoimmunity. Second, there is no basis for treating such divergent immune disorders as allergy and autoimmunity interchangeability. Third, there is no experimental support for the hypothesis that prenatal androgen predisposes to autoimmunity. A slender thread connects a series of controversial topics. How do sex hormones influence the immune response? What is the relationship between the CNS and the immune system? Are men immunologicaUy inferior to women? Are women mathematically inferior to men? Are left-handed people predisposed to develop autoimmune disease, have learning disorders, or be geniuses? None of these issues is resolved, yet some have achieved rapid notoriety, not because of their scientific substance but because of perceived social implications. In this setting, a particularly high standard of scientific rigor and social conscience is required. Even if future studies confirm a
K] (-.,,-.
developmental basis for an association between left-handedness and immune diseases or between gender and certain skills, these associations explain neither autoimmunity nor scholastic aptitude in the vast majority of people.
n-I References 1 GeschMnd, N. and Behan, P. (1982) Proc. Natl Acad. Sci. USA 79, 5097-5100 2 Diamond, M. C., DoMing, G. A. and Johnson, R. E. (1981) Exp. Neurol. 71, 261-268 3 McGloneJ. (1980) Behav. Brain Sci. 3, 215-263 4 Inglis, J. and Lawson, J. S. (1981) Science2t2, 693-695 5 Porac, C. andCoren, S.(1981)LateralPreferenceeandHumanBehaviour, pp. 35-45, Springer, New York 6 Cohn, D. A. (1979) Arthritis Rheum. 22, 1218-1233 7 Warner, N. L., Uhr, J. W., Thorbecke, J. and Ovary, Z. (1969)J. ImmunoL 103, 1317-1330 8 Warner, N. L., Szenberg, A. and Burner, F. M. (1962) Aust. J. Exp. BioL Med. Sci. 40, 373-387 9 Ivanyi, P. (1978) Proc. R. Soc. London Set. B. 202, 117-158 10 Ader, R. and Cohen, N. (1975) Psychosom. Med. (NY) 37, 333-340 11 Stein, M., Schleifer, M. D. and Keller, C. E. (1981) in Psychoneuroimmunolog~ (Ader, R., ed.), pp. 429-447, Academic Press, New York 12 MacLusky, N. J. and Naftolin, F. (1981)Science 211, 1294-1303 13 Masi, A. R. and Medsger, T. A., Jr. (1979) in Arthritis and Allied Conditions (McCarty, D. J., ed.), pp. 11-35, Lea and Febiger, Philadelphia 14 Eidinger, D. and Garrett, T. J. (1972)J. Exp. Med. 136, 1098-1116 15 Graft, R. J., Lappe, M. A. and Snell, G. D. (1969) Transplantation 7, 105-111 16 Roubinian, J. R., Papoian, R. and Talal, N. (1977)J. Clin. Invest. 59, 1066-1070 17 Roubinlan, J. R., Tala, N., Greenspan, J. S., Goodman, J. R. and Siiteri, P. R. (1978)J. Exp. Med. 147, 1568-1583 18 Benbow, C. P. and Stanley, J. C. (1983) Science222, 1029 1031 19 Kolata, G. (1983) Science 222, 1312-1315 20 Science(1981) 212, 114-121 DAVID WOFSY Arthritis~Immunology Unit, VeteransAdministration Medical Center and the Department of Medicine, University of California, San Francisco, CA 94143, USA.
I Prostaglandins and Immunity
The prostaglandins are a family of biologically active compounds generated from unsaturated fatty acids. They are produced and found in every tissue of the body and their diverse biological activities and possible role in human disease processes are receiving much attention. There is increasing evidence that these compounds are a vital component of the balance achieved by normal immunoregulatory mechanisms. How this balance is achieved, the cells involved, and the consequence of an imbalance in prostaglandin production or consumption are the subject of the articles which follow.
Prostaglandin structure and chemistry: a primer The prostaglandins are difficult to study because they are produced locally, are found in very minute quantities and, since they are metabolized quickly, are detectable for only short periods of time. Their detection and quantitation generally relies on radioimmunoassay or gas chromatography-mass spectrometry, methods which each have inherent limitations. The prostaglandins have been considered 'local hormones', having essentially no systemic activities. This © 1984,ElsevierScience PublishersB.V.,Amsterdam 0167 4919/84/$02.00
opinion may, however, require modification in selected circumstances, such as those described below. Prostaglandins are synthesized within or adjacent to cell membranes, from at least three, closely related 20-carbon-atom parent compounds. Arachadonic acid is the most widely known of these precursors. Synthesized metabolites are not stored, as are biogenic amines, but are formed via the activity of cyclo-oxygenase immediately prior to their release. This enzymatic pathway is present in most mam-
Immunology Today, vol. 5, No. 6, 1984
Hormones, handedness, and autoimmunity It has been reported that left-handedness and autoimmune disease are associated ~. This was the conclusion from a three-part study. In the first part, subjects answered a questionnaire designed to test laterality and to establish personal and family medical histories. Left-handed subjects reported significantly more immune disorders and developmental learning disorders than right-handed subjects, but the two study groups were chosen from different populations. The diseases reported by the subjects that were classed as immune disorders were celiac disease, dermatomyositis, diabetes, Hashimoto's thyroiditis, myxedema, regional ileitis, rheumatoid arthritis, thyrotoxicosis, ulcerative colitis, and uveitis. In the second part of the study, all subjects were chosen from the same population and only immune diseases established in a hospital were counted. Left-handed subjects again reported an increased frequency of immune disorders and learning disorders in themselves and in family members. The third part of the study concentrated on patients with specific immune diseases. There was a slight increase in the frequency of left-handedness in patients with myasthenia gravis, but no increase in left-handedness among patients with multiple sclerosis, rheumatoid arthritis, or 'mixed-collagen vascular diseases'. These findings provide limited evidence for an association between left-handedness, learning disorders and diseases that may be autoimmune in origin. Geschwind and Behan postulate that this association reflects the prenatal influence of fetal testosterone on the developing immune and central nervous systems. They propose two hypotheses. The first is that during embryogenesis, testosterone slows neuronal development in the left hemisphere of the brain, predisposing to learning disorders, right cerebral dominance, and left-handedness; the second is that testosterone impairs development of the immune system, predisposing to autoimmunity. Although the role of male sex hormones is pivotal in these hypotheses, Geschwind and Behan did not report the effect of gender on either left-handedness or autoimmunity in their subjects, nor did they demonstrate concordance between immune disorders and learning disorders. Their hypotheses therefore are not based primarily on their own findings, but rather on their interpretation of other observations. They cite studies in rats demonstrating that part of the posterior cortex develops asymmetrically, the right side being thicker in males and the left side thicker in females 2. Sex-related functional asymmetry of the brain has also been reported in human beings3-5; left-handedness, for example, is more common in men than in women 5. These observations are consistent with the hypothesis that testosterone favors development of the right hemisphere relative to the left hemisphere. Several studies support the notion that androgen impairs prenatal development of the immune system. In mice, high androgen sensitivity correlates with low immune responses independent of postnatal androgen concentrations 6. In chickens, prenatal administration of androgen arrests development of the bursa and produces
cortical atrophy of the thymus 7'8. In the light of these findings, Geschwind and Behan propose two mechanisms that could explain an association between fetal androgen and subsequent autoimmune disease. First, by retarding. development of the fetal thymus, testosterone could impair recognition of self-antigens and thereby predispose to autoimmunity. While this is consistent with testosterone-induced thymic atrophy in chick embryos 8, it does not explain conflicting findings in mice where high androgen sensitivity and low immune responses correlate with large thymic size +. Alternatively, they propose that an association between fetal androgen and autoimmunity might reflect linkage between genes governing androgen sensitivity and immune response genes. They note that polygenic control of testosterone metabolism involves some genes that are linked to the major histocompatibility (H-2) complex of the mouse 9. However, these H-2-1inked genes do not account for the association between immune responsiveness and androgen sensitivity, which is controlled by genes that are not linked to the H - 2 region 6. One possible mechanism not considered by Geschwind and Behan involves direct effects of the CNS on the immune system. Several studies suggest that the CNS may influence immune regulation I°'11. For example, hypothalamic abnormalities can alter immune responses 11. Interestingly, testosterone may affect development of the hypothalamus ~2. Thus, androgen could conceivably influence the immune system, not through a direct effect on lymphoid tissue but indirectly, by altering the effects of the CNS on immunoregulation. If increased fetal androgen leads to autoimmune disease, then males should be at particular risk. On the contrary, females are more susceptible than males to most autoimmune diseases 19. Furthermore, in postnatal development, androgen exerts an immunosuppressive effect that may actually protect against autoimmunity 14-~7. It is difficult to reconcile these observations with any mechanism relating androgen sensitivity, left-handedness, and autoimmunity. Geschwind and Behan propose that prenatal androgen sensitivity predisposes to autoimmunity, but that high postnatal androgen concentrations protect men against autoimmunity. While it is possible that testosterone exerts diametrically opposing effects prenatally and postnatally, there is no evidence that prenatal androgen exposure predisposes to autoimmunity. Geschwind's theories have received added attention recently in conjunction with studies linking male gender, superior mathematical ability, and left handedness ~8.~9.A series of talent searches conducted at Johns Hopkins University and widely reported in the scientific and lay press have shown that boys consistently score higher than girls in tests of mathematical aptitude. The suggestion that this observation might reflect inherent genetic differences between boys and girls appropriately generated considerable controversy 2°. This controversy has been rekindled by a recent preliminary report suggesting an increased frequency of left-handedness and allergies among mathematically gifted children19+ Geschwind © 198'[, Elsevier Science Publishers B.V., Amsterdam
0167
4919/84/$02.00
Immunology "lbday, vol. 5, No. 6, 1984
170
contends that his theories explain these findings 19. He proposes that increased testosterone in boys favors development of the right hemisphere of the brain, where mathematical ability is thought to reside, thus increasing the likelihood of both left-handedness and mathematical genius. Geschwind further speculates that real-development of the left cortex is responsible for an increased frequency of developmental verbal disorders (e. g., dyslexia, stuttering) in left-handed people in general and boys in particular 1. It is beyond the scope of this commentary to review each of the areas encompassed by Geschwind's hypotheses. From an immunological standpoint, however, they rest on a weak foundation. First, the data are not compelling. Some important information (e.g., the gender of their subjects) were not presented by Geschwind and Behan and not all of the data presented support an association between left-handedness and autoimmunity. Second, there is no basis for treating such divergent immune disorders as allergy and autoimmunity interchangeability. Third, there is no experimental support for the hypothesis that prenatal androgen predisposes to autoimmunity. A slender thread connects a series of controversial topics. How do sex hormones influence the immune response? What is the relationship between the CNS and the immune system? Are men immunologicaUy inferior to women? Are women mathematically inferior to men? Are left-handed people predisposed to develop autoimmune disease, have learning disorders, or be geniuses? None of these issues is resolved, yet some have achieved rapid notoriety, not because of their scientific substance but because of perceived social implications. In this setting, a particularly high standard of scientific rigor and social conscience is required. Even if future studies confirm a
K] (-.,,-.
developmental basis for an association between left-handedness and immune diseases or between gender and certain skills, these associations explain neither autoimmunity nor scholastic aptitude in the vast majority of people.
n-I References 1 GeschMnd, N. and Behan, P. (1982) Proc. Natl Acad. Sci. USA 79, 5097-5100 2 Diamond, M. C., DoMing, G. A. and Johnson, R. E. (1981) Exp. Neurol. 71, 261-268 3 McGloneJ. (1980) Behav. Brain Sci. 3, 215-263 4 Inglis, J. and Lawson, J. S. (1981) Science2t2, 693-695 5 Porac, C. andCoren, S.(1981)LateralPreferenceeandHumanBehaviour, pp. 35-45, Springer, New York 6 Cohn, D. A. (1979) Arthritis Rheum. 22, 1218-1233 7 Warner, N. L., Uhr, J. W., Thorbecke, J. and Ovary, Z. (1969)J. ImmunoL 103, 1317-1330 8 Warner, N. L., Szenberg, A. and Burner, F. M. (1962) Aust. J. Exp. BioL Med. Sci. 40, 373-387 9 Ivanyi, P. (1978) Proc. R. Soc. London Set. B. 202, 117-158 10 Ader, R. and Cohen, N. (1975) Psychosom. Med. (NY) 37, 333-340 11 Stein, M., Schleifer, M. D. and Keller, C. E. (1981) in Psychoneuroimmunolog~ (Ader, R., ed.), pp. 429-447, Academic Press, New York 12 MacLusky, N. J. and Naftolin, F. (1981)Science 211, 1294-1303 13 Masi, A. R. and Medsger, T. A., Jr. (1979) in Arthritis and Allied Conditions (McCarty, D. J., ed.), pp. 11-35, Lea and Febiger, Philadelphia 14 Eidinger, D. and Garrett, T. J. (1972)J. Exp. Med. 136, 1098-1116 15 Graft, R. J., Lappe, M. A. and Snell, G. D. (1969) Transplantation 7, 105-111 16 Roubinian, J. R., Papoian, R. and Talal, N. (1977)J. Clin. Invest. 59, 1066-1070 17 Roubinlan, J. R., Tala, N., Greenspan, J. S., Goodman, J. R. and Siiteri, P. R. (1978)J. Exp. Med. 147, 1568-1583 18 Benbow, C. P. and Stanley, J. C. (1983) Science222, 1029 1031 19 Kolata, G. (1983) Science 222, 1312-1315 20 Science(1981) 212, 114-121 DAVID WOFSY Arthritis~Immunology Unit, VeteransAdministration Medical Center and the Department of Medicine, University of California, San Francisco, CA 94143, USA.
I Prostaglandins and Immunity
The prostaglandins are a family of biologically active compounds generated from unsaturated fatty acids. They are produced and found in every tissue of the body and their diverse biological activities and possible role in human disease processes are receiving much attention. There is increasing evidence that these compounds are a vital component of the balance achieved by normal immunoregulatory mechanisms. How this balance is achieved, the cells involved, and the consequence of an imbalance in prostaglandin production or consumption are the subject of the articles which follow.
Prostaglandin structure and chemistry: a primer The prostaglandins are difficult to study because they are produced locally, are found in very minute quantities and, since they are metabolized quickly, are detectable for only short periods of time. Their detection and quantitation generally relies on radioimmunoassay or gas chromatography-mass spectrometry, methods which each have inherent limitations. The prostaglandins have been considered 'local hormones', having essentially no systemic activities. This © 1984,ElsevierScience PublishersB.V.,Amsterdam 0167 4919/84/$02.00
opinion may, however, require modification in selected circumstances, such as those described below. Prostaglandins are synthesized within or adjacent to cell membranes, from at least three, closely related 20-carbon-atom parent compounds. Arachadonic acid is the most widely known of these precursors. Synthesized metabolites are not stored, as are biogenic amines, but are formed via the activity of cyclo-oxygenase immediately prior to their release. This enzymatic pathway is present in most mam-
