Immunology Today, vol. 5, No. 7, 1984
190
Hormones, handedness and immunity SIR, We appreciate the opportunity to respond to David Wofsy's comments on our findings on the association of lefthandedness and immune disorders (Immunol. Today 1984, 5, 169-170). While there are a few useful statements in Wofsy's paper, there are many omissions of important data and inaccuracies. In addition, we will supply further information that has been gathered since our first publication. In reporting our findings Wofsy fails to indicate the large numbers of individuals studied and the striking magnitude of the effects found. Our first two series contained 500 strong left-handers and 900 strong right-handers. Immune diseases were two-and-one-half times more frequent in the left-handers than in the right-handers and were also much more common in the relatives of the lefthanders. In addition, childhood learning disorders were 10 times as common in the Strong left-handers as in the righthanders and were also found more often in their relatives. All of the above results easily achieved statistical significance. Since the publication of the original paper we have studied another large series with comparable results. In our original paper 1 we also studied a group of patients with myasthenia gravis, in whom there was nearly twice the rate of left-handedness of our general population controls, and with migraine in whom strong left-handedness was twice as common as in controls. We stated, however, 'We expected the study of the patient groups to give results less clearcut (than those of our studies of lefthanders and right-handers) since we did not have available groups of patients with those immune disorders (i.e., involving thyroid or bowel) that our first study had found most often in the lefthanders'. Furthermore, we stressed the small size of the patient groups available then. Since then we have studied patient groups with celiac disease, regional ileitis, ulcerative colitis, and thyroid immune disorders and found a sharply increased rate of left-handers in both the patients and the relatives. In addition, we have found elevated rates of lefthandedness in childhood allergies and migraine 2. Confirmations have been forthcoming from other independent groups. At the American Thyroid Association © 1981-, Elsevier Science PublLshel~ B.V., Amsterdam 0167
meeting in New Orleans in October, 1983, Lawrence Wood reported a strikingly increased rate of non-righthandedness in thyroid immune disease. In the Johns Hopkins study of mathematically gifted children an elevated rate of left-handedness was found. Over 60 % of this population had allergies, a rate far above that of controls ~. Marcel Kinsbourne and Brenda Bemporad have informed us that left-handed childhood dyslexics have more relatives with immune disorders than do right-handed dyslexics. In view of the repeated confirmations in very large numbers of people of a powerful association between lefthandedness and immune disorders and learning disorders, Wofsy's statement that 'these findings provide limited evidence' for such associations is clearly in error. We are, of course, in full agreement with Wofsy that much more information is required about this pattern of associations and much of this is now being collected. But his statement that our hypotheses 'are not based primarily on their own findings but rather on their interpretation of other observations' is dearly incorrect. Our hypothesis, like any scientific hypothesis, is based heavily both on our own observations and on other data. Wofsy devotes most of his discussion to the working hypothesis advanced in our original paper. We did not advance as an alternative hypothesis the possibility that 'an association between fetal androgen and autoimmunity might reflect linkage between genes governing androgen sensitivity and immune response genes'. What we actually said was 'The hypothesis that testosterone has a major role in the development of immunity is in conformity with several experimental studies. Iv~nyi 4 has shown that several loci on the major histocompatibility complex in the mouse control not only the immune system but also various aspects of male differentiation, including mass of testis and thymus, blood testosterone, testosteronebinding globulin levels, sensitivity to testosterone and expression of H-Y antigen on thymus'. In other words, while these data might suggest linked genes with independent actions, an alternative hypothesis which deserves consideration is that these genes affect immunity at least in part indirectly through their effects on male differentiation. Whether this is correct or not can only be settled by experiment. Wofsy cites Gohn 5 in support of the statement that 'H-2-1inked genes do not account for the association between immune responsiveness and androgen
4919/84/$02.00
sensitivity, which is controlled by genes that are not linked to the H-2 region'. Cohn, in fact, states the exact opposite: '... sensitivity, to androgen is a genetically controlled trait thought to be regulated by polygenes with loci postulated at the Horn- 1 locus near the K end of the H-2 complex or at the Tfm locus on the Xchromosome' (our italics). Wofsy's error is based on a misinterpretation of C ohn's statement that 'sensitivity to androgen is not linked to H-2 type' which is, of course, perfectly compatible with the above statement. We also pointed out in our original paper that Ohno6 had proposed that B2 microglobulin was necessary for the expression of H-Y antigen in the development of the testes. A recent publication 7 brings evidence that childhood dyslexia (a male-predominant condition with a high rate of lefthandedness) is linked to chromosome 15. In the human, as is well known, this chromosome contains the locus for B 2 - -microglobulin. It is, of course, not yet known whether the B2 - -microglobulin locus is the one involved in dyslexia. Wofsy cites several papers showing testosterone effects on the thymus, consistent with our hypothesis. He cites Cohn 5 as having presented 'conflicting findings in mice where high androgen sensitivity and low immune responses correlate with large thymic size'. This gives the impression that within a single strain of mice large thymic size correlates with the above features. Cohn does not present such within-strain data. Instead he shows that the H A R strain has higher average thymus weight than the LAR strain. Yet although the H A R strain is described as showing high androgen responsiveness, neither testosterone nor castration affected immune responses in this strain in contrast to many findings in other species in other experimental studies. In fact in the strains studied by Cohn, high androgen sensitivity was manifested in non-immune organs. The data might be compatible with absence of androgen sensitivity in the immune system. In order to explain these fascinating but perplexing findings Cohn raises 'the possibility that during prenatal development androgens present in the fetus exert a critical influence on the immune s y s t e m . . . We suggest that in individuals highly sensitive to this steroid, androgens produced by the fetal testes, adrenals, or placenta act on the developing lymphomyeloid complex to create an immune system programmed for low immune responses'. We do not disagree with Wofsy's suggestion that prenatal androgens
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Immunology Today, vol. 5, No. 7, 1984
might affect immune responsiveness by their actions on the hypothalamus. We doubt, however, that this can be the only mechanism, since as Wofsy himself points out, fetal testosterone does alter the bursa of Fabricius and the thymus. Wofsy discusses our hypothesis that fetal androgen predisposes to later immune disorders. He is correct in saying that our hypothesis implies that 'males should be at particular risk' but, surprising as it may first appear to the reader, he may well be wrong in asserting that 'females are more susceptible than males to most autoimmune diseases'. It is correct that females manifest higher rates of autoimmune diseases but this does not rule out the possibility that males, despite higher susceptibility, are protected by their own testosterone at puberty. Indeed, both Wofsy and Cohn s point out data on protective effects of postnatal androgen against autoimmunity. If our working hypothesis is correct then the male exposed to normal or high testosterone levels in utero who later becomes hypogonadal should have an especially high rate of immune disorder, having been made susceptible by fetal exposure, and lacking the later protective androgen effect. Patients with Klinefelter's syndrome conform precisely to this prediction. Robert Lahita (Rockefeller University, New York) has informed us that these patients appear to have very high rates of lupus erythematosus. This is an important issue and deserves careful formal study. Wofsy states correcdy that the literature does not contain evidence in support of our hypothesis that prenatal androgen exposure predisposes to autoimmunity. In order to test our hypothesis one of us (P.B.) has now carried out studies on animals exposed to testosterone in utero and has found that they have altered Tcell subsets and a higher level of thyroid antibodies. In his closing summary Wofsy states that the 'data are not compelling'. In view of the fact that in several different studies by different groups in over 3000 individuals a strikingly elevated rate of immune disorders has been found in left handers, it is difficult to see how the data could be more compelling. The statement that the hypothesis 'rests on a weak immunological foundation' is equally perplexing in view, on one hand, of Wofsy's agreement with many of our arguments and, on the other, of the weakness or inaccuracy of his criticisms. The statement that 'there is no basis for treating . . . allergy and autoimmunity interchangeably' is curious. The simple fact is that our data
show that both are elevated in left handers. In the last paragraph of his commentary Wofsy refers to 'a series of controversial topics'. Unfortunately science is not a suitable activity for those who dislike controversy, and the readers of Immunology Today, Science, or Nature know full well that in science there are no non-controversial topics. He goes on to pose a series of questions, some of which we have not addressed nor would we ever address them in the manner stated. In his last sentence Wofsy hedges his bets, stating 'Even if future studies confirm of a 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'. We have never argued that we can explain all autoimmunity, all learning disabilities, or all talents. What we have done is to document a novel association of immune disease. Our working hypothesis has been fruitful in directing experimental studies but we have every expectation that future findings will certainly lead to modification of this first attempt at understanding the causes of ** This letter was shown to David Wofsy, whose reply follows: SIR,
In my discussion of the studies and hypotheses of Norman Geschwind and Peter Behan, I made four specific criticisms that still pertain: 1. Some important data collected by Geschwind and Behan were not presented in their original report, nor are these data included in the response to my commentary. For example, Geschwind and Behan do not describe the effect of gender on either left-handednessor autoimmunity in their subjects. These data are relevant to the hypothesis that male sex hormones are responsible for a link between left-handedness and autoimmunity. Furthermore, if, as proposed, the increased frequency of antoimmunity and learning disorders in lefthanded people reflects a common predisposing factor (e.g. androgen), it would be helpful to know if there was concordance between autoimmune disorders and learning disorders. The new data to which Geschwind and Behan refer in their letter is virtually all unpublished and therefore difficult to evaluate. We are left instead with a reaffirmation of their confidence in their interpretation of the data, but not with the additional information that would help the rest of us to make an independent judgement.
this association. If these studies help to prevent or alleviate even a small proportion of the impairments produced by immune disease or learning disabilities, or to extend even to a minor extent the limits of human potential, the effort expended will have been amply repaid. NORMAN GESCHWIND* PETER BEHAN ~
*Neurological Unit, Beth Israel Hospital, Boston, MA 02215, USA. TInstitute of Neurological Sciences, Southern General Hospital, Glasgow, UK.
References 1 2
Gesehwind, N. and Behand, P. (1982) Proc. Natl Acad. ScL USA 79, 5097-5100 Gesehwind, N. and Behan, P. in Cerebral Dominance: The Biological Foundations (Geschwind, N. and Galaburda, A., eds), H a r v a r d University Press, Cambridge,
MA (in press) Kolata,G. (1983) Science 222, 1312 Iv~Inyi,P. (1978)Proc. R. Soc. London Set. B BioL Sci. 202, 117-158 5 Cohn, D. A. (1979) Arthritis Rheum. 22, 1218-2233 6 Piano,S. (1977) ImmunoL Rev. 33, 59-69 7 Smith, S. B., Kimberling, W. J., Pennington, B. F. and Lubs, H. A. (1983) Science 219, 1345-1347 3 4
9. Not all of the data presented by Geschwind and Behan support an association between left-handedness and autoimmunity. Myasthenia gravis was associated with left-handedness only according to the loosest definition of lefthandedness; for people who were moderately or strongly left-handed, there was no such association. Moreover, there was no increase in left-handedness among 109 patients with rheumatoid arthritis, 168 patients with collagen vascular diseases, or 118 patients with multiple sclerosis. One cannot emphasize the weak findings in myasthenia gravis and then choose to ignore the findings in other autoimmune diseases. 3. The proposed hypotheses are defended by some specious reasoning. For example, there is no basis for using the reported frequency of childhood allergies in math scholars to support an hypothesis concerning left-handedness and autoimmunity, especially in the absence of any published data linking lefthandedness and allergies or linking the pathogenesis of allergic disease and autoimmune disease. It is difficult to comment on unpublished observations concerning left-handednessand allergies when the letter from Geschwind and Behan does not include their results. 4. Through a series of loose associations, Geschwind and Behan extend their hypotheses concerning sex hormones, left-handedness, and auto-
© 1984,FA~evierSciencePublishersB.V.. Amsterdam 0187- 4019/84/$02.00
190
Hormones, handedness and immunity SIR, We appreciate the opportunity to respond to David Wofsy's comments on our findings on the association of lefthandedness and immune disorders (Immunol. Today 1984, 5, 169-170). While there are a few useful statements in Wofsy's paper, there are many omissions of important data and inaccuracies. In addition, we will supply further information that has been gathered since our first publication. In reporting our findings Wofsy fails to indicate the large numbers of individuals studied and the striking magnitude of the effects found. Our first two series contained 500 strong left-handers and 900 strong right-handers. Immune diseases were two-and-one-half times more frequent in the left-handers than in the right-handers and were also much more common in the relatives of the lefthanders. In addition, childhood learning disorders were 10 times as common in the Strong left-handers as in the righthanders and were also found more often in their relatives. All of the above results easily achieved statistical significance. Since the publication of the original paper we have studied another large series with comparable results. In our original paper 1 we also studied a group of patients with myasthenia gravis, in whom there was nearly twice the rate of left-handedness of our general population controls, and with migraine in whom strong left-handedness was twice as common as in controls. We stated, however, 'We expected the study of the patient groups to give results less clearcut (than those of our studies of lefthanders and right-handers) since we did not have available groups of patients with those immune disorders (i.e., involving thyroid or bowel) that our first study had found most often in the lefthanders'. Furthermore, we stressed the small size of the patient groups available then. Since then we have studied patient groups with celiac disease, regional ileitis, ulcerative colitis, and thyroid immune disorders and found a sharply increased rate of left-handers in both the patients and the relatives. In addition, we have found elevated rates of lefthandedness in childhood allergies and migraine 2. Confirmations have been forthcoming from other independent groups. At the American Thyroid Association © 1981-, Elsevier Science PublLshel~ B.V., Amsterdam 0167
meeting in New Orleans in October, 1983, Lawrence Wood reported a strikingly increased rate of non-righthandedness in thyroid immune disease. In the Johns Hopkins study of mathematically gifted children an elevated rate of left-handedness was found. Over 60 % of this population had allergies, a rate far above that of controls ~. Marcel Kinsbourne and Brenda Bemporad have informed us that left-handed childhood dyslexics have more relatives with immune disorders than do right-handed dyslexics. In view of the repeated confirmations in very large numbers of people of a powerful association between lefthandedness and immune disorders and learning disorders, Wofsy's statement that 'these findings provide limited evidence' for such associations is clearly in error. We are, of course, in full agreement with Wofsy that much more information is required about this pattern of associations and much of this is now being collected. But his statement that our hypotheses 'are not based primarily on their own findings but rather on their interpretation of other observations' is dearly incorrect. Our hypothesis, like any scientific hypothesis, is based heavily both on our own observations and on other data. Wofsy devotes most of his discussion to the working hypothesis advanced in our original paper. We did not advance as an alternative hypothesis the possibility that 'an association between fetal androgen and autoimmunity might reflect linkage between genes governing androgen sensitivity and immune response genes'. What we actually said was 'The hypothesis that testosterone has a major role in the development of immunity is in conformity with several experimental studies. Iv~nyi 4 has shown that several loci on the major histocompatibility complex in the mouse control not only the immune system but also various aspects of male differentiation, including mass of testis and thymus, blood testosterone, testosteronebinding globulin levels, sensitivity to testosterone and expression of H-Y antigen on thymus'. In other words, while these data might suggest linked genes with independent actions, an alternative hypothesis which deserves consideration is that these genes affect immunity at least in part indirectly through their effects on male differentiation. Whether this is correct or not can only be settled by experiment. Wofsy cites Gohn 5 in support of the statement that 'H-2-1inked genes do not account for the association between immune responsiveness and androgen
4919/84/$02.00
sensitivity, which is controlled by genes that are not linked to the H-2 region'. Cohn, in fact, states the exact opposite: '... sensitivity, to androgen is a genetically controlled trait thought to be regulated by polygenes with loci postulated at the Horn- 1 locus near the K end of the H-2 complex or at the Tfm locus on the Xchromosome' (our italics). Wofsy's error is based on a misinterpretation of C ohn's statement that 'sensitivity to androgen is not linked to H-2 type' which is, of course, perfectly compatible with the above statement. We also pointed out in our original paper that Ohno6 had proposed that B2 microglobulin was necessary for the expression of H-Y antigen in the development of the testes. A recent publication 7 brings evidence that childhood dyslexia (a male-predominant condition with a high rate of lefthandedness) is linked to chromosome 15. In the human, as is well known, this chromosome contains the locus for B 2 - -microglobulin. It is, of course, not yet known whether the B2 - -microglobulin locus is the one involved in dyslexia. Wofsy cites several papers showing testosterone effects on the thymus, consistent with our hypothesis. He cites Cohn 5 as having presented 'conflicting findings in mice where high androgen sensitivity and low immune responses correlate with large thymic size'. This gives the impression that within a single strain of mice large thymic size correlates with the above features. Cohn does not present such within-strain data. Instead he shows that the H A R strain has higher average thymus weight than the LAR strain. Yet although the H A R strain is described as showing high androgen responsiveness, neither testosterone nor castration affected immune responses in this strain in contrast to many findings in other species in other experimental studies. In fact in the strains studied by Cohn, high androgen sensitivity was manifested in non-immune organs. The data might be compatible with absence of androgen sensitivity in the immune system. In order to explain these fascinating but perplexing findings Cohn raises 'the possibility that during prenatal development androgens present in the fetus exert a critical influence on the immune s y s t e m . . . We suggest that in individuals highly sensitive to this steroid, androgens produced by the fetal testes, adrenals, or placenta act on the developing lymphomyeloid complex to create an immune system programmed for low immune responses'. We do not disagree with Wofsy's suggestion that prenatal androgens
191
Immunology Today, vol. 5, No. 7, 1984
might affect immune responsiveness by their actions on the hypothalamus. We doubt, however, that this can be the only mechanism, since as Wofsy himself points out, fetal testosterone does alter the bursa of Fabricius and the thymus. Wofsy discusses our hypothesis that fetal androgen predisposes to later immune disorders. He is correct in saying that our hypothesis implies that 'males should be at particular risk' but, surprising as it may first appear to the reader, he may well be wrong in asserting that 'females are more susceptible than males to most autoimmune diseases'. It is correct that females manifest higher rates of autoimmune diseases but this does not rule out the possibility that males, despite higher susceptibility, are protected by their own testosterone at puberty. Indeed, both Wofsy and Cohn s point out data on protective effects of postnatal androgen against autoimmunity. If our working hypothesis is correct then the male exposed to normal or high testosterone levels in utero who later becomes hypogonadal should have an especially high rate of immune disorder, having been made susceptible by fetal exposure, and lacking the later protective androgen effect. Patients with Klinefelter's syndrome conform precisely to this prediction. Robert Lahita (Rockefeller University, New York) has informed us that these patients appear to have very high rates of lupus erythematosus. This is an important issue and deserves careful formal study. Wofsy states correcdy that the literature does not contain evidence in support of our hypothesis that prenatal androgen exposure predisposes to autoimmunity. In order to test our hypothesis one of us (P.B.) has now carried out studies on animals exposed to testosterone in utero and has found that they have altered Tcell subsets and a higher level of thyroid antibodies. In his closing summary Wofsy states that the 'data are not compelling'. In view of the fact that in several different studies by different groups in over 3000 individuals a strikingly elevated rate of immune disorders has been found in left handers, it is difficult to see how the data could be more compelling. The statement that the hypothesis 'rests on a weak immunological foundation' is equally perplexing in view, on one hand, of Wofsy's agreement with many of our arguments and, on the other, of the weakness or inaccuracy of his criticisms. The statement that 'there is no basis for treating . . . allergy and autoimmunity interchangeably' is curious. The simple fact is that our data
show that both are elevated in left handers. In the last paragraph of his commentary Wofsy refers to 'a series of controversial topics'. Unfortunately science is not a suitable activity for those who dislike controversy, and the readers of Immunology Today, Science, or Nature know full well that in science there are no non-controversial topics. He goes on to pose a series of questions, some of which we have not addressed nor would we ever address them in the manner stated. In his last sentence Wofsy hedges his bets, stating 'Even if future studies confirm of a 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'. We have never argued that we can explain all autoimmunity, all learning disabilities, or all talents. What we have done is to document a novel association of immune disease. Our working hypothesis has been fruitful in directing experimental studies but we have every expectation that future findings will certainly lead to modification of this first attempt at understanding the causes of ** This letter was shown to David Wofsy, whose reply follows: SIR,
In my discussion of the studies and hypotheses of Norman Geschwind and Peter Behan, I made four specific criticisms that still pertain: 1. Some important data collected by Geschwind and Behan were not presented in their original report, nor are these data included in the response to my commentary. For example, Geschwind and Behan do not describe the effect of gender on either left-handednessor autoimmunity in their subjects. These data are relevant to the hypothesis that male sex hormones are responsible for a link between left-handedness and autoimmunity. Furthermore, if, as proposed, the increased frequency of antoimmunity and learning disorders in lefthanded people reflects a common predisposing factor (e.g. androgen), it would be helpful to know if there was concordance between autoimmune disorders and learning disorders. The new data to which Geschwind and Behan refer in their letter is virtually all unpublished and therefore difficult to evaluate. We are left instead with a reaffirmation of their confidence in their interpretation of the data, but not with the additional information that would help the rest of us to make an independent judgement.
this association. If these studies help to prevent or alleviate even a small proportion of the impairments produced by immune disease or learning disabilities, or to extend even to a minor extent the limits of human potential, the effort expended will have been amply repaid. NORMAN GESCHWIND* PETER BEHAN ~
*Neurological Unit, Beth Israel Hospital, Boston, MA 02215, USA. TInstitute of Neurological Sciences, Southern General Hospital, Glasgow, UK.
References 1 2
Gesehwind, N. and Behand, P. (1982) Proc. Natl Acad. ScL USA 79, 5097-5100 Gesehwind, N. and Behan, P. in Cerebral Dominance: The Biological Foundations (Geschwind, N. and Galaburda, A., eds), H a r v a r d University Press, Cambridge,
MA (in press) Kolata,G. (1983) Science 222, 1312 Iv~Inyi,P. (1978)Proc. R. Soc. London Set. B BioL Sci. 202, 117-158 5 Cohn, D. A. (1979) Arthritis Rheum. 22, 1218-2233 6 Piano,S. (1977) ImmunoL Rev. 33, 59-69 7 Smith, S. B., Kimberling, W. J., Pennington, B. F. and Lubs, H. A. (1983) Science 219, 1345-1347 3 4
9. Not all of the data presented by Geschwind and Behan support an association between left-handedness and autoimmunity. Myasthenia gravis was associated with left-handedness only according to the loosest definition of lefthandedness; for people who were moderately or strongly left-handed, there was no such association. Moreover, there was no increase in left-handedness among 109 patients with rheumatoid arthritis, 168 patients with collagen vascular diseases, or 118 patients with multiple sclerosis. One cannot emphasize the weak findings in myasthenia gravis and then choose to ignore the findings in other autoimmune diseases. 3. The proposed hypotheses are defended by some specious reasoning. For example, there is no basis for using the reported frequency of childhood allergies in math scholars to support an hypothesis concerning left-handedness and autoimmunity, especially in the absence of any published data linking lefthandedness and allergies or linking the pathogenesis of allergic disease and autoimmune disease. It is difficult to comment on unpublished observations concerning left-handednessand allergies when the letter from Geschwind and Behan does not include their results. 4. Through a series of loose associations, Geschwind and Behan extend their hypotheses concerning sex hormones, left-handedness, and auto-
© 1984,FA~evierSciencePublishersB.V.. Amsterdam 0187- 4019/84/$02.00
