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Environmental factors versus genetic determinants of childhood inhalant allergies
THE JOURNAL OF
ALLERGY AND
CLINICAL IMMUNOLOGY VOLUME 86
NUMBER 3, PART 1
Continuing Medical Education This continuing medical education self-assessment program is sponsored by The American Academy of Allergy and Immunology.
Environmental factors versus genetic determinants of childhood inhalant allergies Dennis R. Ownby, MD Detroit, Mich.
A classic question in many areas of medicine is nature versus nurture. When an individual develops an allergic disease, is the disease the result of heredity or the environment? Since the pioneering study of Cooke and Vander Veer, 1 published in 1916, the familial nature of atopic disease has not been seriously disputed; however, many studies have also demonstrated the importance of the environment on the genesis of allergic disease. 2-5 There are multiple reasons for considering the relative importance of genetic and environmental effects in the development of allergies. Parents ask about the risk of allergy in their children and about methods for reducing the risk of allergy. Patients inquire about why they have developed allergies and why allergies developed at a particular time. Assessment of the risk of allergy is also important in efforts to reduce occupational allergic disease and in designing studies to prevent other allergic diseases. From the Department of Pediatrics and CommunicableDiseases, University of Michigan, and Pediatric AllergyImmunologyResearch Laboratory,Henry Ford Hospital, Detroit, Mich. Reprint requests: Dennis R. Ownby, MD, Director, Pediatric Allergy ImmunologyResearch Laboratory, Henry Ford Hospital, Detroit, MI 48202. 1/2/17294
Abbreviations used HLA: Human leukocyte antigen Ir: Immune response EA: Egg albumin IT: Immunotherapy DPT: Diphtheria toxoid, pertussis vaccine, and tetanus toxoid
GENETICS OF ALLERGY Allergic disease continues to defy precise explanation in genetic terms. 6, 7 Many early studies evaluated the question of allergic inheritance by determining the prevalence of a family history of allergic disease in individuals who did or did not have a particular allergic disease. Although there are differences between the studies, as many as 40% to 80% of individuals with allergic rhinitis or asthma had positive family histories compared to 20% or less in individuals without allergic disease. 7 Many studies have evaluated the risk of a child becoming allergic based on the parental history of allergy. In general, the risk of allergy is believed to be about 20%, but this increases to 50% if one parent is allergic and in-
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creases the risk further to 66% if both parents are allergic. 8-1~ A large prospective study reported by Horwood et al. n confirmed the increased risk of childhood asthma in children of allergic parents, but this study found a complex relationship. The study is based on 1056 children followed from birth in the Christchurch, New Zealand, area. Family histories were obtained prenatally, and the children were followed at 4 months of age, and then annually to 6 years of age. Multiple variables, including early feeding, home environment, psychosocial factors, and family backgrounds were evaluated. The risk of a child developing asthma was markedly different between sexes. In agreement with other studies, boys were more likely to develop asthma than girls (14.3% versus 6.3%; p < 0.001). Of more interest was that the risk factors for boys and girls differed. The only risk factor for asthma in girls was eczema in the first year of life. A family history of asthma, allergic rhinitis, or eczema, either in the parents or siblings, was not significantly related to asthma in. girls. In contrast, boys were at increased risk of asthma if there was a history of asthma or allergic rhinitis in the parents or asthma in a sibling. 11 This large prospective study concluded that there was limited inheritance of early childhood asthma.11 Other investigators have observed the increased risk of allergy in male compared to female subjects. Magnusson 12noted that the risk of allergy in an infant was higher if the mother was allergic than if the father was allergic. Happle and Schnyder 13 also observed that atopic disease was more frequent in infants if the mother alone was allergic compared to infants when the father alone was allergic. They believed that this difference in hereditary risk was evidence for the CarteP 4 effect. Carter 14 demonstrated that pyloric stenosis occurs more frequently in relatives of affected girls than in relatives of affected boys. Carter explained these observations by proposing that pyloric stenosis was determined by polygeneic inheritance. Predisposing genes are equally distributed between sexes, but the threshold for disease is higher in female than in male subjects. If this is true, then female subjects would be less likely to be affected; however, affected female subjects would have more predisposing genes and thus be more likely to transmit these genes to their offspring. Happle and Schnyder 13 evaluated the children of men and women with atopic asthma. In children of atopic fathers, 32 of 98 (33%) were affected by some f o r m of atopic disease compared to 45 of 93 (45%) of the children of atopic mothers. When children with asthma were considered, only 25% had atopic fathers compared to 40% with atopic mothers. The investigators believed that these
J. ALLERGY CLIN. IMMUNOL. SEPTEMBER 1990
data demonstrated that the Carter 14 effect may play a role in allergic disease, providing additional evidence for polygenetic inheritance in allergy. Another method to evaluate the role of genetics in allergic disease has been the study of twins. 6, 7 Twin studies are usually based on comparing the concordance rates for various allergic diseases between monozygotic and dizygotic twins. If monozygotic twins have a significantly greater degree of concordance than dizygotic twins, the difference is assumed to be genetic, since monozygotic twins are genetically identical. Lubs 15analyzed data from the Swedish twin registry on 6996 pairs of adult twins for the concordance of allergic disease. Asthma was reported in 3.8%, hay fever by 14.8%, and eczema by 2.5% of these twins. As expected, concordance rates for asthma, hay fever, and eczema were significantly higher in the monozygotic than in the dizygotic twins, but the concordance rates in the monozygotic twins were modest, from 15.4% to 21.4%. Lubs 15 stated that, although these data supported a significant genetic component, the effect of the genetic component was small, since 79% to 85% of the monozygotic twin pairs were discordant for these three allergic diseases. Lubs is also analyzed these data from the dizygotic twin pairs to determine the relative risk of allergy in a first-degree relative of an allergic individual. Again the risks were significant and relatively small, ranging from 1.3 to 3.1 times the risk of the population. Interestingly, the risk in first-degree relatives was somewhat disease specific with a higher risk of asthma in the relatives of an individual with asthma than with eczema and vice versa. An important strength of Lubs' study is the fact that it is population based and not subject to the biases induced by the selection of twins by selfreferral or from referral populations. In a more recent study, Hopp et al. 16 reported the intrapair coefficients for monozygotic and dizygotic twins evaluated for total serum IgE concentration, methacholine responsiveness, and skin test reactivity to common aeroallergens. This study was based on 61 pairs of monozygotic and 46 pairs of dizygotic twins. Monozygotic twins were significantly more concordant for serum IgE, methacholine sensitivity, total skin test reactivity, and skin test reactivity to trees. (Correlation coefficients ranged from 0.64 to 0.82 in the monozygotic pairs compared to values of 0.08 to 0.52 for dizygotic pairs.) The significance of the methacholine sensitivity was lost, however, if the results of the monozygotic twins were compared to the results of only the like-sex dizygotic twins. Hopp et al. 16 interpreted these results as demonstrating a genetic basis for a general allergic tendency, as re-
VOLUME 86 NUMBER 3, PART 1
flected by total serum IgE and total skin test reactivity, but that the environment was more important in determining a personal allergic pattern, such as a skin test reactivity to specific allergens. A study of dizygotic and monozygotic twins by Wuthfich et al. 17comparing skin tests, RAST results, and total serum IgE concentrations also concluded that the general tendency to be allergic is genetically influenced but that specific allergic sensitivities are "governed mainly by environmental influences." An interesting means for examining the relative importance of genetic versus environmental influences on the development of allergic disease is to evaluate twins reared together compared to twins reared apart. In a review, Blumenthal et al. 7 stated that no differences in concordance for asthma or seasonal rhinitis were noted in monozygotic twins reared together or apart, suggesting a dominant genetic effect. Although they provide evidence for a genetic effect, twin studies do not provide information about the mode of genetic inheritance. Since total serum IgE concentrations are closely related to the risk and severity of allergic disease, multiple attempts have been made to elucidate the mode of inheritance for serum IgE concentration. 6-7",8-27 These studies are relatively consistent in finding that serum lgE levels are more likely genetically controlled than controlled by the environment, but the mode of inheritance is as yet unclear. ~s-27Family studies suggest that IgE levels have a heritability of about 50%. Early studies by Marsh et al., ~s Gerrard et al., 19 and Rao et al. 2~ suggested recessive inheritance of high IgE levels. As pointed out by Marsh et al. ,6 analysis of serum IgE levels for a genetic effect is complicated by the lack of a distinct bimodal distribution of IgE concentrations in study populations. The mode of inheritance for serum IgE is further confused by more recent data by Blumenthal et al. 7 from seven large pedigrees. When these data are analyzed together, they were not consistent with either a monogeneic or purely environmental effect. With individual analysis of each pedigree, these data from five families were most consistent with a recessive mode of inheritance in contrast to the other two families in which a dominant model of inheritance elicited the best fit to these data. It is unlikely that the inheritance of serum IgE concentration will be clearly defined unless the inheritance of serum IgE can be demonstrated to be linked to another genetic marker.6.7.24.25 Although it is currently not possible to define precisely the inheritance of serum IgE concentrations, the concentration of IgE in an infant's cord blood has been found in multiple studies to be a predictor of allergic risk. 28"36 The predictive value of cord-blood
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IgE is better than that of the family history of allergy, although some investigators suggest using both the family history and cord-blood IgE to predict allergic risk. 28-36Presumably the cord-blood IgE concentration is a reflection of the genetic risk for developing allergic disease. From 52% to 82% of infants with elevated cord-blood IgE develop allergy in childhood compared to only 5% to 30% if cord-blood IgE is n o r m a l . 2s-36 The most convincing data come from the prospective study of 1651 unselected Scandinavian infants followed from birth to 7 years of age. 3~ 36 In this study an elevated cord-blood IgE was defined as ->0.9 IU/ml, which was the limit of sensitivity of the assay used. This concentration of cord-blood IgE had a sensitivity for predicting atopic disease of 82% and a specificity of 70%. 30. 36 Other studies have produced similar results with cord-blood IgE concentrations ranging from 0.6 to 1.3 IU/ml being considered as elevated.~8. 29. 31-35 O'Connor et a l . 37 have stated that the predictive accuracy of cord-blood IgE measurements can be decreased because of admixture of maternal with fetal blood at parturition, resulting in falsely elevated IgE levels. These investigators report using IgA measurements to monitor for maternal admixture, with admixture resulting in cord-blood lgE concentrations of > 1.0 IU/ml in six of 32 (19%) cases of a total of 201 cases examined. Studies have also been performed to evaluate the relationship between allergic diseases and the major histocompatibility complex in man. 6, 7 Early studies attempted to link specific allergic diseases or serum IgE concentrations to HLA types. 25 Some studies have reported significant positive associations between asthma, hay fever, eczema, and the HLA system, but none of these associations has been strong enough and reproducible enough to be clinically u s e f u l . 6' 7 Animal studies have demonstrated that the ability to immunologically recognize and respond to an antigen is genetically determined, 39 but the existence of these Ir genes in humans has been difficult to demonstrate conclusively. Levine et al. 4~provided the first evidence that the Ir to ragweed antigen E was genetically linked to the HLA system in a family study. Other investigators were also able to find an association between IgE response and HLA, but the association is not totally consistent. 7 Work by Marsh et al. 4~ has demonstrated an association between both HLA Dw2 and HLA DR2 and the IgE and IgG response to ragweed allergen Ra5 from both natural ragweed exposure and immunotherapy. Subsequent work by Marsh 42 has demonstrated very strong associations between a purified ragweed allergen (Amb a V) and the DR2/Dw2 HLA specificity. Marsh 42 also suggests that it will soon be pos-
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J. ALLERGY CLIN. IMMUNOL. SEPTEMBER 1990
sible to define the DNA sequence coding for this Ix specificity. In summary, genetic studies have consistently demonstrated a significant genetic influence on an individual's risk for allergic disease. The strength of the genetic influence varies between studies, ranging from mild to fairly strong. This genetic influence is probably the result of multiple genes and is reflected in the basal serum IgE concentration, either at birth or later in life. The second major genetic mechanism involved in human allergy is regulation of response by IR genes. The precise control by IR genes has been difficult to demonstrate, in part because of the multiple antigens in most natural allergens.
lieved that the increased cord-blood IgE associated with maternal smoking was also associated with an increased risk of allergy in the infants. Increased cordblood lgE and IgD concentrations in smoking mothers are consistent with studies demonstrating increased serum IgE and IgD in adult smokers. 47"49 The cause of the increased IgE in adult smokers is not known, but it does not appear to be caused by increased production of IgE to common airborne allergens. The question of a relationship between maternal smoking and cord-blood IgE concentration is potentially very important because it suggests that the risk of childhood allergy could be reduced by smoking cessation during pregnancy.
ENVIRONMENTAL INFLUENCES
Effect of maternal IgG on IgE
Once conception has occurred, an individual's genetic constitution is fixed, and the environment begins to exert its effects on development. Presumably, the only agents that could affect an infant in utero are those capable of passing from the maternal to the fetal circulation across the placenta, including some drugs, products from tobacco smoke, and perhaps some food allergens. Human infants have been found to produce IgE as early as the eleventh week of gestation, and IgE is detectable in the amniotic fluid by the thirteenth week? 8 Although IgE production is possible during most of gestation, in utero sensitization is rare. Six studies used RAST to measure IgE specific for common allergens in cord-blood samples; positive tests were found in only 0% to 2% of the samples.~9. 3o. ~2.43-45 Three of these studies, totaling 275 infants, failed to find any positive tests? ~ 43.45 In contrast is the study by Weil et al.46 examining parasitespecific IgE in infants of infected mothers. In this study, 14 of 57 (26%) infants demonstrated IgE antibody to microfilaria. Taken together, these studies suggest that in utero infants can produce specific IgE but that in most cases the antigenic stimulus is insufficient to initiate IgE production. The stimulus may be insufficient because of the limited quantity of antigen reaching the infant or because of the characteristics of the antigen. Michel et al. 29 reported that cord-blood IgE concentrations were increased in infants of mothers administered progesterone during pregnancy. 33 The question of whether the progesterone-associated increase in IgE is also associated with an increased risk of subsequent allergy is difficult to answer because of the small number of infants involved. Magnusson 35 reported that cord-blood IgE concentrations were elevated in smoking mothers and that cord-blood IgD concentrations were increased if either the mother or the father smoked. Magnusson 3S be-
In contrast to IgE, all infants normally receive large quantities of all IgG subclasses from their mothers via placenta passage. Jarrett and Hall 5~ have used a rat model to evaluate the relationship between a mother's antigen exposure and the risk of allergic sensitization in offspring. Initially, attempts were made to alter the sensitization potential of rat pups by feeding EA to the mothers either during pregnancy or during lactation.SO The feeding of EA did not alter the EA-specific IgE response of the pups to an immunization protocol designed to produce a maximal IgE response after a primary immunization and one booster injection. In contrast to the feeding experiments, immunization of the female rats before mating resulted in a profound decrease in the amount of EA-specific IgE when the pups were subsequently immunized with EA. Additional experiments demonstrated that the suppression of IgE was the result of EA-specific IgG that the pups were acquiring from their mothers during suckling? ~ In rats, maternal IgG is normally acquired by pups via breast milk until they are weaned at 20 days of age. At 20 days' the pups' IgG anti-EA was equal to that of their mothers; however, after they were weaned, antibody levels gradually declined to undetectable levels by 7 to 8 weeks of age. Again, with the same immunization protocol to induce IgE, the investigators found depression of both the primary and secondary responses in pups of immune mothers at 6 to 7 weeks and 9 to 10 weeks of age? j' 52 When the pups were immunized at 13 to 14 weeks, the secondary but not the primary IgE response was still suppressed. It was not until 17 to 18 weeks of age that pups from immune mothers produced IgE responses similar to responses of pups from nonimmune mothers. 51-53 Although age-related animal data cannot be directly applied to humans, there are reasons to suspect that the rat-model data are relevant. The response of human
VOLUME86
Environmental factors versus genetic determinants
infants to measles vaccine has been reported to be blunted by even minute quantities of maternal lgG, an effect lasting until 12 to 18 months of age. ~ Dannaeus and Inganas ~5 found that maternally acquired IgG antibodies to milk and egg appeared to reduce the risk of atopic sypmtoms during the first two years of life. Another opportunity for examining the effect of maternal IgG antibodies on the risk of allergic sensitization is with the follow-up of infants born to mothers receiving IT. IT is expected to induce IgG antibodies specific for the administered allergens, and these IgG antibodies would then be transferred transplacentally to the infant. If the IgG antibodies decreased the risk of sensitization, infants born of pregnancies during which the mother received IT would be at less risk for allergies than siblings born before the mother's treatment with IT. Glovsky et al. s6 reported on 28 children, 14 of whom were born before maternal IT and 14 born while the mother was receiving IT. Based on histories and skin tests, 15 of the 28 children were considered atopic. Of the children exposed in utero to IT, only four of 14 were atopic compared to atopy in 11 of 14 nonexposed children (p < 0.05). 56 In contrast, Settipane et al. 57 evaluated 78 children in a similar fashion and found no statistically significant differences between children born before and children born during maternal IT. 57 Of the 40 children born during IT, 15 (38%) had developed asthma or allergic rhinitis compared to disease in 17 of 38 (45%) children born before maternal IT. Settipane et al. s7 also examined 13 children for skin test sensitivity to pollen that had been included in their mother's IT in comparison to 11 children born before maternal IT. No significant difference in skin test sensitivity was found. These studies suggest that if maternal IgG antibodies influence the risk of sensitization, the influence is either modest or short-lived.
Another argument in favor of the hypothesis of the importance of early pollen exposure was the demonstration of a significant correlation between the risk of sensitization to a pollen and variables that are closely related to the intensity of a pollen season. A significant correlation was found between birch-pollen allergy in individuals and the variables related to the quantity of birch pollen in the year the individual was bom.5 Similar studies have found correlations between risk of sensitization and pollen intensity with grass and mugwort. 6~ Surprisingly, the effect of the month of birth phenomenon can be observed in some populations up to the 20- to 29-year-old age group2' 6t Bjorksten and Suoniemi 61 have estimated that if all individuals younger than 19 years of age had been born in the months of lowest risk (July or August), the prevalence of skin test reactivity would have been reduced by 28% for birch, 22% for grass, and 19% for mugwort. Several additional studies have evaluated the risk of allergic sensitivity in relationship to early or late allergen exposure. Suoniemi et al. ~2 found a significant relationship between cat exposure during the first 6 months of life and skin test sensitivity to cat in teenagers. They did not find a significant relationship between skin test sensitivity to cat and current exposure to cats in these teenagers. Similar results were obtained by Vanto and Koivikko 63 who found that children who had had contact with a dog as a family pet when they were less than 1 year of age had more positive tests than children who were initially exposed later in life or children with no regular contact.
NUMBER 3, PART 1
M o n t h of b i r t h
A number of studies have suggested that the month of birth influences an infant's risk of subsequent inhalant allergy. 58~ The general theory developed from these studies is that the more intense an allergen exposure is during the first 6 to 12 months of life, the more likely an infant is to develop allergy to the allergen. 58~6 As the infant approaches a year of age, the risk of inhalant allergy appears to decrease. Studies from Finland demonstrate that the maximal risk of sensitization to birch pollen is found in infants born between February and April, just before the birchpollen season in May2 The maximal risk of grass and mugwort allergy was found in individuals born in April or May, corresponding to the later pollination seasons for grass and mugwort. 6t
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Infant feeding
The concept that infant feeding practices are related to the risk of allergy started with a study in 1936 by Grulee and Sanford 67 who reported that breast-feeding protects against eczema. In the following years, many studies have been performed to evaluate the protective effect of breast-feeding. Although most of these studies have focused on atopic dermatitis or food allergies, some studies have also considered inhalant allergy. A recent detailed review by Kramer 68 identified 22 studies evaluating breast-feeding as a method for reducing atopic dermatitis. Kramer68 evaluated all these studies with 12 standards to determine how adequately the study had been performed. Four standards related to exposure, including no reliance on prolonged maternal recall, blind ascertainment, and sufficient duration and exclusivity of breast-feeding. Similarly, four standards were applied to outcome measure and four standards were applied to the statistical analysis. Of the 22 studies dealing with breast-feeding and atopic dermatitis, seven studies found some protective effect and
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15 did not. None of the studies meet all 12 standards, and there was no clear evidence that studies reporting an effect of breast-feeding were more or less rigorously performed than studies demonstrating no effect. Kramer 68 also reviewed 13 studies examining the effect of breast-feeding on asthma. Seven of the studies reported some protective effect on asthma, whereas six studies did not. There were also seven studies evaluating breast-feeding and allergic rhinitis, with two of the seven studies reporting some protective effect. The major conclusion of Kramer's study was that there were no clear reasons for the inconsistent results reported by these studies, but given the negative results of some of the larger and relatively welldone studies, it was hard to believe that breast-feeding produced much of a protective effect. Kramer 68 also concluded that "future s t u d i e s . . , should improve both the biologic and methodologic aspects of their design and analysis." Other recent reviews have stated that on balance the current literature suggests some protective effect of diet limitation on the development of allergy. 69 A concern raised about studies of the protective effect of breast-feeding is the possibility that infants are sensitized in utero by the transplancental passage of food allergens or the passage of food allergens into breast milk and then into the infant. Several studies have sought to test this hypothesis. F~ilth-Magnusson and Kjellman 7~ prospectively studied 212 women from midpregnancy. All the women had a personal history of allergy. The mothers were randomized to a diet strictly excluding cow's milk and egg from the twenty-eighth week to delivery or to a regular diet. Dietary compliance was judged by measurement of IgG antibodies to egg and milk. After delivery, breast-feeding was advised along with delayed introduction of solid foods. When the infants were evaluated at 6 and 18 months, there was no evidence of any protective effect in the infants of the mothers on the low allergen diet. 68
Viral infections Viral respiratory infections have long been known to precipitate wheezing in children, but considerable debate has revolved around the question of whether viral infections lead to an increased risk of allergy or whether certain manifestations of viral infections only occur in children who are genetically predisposed to develop allergy. 71, 72 Frick et al.73 followed 24 infants with bilateral parental histories of allergy for the development of signs of allergic disease. The infants were evaluated at 3-month intervals. Included in the evaluation were blood samples for total serum IgE and for IgE specific for six common allergens. Allergic symptoms occurred in 21 of the 24 at-risk infants.
J. ALLERGY CLIN. IMMUNOL. SEPTEMBER 1990
Allergic sensitization, defined as the initial detection of allergen-specific IgE, occurred coincidentally with rising virus antibody titers in 62% of the children. 73 The rises in viral antibody titers in children developing allergic sensitization were not different from rises observed in an age-matched group of nonatopic children. In subsequent studies, Frick and Brooks 74 have demonstrated that, in dogs selected for a high risk of allergy, injection of pups with live attenuated distemperhepatitis vaccine, followed by injection of ragweed and grass pollen, resulted in more IgE than that found in litter mates administered only the pollen injections. Other animal models have also demonstrated that IgE production can be enhanced by concomitant viral infection and allergen exposure. 7s, 76 The mechanism responsible for the increase in IgE with viral infections is not known, but alterations in the interactions between helper and suppressor lymphocytes are believed to be important. 77 An additional microbial agent, not commonly considered in the pathogenesis of allergy is pertussis vaccine. Killed Bordetella pertussis organisms increase the sensitivity of rats and mice to histamine and increase the potential for IgE production. 78 Sen et a l . 79 compared the effects of DPT vaccine versus diphtheria-tetanus vaccine in healthy children. They found that when children receiving pertussis were compared to children not receiving the pertussis, children administered pertussis had a marked increase in histamine-induced skin whealing, a decrease in epinephrine-induced hyperglycemia, and a decrease in tachycardia induced by administration of isoproterenol. These effects were most marked the day after the DPT injection and persisted for up to 20 days. Since these effects of pertussis vaccine in children are similar to effects found in animal models, it appears likely that children receiving pertussis vaccination would be at increased risk of allergic sensitization for at least a few days after the injection. Unfortunately, no studies have examined allergic sensitivity in children in relationship to the months during which they received DPT immunizations.
Cigarette-smoke exposure As previously mentioned, maternal cigarette smoking has been associated with increased cord-blood IgE concentrations, 35 and there is evidence suggesting that passive exposure to cigarette smoke may increase allergic sensitization in children. 8~ 8, KjellmanSO reported modest increases in total serum IgE concentrations in children exposed to cigarette smoke. Weiss et al.8~ evaluated a large number of children for respiratory effects associated with exposure to parental smoking. Prick skin tests to several environmental
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Environmental factors versus genetic determinants
allergens were included in the evaluation. They found that the probability of a child having at least one positive skin test was doubled if the mother smoked, sl These data on the effects of passive smoking in children are in agreement with adult human and animal studies.3, 82, 83 Two studies of sensitization to occupational allergens have demonstrated that smoking workers have a significantly greater risk of allergy compared to similarly exposed but nonsmoking coworkers.8O. 81 A study with rats found that animals exposed to an aerosolized allergen concomitantly with cigarette smoke were significantly more likely to form IgE antibodies to the allergen than were control animals only exposed to the allergen, s2 The previously mentioned study by Horwood et a1.11 evaluated the risk of a child developing asthma in relationship to a large number of environmental influences, included parental smoking. In the cohort of 1056 children, boys were significantly more likely to develop asthma than were girls (14.3% versus 6.3%), but there was no association between the risk of asthma and either paternal or maternal smoking. O w n b y and McCullough 84 evaluated 191 children for a relationship between the presence and quantity o f IgE to a group of c o m m o n inhalant allergens and parental smoking. One hundred of the children were randomly selected from healthy children receiving well-child care, and the other 91 children were referred for allergy evaluations. No significant differences between either the frequency o f positive specific IgE tests nor the quantity o f specific IgE were found in either patient group in relationship to maternal, paternal, or parental smoking. The prevalence of maternal smoking was more than doubled in the children referred for allergy evaluation compared to the children receiving well-child care. This finding is consistent with other studies demonstrating increased respiratory symptoms in children exposed to cigarette smoke.
it may prime an infant for subsequent l g E production. Given the difficulties in trying to control human genetics, it is unlikely that genetic manipulation will be able to prevent allergy in the near future, but environmental controls may help reduce morbidity from allergy by delaying the onset of inhalant allergy and reducing the severity of symptoms.
CONCLUSION
Inhalant allergy develops in children as the result of multiple interactions between the immune system and the environment. Although the current state of knowledge does not permit precise identification of the relative importance of genetic and environmental influences, it appears that genetic control is most important in determining the overall risk of allergy. This is observed in the control of total serum IgE concentrations and the likelihood o f forming IgE after allergen exposure. Environmental influences are probably most important in determining the specific allergens to which a person will develop sensitivity. Early allergen exposure may be especially important because
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REFERENCES
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22. Blumenthal MN, Namboodise K, Mendell N, Gleich G, Elston RC, Yunis E. Genetic transmission of serum IgE levels. Am J Med Genet 1981;10:219-28. 23. Meyers DA, Bias WB, Marsh DG. A genetic study of total IgE in the Amish. Hum Herod 1982;31:15-23. 24. Hasstedt SJ, Meyer DA, Marsh DG. Inheritance of immunoglobulin E: genetic model fitting. Am J Med Genet 1983;14: 61-6. 25. Meyers DA, Hasstedt SJ, March DG, et al. The inheritance of immunoglobulin E: genetic linkage analysis. Am J Med Genet 1983;16:575-81. 26. Borecki IB, Rat DC, Lalouel JM, McGue M, Gerrard JW. Demonstration of a common major gene with pleiotropic effects on immunoglobulin E levels and allergy. Genet Epidemiol 1985;2:327-38. 27. Meyers DA, Beaty TH, Freidhoff LR, March DG. Inheritance of total serum IgE (basal levels) in man. Am J Hum Genet 1987;41:51-62. 28. Dannaeus A, Johansson SGO, Foucard T. Clinical and immunologic aspects of food allergy in childhood. Acta Paediatr Scand 1978;67:497-504. 29. Michel FB, Bousquet J, Greillier P, Robinet-Levy M, Coulomb Y. Comparison of cord blood immunoglobulin E concentrations and maternal allergy for the prediction of atopic diseases in infancy. J ALLERGYCLIN IMMUNOL1980;65:422-30. 30. Croner S, Kjellman N-I M, Eriksson B, Roth A. IgE screening in 1701 newborn infants and the development of atopic diseases during infancy. Arch Dis Child 1982;57:364-8. 31. Duchateau J, Casimir G. Neonatal serum IgE concentrations as predictor of atopy. Lancet 1983;1:413-4. 32. Businco L, Marchetti F, Pellegrini G, Perlini R. Predictive value of cord blood IgE levels in "at-risk" newborn babies and influence of type of feeding. Clin Allergy 1983;13:503-8. 33. Bousquet J, Menardo J-L, Viala J-L, Michel F-B. Predictive value of cord serum IgE determination in the development of "early-onset" atopy. Ann Allergy 1983;51:291-5. 34. Croner S, Kjellman N-I M. Predictors of atopic disease: cord blood IgE and month of birth. Allergy 1986;41:68-70. 35. Magnusson CGM. Maternal smoking influences serum IgE and IgD levels and increases the risk for subsequent infant allergy. J ALLERGYCLIN IMMUNOL 1986;78:898-904. 36. Kjellman N-I M, Croner S. Cord blood IgE determination for allergy prediction--a follow-up to seven years of age in 1651 children. Ann Allergy 1984;53:167-71. 37. O'Connor RO, Zeiger RS, Mellon M, et al. The occurrence of falsely elevated IgE concentrations in cord blood due to contamination with maternal blood [Abstract]. New Engl Reg Allergy Proc 1984;5:149. 38. Miller DL, Hirvonen T, Gitlin D. Synthesis of IgE by the human conceptus. J ALLERGYCLIN IMMUNOL1973;52:182-8. 39. Benacerraf B, McDevitt HO. Histocompatibility-linked immune response genes. Science 1972;175:273-9. 40. Levine BB, Stember RH, Fotino M. Ragweed hay fever: genetic control and linkage to HLA haplotypes. Science 1972; 178:1201-3. 41. Marsh D, Meyers D, Friedhoff L, et al. HLA-DW2-A genetic markers for human immune response to short ragweed allergen RAS. II. Response after ragweed immunotherapy. J Exp Med 1982;155:1452-63. 42. Marsh DG. Molecular studies of human immune recognition of allergens. Allergy 1988;43(suppl 8):7-9. 43. Kjellman N-I M, Johansson SGO. Soy versus cow's milk in infants with a biparental history of atopic disease: development of atopic disease and immunoglobulins from birth to 4 years of age. Clin Allergy 1979;9:347.
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44. Delepsse M, Sarfati M, Lang G, Sehon AH. Prenatal and neonatal synthesis of IgE. Monogr Allergy 1983;18:83-90. 45. Hamburger RN, Heller S, Mellon M, O'Connor RD, Zeiger RS. Current status of the clinical and immunologic consequences of a prototype allergic disease prevention program. Ann Allergy 1983;51:281-90. 46. Weil GJ, Hussain R, Kumaraswami V. Prenatal allergic sensitization to helminth antigens in offspring of parasite-infected mothers. J Clin Invest 1983;71:1124-32. 47. Gerrard JW, Heiner DC, Ko CG, Mink J, Meyers A, Dosman JA. Immunoglobulin levels in smokers and nonsmokers. Ann Allergy 1980;44:261-2. 48. Bahna SL, Heiner DC, Myhre BA. Immunoglobulin E pattern in cigarette smokers. Allergy 1983;38:57-64. 49. Bahna SL, Heiner DC, Myhre BA. Changes in serum IgD in cigarette smokers. Clin Exp Immunol 1983;51:624-30. 50. Jarrett E, Hall E. Selective suppression of IgE antibody responsiveness by maternal influence. Nature 1979;280: 145-7. 51. Jarrett EEL, Hall E. IgE suppression by maternal IgG. Immunology 1983;48:49-58. 52. Jarrett EEL, Hall E. The development of IgE-suppressive immunocompetence in young animals: influence of exposure to antigen in the presence or absence of maternal immunity. Immunology 1984;54:365-73. 53. Jarrett EEL, Hall E. Perinatal-maternal relationships in the regulation of IgE antibody responsiveness. J ALLERGYCLIN IMMtrNOL 1986;78:1000-2. 54. Albrecht P, Ennis FA, Saltzman EJ, Krugman S. Persistence of maternal antibody in infants beyond 12 months: mechanism of measles vaccine failure. J Pediatr 1977;91:715-8. 55. Dannaeus A, Inganas M. A follow-up study of children with food allergy: clinical course in relation to serum IgE- and IgGantibody levels to milk, egg, and fish. Clin Allergy 1981; 11:533-9. 56. Glovsky MM, Rejzek E, Ghekiere L. Can tolerance be induced in utero in children by immunotherapy of atopic pregnant mothers [Abstract]? J ALLERGYCLIN IMMUNOL1982;69:100. 57. Settipane RA, Chafee FH, Settipane GA. Pollen immunotherapy during pregnancy: long-term follow-up of offspring. Allergy Proc 1988;9:555-61. 58. Pearson DJ, Freed DLJ, Taylor B. Respiratory allergy and month of birth. Clin Allergy 1980;10:585-91. 59. Kemp AS. Relationship between the time of birth and the development of immediate hypersensitivity to grass-pollen antigens. Med J Aust 1979;1:263-6. 60. Smith JM, Springett VH. Atopic disease and month of birth. Clin Allergy 1979;9:153-7. 61. Bjorksten F, Suoniemi I. Time and intensity of first pollen contacts and risk of subsequent pollen allergies. Acta Med Scand 1981;209:299-303. 62. SuoniemiI, BjorkstenF, HaahtelaT. Dependence of immediate hypersensitivity in the adolescent period on factors encountered in infancy. Allergy 1981;36:263-70. 63. Vanto T, Koivikko A. Dog hypersensitivity in asthmatic children. Acta Paediatr Scand 1983;72:571-5. 64. Quoix E, Bessot JC, Kopferschmitt-Kubler MC, Fraisse P, Pauli G. Positive skin tests t o aeroallergens and month of birth. Allergy 1988;43:127-31. 65. Carosso A, Ruffino C, Gugiani M. The effect of birth season on pollinosis. Ann Allergy 1986;56:300-3. 66. Businco L, Cantani A, Farinella F, Businco E. Month of birth and grass pollen or mite sensitization in children with respiratory allergy: a significant relationship. Clin Allergy 1988; 18:269-74.
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67. Grulee CG, Sanford HN. The influence of breast and artificial feeding on infantile eczema. J Pediatr 1936;9:223-5. 68. Kramer MS. Does breast feeding help protect against atopic disease? Biology, methodology, and a golden jubilee of controversy. J Pediatr 1988;112:181-90. 69. Zeiger RS, Heller S, Melton M, O'Connor R, Hamburger RN. Effectiveness of dietary manipulation in the prevention of food allergy in infants [Symposium]. J ALLERGYCLIN IMMUNOL 1986;78:224-38. 70. Fiilth-Magnnsson K, Kjellman N-IM. Development of atopic disease in babies whose mothers were receiving exclusion diet during pregnancy--a randomized study. J ALLERGYCLIN IMMtmOL 1987;80:869-75. 71. Welliver RC, Kaul TN, Ogra PL. The appearance of cell-bound IgE in respiratory tract epithelium after respiratory-syncytiai virus infection. N Engl J Med 1980;303:1198-1202. 72. Welliver RC, Sun M, Rinaldo D, Ogra PL. Predictive value of respiratory syucytial virus-specific IgE responses for recurrent wheezing following bronchiolitis. J Pediatr 1986; 109:77680. 73. Frick OL, German DF, Mills J. Development of allergy in children. I. Association with virus infections. J ALLERGYCLtN IMMUNOL 1979;63:228-41. 74. Frick OL, Brooks DL. lmmunoglobulin E antibodies to pollens augmented in dogs by virus vaccines. Am J Vet Res 1983; 44:440. 75. Sakamoto M, Ida S, Takishima T. Effect of influenza virus infection on allergic sensitization to aerosolized ovalbumin in mice. J Immunol 1984;132:2614-7.
76. Holt PG, Vines J, Bilyk N. Effect of influenza virus infection on allergic sensitization to inhaled antigen in mice. Int Arch Allergy Appl Immunol 1988;86:121-3. 77. Frick OL. Effect of respiratory and other virus infections on IgE immunoregulation. J ALLERGY CLIN IMMONOL 1986; 78:1013-8. 78. Arora S, Sanyal RK, West GB. The sensitizing action of Bordetella pertussis vaccine, lnt Arch Allergy Appl lmmunol 1970;357-62. 79. Sen DK, Arora S, Gupta S, Sanyal RK. Studies of adrenergic mechanisms in relation to histamine sensitivity in children immunized with Bordetella pertussis vaccine. J ALLERGYCLIN 1MMUNOL1974;54:25-31. 80. Kjellman N-IM. Effect of parental smoking on IgE levels in children. Lancet 1981;1:993-4. 81. Weiss ST, Tager IB, Munzo A, Speizer FE. The relationships of respiratory infections in early childhood to the occurrence of increased levels of bronchial responsiveness and atopy. Am Rev Respir Dis 1985;131:573-8. 82. Zetterstrom O, Osterman K, Machado L, Johansson SGO. Another smoking hazard: raised serum IgE concentration and increased risk of occupational allergy. Br Med J 1981; 283:1215-7. 83. Zetterstrom O, Nordvall SL, Bjorkstein B, Ahlstedt S, Stelander M. Increased IgE antibody responses in rats exposed to tobacco smoke. J ALLERGYCLIN IMMUNOL1985;75:594-8. 84. Ownby DR, McCullough J. Passive exposure to cigarette smoke does not increase allergic sensitization in children. J ALLERGYCLIN IMMUNOL1988;82:634-8.
ALLERGY AND
CLINICAL IMMUNOLOGY VOLUME 86
NUMBER 3, PART 1
Continuing Medical Education This continuing medical education self-assessment program is sponsored by The American Academy of Allergy and Immunology.
Environmental factors versus genetic determinants of childhood inhalant allergies Dennis R. Ownby, MD Detroit, Mich.
A classic question in many areas of medicine is nature versus nurture. When an individual develops an allergic disease, is the disease the result of heredity or the environment? Since the pioneering study of Cooke and Vander Veer, 1 published in 1916, the familial nature of atopic disease has not been seriously disputed; however, many studies have also demonstrated the importance of the environment on the genesis of allergic disease. 2-5 There are multiple reasons for considering the relative importance of genetic and environmental effects in the development of allergies. Parents ask about the risk of allergy in their children and about methods for reducing the risk of allergy. Patients inquire about why they have developed allergies and why allergies developed at a particular time. Assessment of the risk of allergy is also important in efforts to reduce occupational allergic disease and in designing studies to prevent other allergic diseases. From the Department of Pediatrics and CommunicableDiseases, University of Michigan, and Pediatric AllergyImmunologyResearch Laboratory,Henry Ford Hospital, Detroit, Mich. Reprint requests: Dennis R. Ownby, MD, Director, Pediatric Allergy ImmunologyResearch Laboratory, Henry Ford Hospital, Detroit, MI 48202. 1/2/17294
Abbreviations used HLA: Human leukocyte antigen Ir: Immune response EA: Egg albumin IT: Immunotherapy DPT: Diphtheria toxoid, pertussis vaccine, and tetanus toxoid
GENETICS OF ALLERGY Allergic disease continues to defy precise explanation in genetic terms. 6, 7 Many early studies evaluated the question of allergic inheritance by determining the prevalence of a family history of allergic disease in individuals who did or did not have a particular allergic disease. Although there are differences between the studies, as many as 40% to 80% of individuals with allergic rhinitis or asthma had positive family histories compared to 20% or less in individuals without allergic disease. 7 Many studies have evaluated the risk of a child becoming allergic based on the parental history of allergy. In general, the risk of allergy is believed to be about 20%, but this increases to 50% if one parent is allergic and in-
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creases the risk further to 66% if both parents are allergic. 8-1~ A large prospective study reported by Horwood et al. n confirmed the increased risk of childhood asthma in children of allergic parents, but this study found a complex relationship. The study is based on 1056 children followed from birth in the Christchurch, New Zealand, area. Family histories were obtained prenatally, and the children were followed at 4 months of age, and then annually to 6 years of age. Multiple variables, including early feeding, home environment, psychosocial factors, and family backgrounds were evaluated. The risk of a child developing asthma was markedly different between sexes. In agreement with other studies, boys were more likely to develop asthma than girls (14.3% versus 6.3%; p < 0.001). Of more interest was that the risk factors for boys and girls differed. The only risk factor for asthma in girls was eczema in the first year of life. A family history of asthma, allergic rhinitis, or eczema, either in the parents or siblings, was not significantly related to asthma in. girls. In contrast, boys were at increased risk of asthma if there was a history of asthma or allergic rhinitis in the parents or asthma in a sibling. 11 This large prospective study concluded that there was limited inheritance of early childhood asthma.11 Other investigators have observed the increased risk of allergy in male compared to female subjects. Magnusson 12noted that the risk of allergy in an infant was higher if the mother was allergic than if the father was allergic. Happle and Schnyder 13 also observed that atopic disease was more frequent in infants if the mother alone was allergic compared to infants when the father alone was allergic. They believed that this difference in hereditary risk was evidence for the CarteP 4 effect. Carter 14 demonstrated that pyloric stenosis occurs more frequently in relatives of affected girls than in relatives of affected boys. Carter explained these observations by proposing that pyloric stenosis was determined by polygeneic inheritance. Predisposing genes are equally distributed between sexes, but the threshold for disease is higher in female than in male subjects. If this is true, then female subjects would be less likely to be affected; however, affected female subjects would have more predisposing genes and thus be more likely to transmit these genes to their offspring. Happle and Schnyder 13 evaluated the children of men and women with atopic asthma. In children of atopic fathers, 32 of 98 (33%) were affected by some f o r m of atopic disease compared to 45 of 93 (45%) of the children of atopic mothers. When children with asthma were considered, only 25% had atopic fathers compared to 40% with atopic mothers. The investigators believed that these
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data demonstrated that the Carter 14 effect may play a role in allergic disease, providing additional evidence for polygenetic inheritance in allergy. Another method to evaluate the role of genetics in allergic disease has been the study of twins. 6, 7 Twin studies are usually based on comparing the concordance rates for various allergic diseases between monozygotic and dizygotic twins. If monozygotic twins have a significantly greater degree of concordance than dizygotic twins, the difference is assumed to be genetic, since monozygotic twins are genetically identical. Lubs 15analyzed data from the Swedish twin registry on 6996 pairs of adult twins for the concordance of allergic disease. Asthma was reported in 3.8%, hay fever by 14.8%, and eczema by 2.5% of these twins. As expected, concordance rates for asthma, hay fever, and eczema were significantly higher in the monozygotic than in the dizygotic twins, but the concordance rates in the monozygotic twins were modest, from 15.4% to 21.4%. Lubs 15 stated that, although these data supported a significant genetic component, the effect of the genetic component was small, since 79% to 85% of the monozygotic twin pairs were discordant for these three allergic diseases. Lubs is also analyzed these data from the dizygotic twin pairs to determine the relative risk of allergy in a first-degree relative of an allergic individual. Again the risks were significant and relatively small, ranging from 1.3 to 3.1 times the risk of the population. Interestingly, the risk in first-degree relatives was somewhat disease specific with a higher risk of asthma in the relatives of an individual with asthma than with eczema and vice versa. An important strength of Lubs' study is the fact that it is population based and not subject to the biases induced by the selection of twins by selfreferral or from referral populations. In a more recent study, Hopp et al. 16 reported the intrapair coefficients for monozygotic and dizygotic twins evaluated for total serum IgE concentration, methacholine responsiveness, and skin test reactivity to common aeroallergens. This study was based on 61 pairs of monozygotic and 46 pairs of dizygotic twins. Monozygotic twins were significantly more concordant for serum IgE, methacholine sensitivity, total skin test reactivity, and skin test reactivity to trees. (Correlation coefficients ranged from 0.64 to 0.82 in the monozygotic pairs compared to values of 0.08 to 0.52 for dizygotic pairs.) The significance of the methacholine sensitivity was lost, however, if the results of the monozygotic twins were compared to the results of only the like-sex dizygotic twins. Hopp et al. 16 interpreted these results as demonstrating a genetic basis for a general allergic tendency, as re-
VOLUME 86 NUMBER 3, PART 1
flected by total serum IgE and total skin test reactivity, but that the environment was more important in determining a personal allergic pattern, such as a skin test reactivity to specific allergens. A study of dizygotic and monozygotic twins by Wuthfich et al. 17comparing skin tests, RAST results, and total serum IgE concentrations also concluded that the general tendency to be allergic is genetically influenced but that specific allergic sensitivities are "governed mainly by environmental influences." An interesting means for examining the relative importance of genetic versus environmental influences on the development of allergic disease is to evaluate twins reared together compared to twins reared apart. In a review, Blumenthal et al. 7 stated that no differences in concordance for asthma or seasonal rhinitis were noted in monozygotic twins reared together or apart, suggesting a dominant genetic effect. Although they provide evidence for a genetic effect, twin studies do not provide information about the mode of genetic inheritance. Since total serum IgE concentrations are closely related to the risk and severity of allergic disease, multiple attempts have been made to elucidate the mode of inheritance for serum IgE concentration. 6-7",8-27 These studies are relatively consistent in finding that serum lgE levels are more likely genetically controlled than controlled by the environment, but the mode of inheritance is as yet unclear. ~s-27Family studies suggest that IgE levels have a heritability of about 50%. Early studies by Marsh et al., ~s Gerrard et al., 19 and Rao et al. 2~ suggested recessive inheritance of high IgE levels. As pointed out by Marsh et al. ,6 analysis of serum IgE levels for a genetic effect is complicated by the lack of a distinct bimodal distribution of IgE concentrations in study populations. The mode of inheritance for serum IgE is further confused by more recent data by Blumenthal et al. 7 from seven large pedigrees. When these data are analyzed together, they were not consistent with either a monogeneic or purely environmental effect. With individual analysis of each pedigree, these data from five families were most consistent with a recessive mode of inheritance in contrast to the other two families in which a dominant model of inheritance elicited the best fit to these data. It is unlikely that the inheritance of serum IgE concentration will be clearly defined unless the inheritance of serum IgE can be demonstrated to be linked to another genetic marker.6.7.24.25 Although it is currently not possible to define precisely the inheritance of serum IgE concentrations, the concentration of IgE in an infant's cord blood has been found in multiple studies to be a predictor of allergic risk. 28"36 The predictive value of cord-blood
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IgE is better than that of the family history of allergy, although some investigators suggest using both the family history and cord-blood IgE to predict allergic risk. 28-36Presumably the cord-blood IgE concentration is a reflection of the genetic risk for developing allergic disease. From 52% to 82% of infants with elevated cord-blood IgE develop allergy in childhood compared to only 5% to 30% if cord-blood IgE is n o r m a l . 2s-36 The most convincing data come from the prospective study of 1651 unselected Scandinavian infants followed from birth to 7 years of age. 3~ 36 In this study an elevated cord-blood IgE was defined as ->0.9 IU/ml, which was the limit of sensitivity of the assay used. This concentration of cord-blood IgE had a sensitivity for predicting atopic disease of 82% and a specificity of 70%. 30. 36 Other studies have produced similar results with cord-blood IgE concentrations ranging from 0.6 to 1.3 IU/ml being considered as elevated.~8. 29. 31-35 O'Connor et a l . 37 have stated that the predictive accuracy of cord-blood IgE measurements can be decreased because of admixture of maternal with fetal blood at parturition, resulting in falsely elevated IgE levels. These investigators report using IgA measurements to monitor for maternal admixture, with admixture resulting in cord-blood lgE concentrations of > 1.0 IU/ml in six of 32 (19%) cases of a total of 201 cases examined. Studies have also been performed to evaluate the relationship between allergic diseases and the major histocompatibility complex in man. 6, 7 Early studies attempted to link specific allergic diseases or serum IgE concentrations to HLA types. 25 Some studies have reported significant positive associations between asthma, hay fever, eczema, and the HLA system, but none of these associations has been strong enough and reproducible enough to be clinically u s e f u l . 6' 7 Animal studies have demonstrated that the ability to immunologically recognize and respond to an antigen is genetically determined, 39 but the existence of these Ir genes in humans has been difficult to demonstrate conclusively. Levine et al. 4~provided the first evidence that the Ir to ragweed antigen E was genetically linked to the HLA system in a family study. Other investigators were also able to find an association between IgE response and HLA, but the association is not totally consistent. 7 Work by Marsh et al. 4~ has demonstrated an association between both HLA Dw2 and HLA DR2 and the IgE and IgG response to ragweed allergen Ra5 from both natural ragweed exposure and immunotherapy. Subsequent work by Marsh 42 has demonstrated very strong associations between a purified ragweed allergen (Amb a V) and the DR2/Dw2 HLA specificity. Marsh 42 also suggests that it will soon be pos-
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sible to define the DNA sequence coding for this Ix specificity. In summary, genetic studies have consistently demonstrated a significant genetic influence on an individual's risk for allergic disease. The strength of the genetic influence varies between studies, ranging from mild to fairly strong. This genetic influence is probably the result of multiple genes and is reflected in the basal serum IgE concentration, either at birth or later in life. The second major genetic mechanism involved in human allergy is regulation of response by IR genes. The precise control by IR genes has been difficult to demonstrate, in part because of the multiple antigens in most natural allergens.
lieved that the increased cord-blood IgE associated with maternal smoking was also associated with an increased risk of allergy in the infants. Increased cordblood lgE and IgD concentrations in smoking mothers are consistent with studies demonstrating increased serum IgE and IgD in adult smokers. 47"49 The cause of the increased IgE in adult smokers is not known, but it does not appear to be caused by increased production of IgE to common airborne allergens. The question of a relationship between maternal smoking and cord-blood IgE concentration is potentially very important because it suggests that the risk of childhood allergy could be reduced by smoking cessation during pregnancy.
ENVIRONMENTAL INFLUENCES
Effect of maternal IgG on IgE
Once conception has occurred, an individual's genetic constitution is fixed, and the environment begins to exert its effects on development. Presumably, the only agents that could affect an infant in utero are those capable of passing from the maternal to the fetal circulation across the placenta, including some drugs, products from tobacco smoke, and perhaps some food allergens. Human infants have been found to produce IgE as early as the eleventh week of gestation, and IgE is detectable in the amniotic fluid by the thirteenth week? 8 Although IgE production is possible during most of gestation, in utero sensitization is rare. Six studies used RAST to measure IgE specific for common allergens in cord-blood samples; positive tests were found in only 0% to 2% of the samples.~9. 3o. ~2.43-45 Three of these studies, totaling 275 infants, failed to find any positive tests? ~ 43.45 In contrast is the study by Weil et al.46 examining parasitespecific IgE in infants of infected mothers. In this study, 14 of 57 (26%) infants demonstrated IgE antibody to microfilaria. Taken together, these studies suggest that in utero infants can produce specific IgE but that in most cases the antigenic stimulus is insufficient to initiate IgE production. The stimulus may be insufficient because of the limited quantity of antigen reaching the infant or because of the characteristics of the antigen. Michel et al. 29 reported that cord-blood IgE concentrations were increased in infants of mothers administered progesterone during pregnancy. 33 The question of whether the progesterone-associated increase in IgE is also associated with an increased risk of subsequent allergy is difficult to answer because of the small number of infants involved. Magnusson 35 reported that cord-blood IgE concentrations were elevated in smoking mothers and that cord-blood IgD concentrations were increased if either the mother or the father smoked. Magnusson 3S be-
In contrast to IgE, all infants normally receive large quantities of all IgG subclasses from their mothers via placenta passage. Jarrett and Hall 5~ have used a rat model to evaluate the relationship between a mother's antigen exposure and the risk of allergic sensitization in offspring. Initially, attempts were made to alter the sensitization potential of rat pups by feeding EA to the mothers either during pregnancy or during lactation.SO The feeding of EA did not alter the EA-specific IgE response of the pups to an immunization protocol designed to produce a maximal IgE response after a primary immunization and one booster injection. In contrast to the feeding experiments, immunization of the female rats before mating resulted in a profound decrease in the amount of EA-specific IgE when the pups were subsequently immunized with EA. Additional experiments demonstrated that the suppression of IgE was the result of EA-specific IgG that the pups were acquiring from their mothers during suckling? ~ In rats, maternal IgG is normally acquired by pups via breast milk until they are weaned at 20 days of age. At 20 days' the pups' IgG anti-EA was equal to that of their mothers; however, after they were weaned, antibody levels gradually declined to undetectable levels by 7 to 8 weeks of age. Again, with the same immunization protocol to induce IgE, the investigators found depression of both the primary and secondary responses in pups of immune mothers at 6 to 7 weeks and 9 to 10 weeks of age? j' 52 When the pups were immunized at 13 to 14 weeks, the secondary but not the primary IgE response was still suppressed. It was not until 17 to 18 weeks of age that pups from immune mothers produced IgE responses similar to responses of pups from nonimmune mothers. 51-53 Although age-related animal data cannot be directly applied to humans, there are reasons to suspect that the rat-model data are relevant. The response of human
VOLUME86
Environmental factors versus genetic determinants
infants to measles vaccine has been reported to be blunted by even minute quantities of maternal lgG, an effect lasting until 12 to 18 months of age. ~ Dannaeus and Inganas ~5 found that maternally acquired IgG antibodies to milk and egg appeared to reduce the risk of atopic sypmtoms during the first two years of life. Another opportunity for examining the effect of maternal IgG antibodies on the risk of allergic sensitization is with the follow-up of infants born to mothers receiving IT. IT is expected to induce IgG antibodies specific for the administered allergens, and these IgG antibodies would then be transferred transplacentally to the infant. If the IgG antibodies decreased the risk of sensitization, infants born of pregnancies during which the mother received IT would be at less risk for allergies than siblings born before the mother's treatment with IT. Glovsky et al. s6 reported on 28 children, 14 of whom were born before maternal IT and 14 born while the mother was receiving IT. Based on histories and skin tests, 15 of the 28 children were considered atopic. Of the children exposed in utero to IT, only four of 14 were atopic compared to atopy in 11 of 14 nonexposed children (p < 0.05). 56 In contrast, Settipane et al. 57 evaluated 78 children in a similar fashion and found no statistically significant differences between children born before and children born during maternal IT. 57 Of the 40 children born during IT, 15 (38%) had developed asthma or allergic rhinitis compared to disease in 17 of 38 (45%) children born before maternal IT. Settipane et al. s7 also examined 13 children for skin test sensitivity to pollen that had been included in their mother's IT in comparison to 11 children born before maternal IT. No significant difference in skin test sensitivity was found. These studies suggest that if maternal IgG antibodies influence the risk of sensitization, the influence is either modest or short-lived.
Another argument in favor of the hypothesis of the importance of early pollen exposure was the demonstration of a significant correlation between the risk of sensitization to a pollen and variables that are closely related to the intensity of a pollen season. A significant correlation was found between birch-pollen allergy in individuals and the variables related to the quantity of birch pollen in the year the individual was bom.5 Similar studies have found correlations between risk of sensitization and pollen intensity with grass and mugwort. 6~ Surprisingly, the effect of the month of birth phenomenon can be observed in some populations up to the 20- to 29-year-old age group2' 6t Bjorksten and Suoniemi 61 have estimated that if all individuals younger than 19 years of age had been born in the months of lowest risk (July or August), the prevalence of skin test reactivity would have been reduced by 28% for birch, 22% for grass, and 19% for mugwort. Several additional studies have evaluated the risk of allergic sensitivity in relationship to early or late allergen exposure. Suoniemi et al. ~2 found a significant relationship between cat exposure during the first 6 months of life and skin test sensitivity to cat in teenagers. They did not find a significant relationship between skin test sensitivity to cat and current exposure to cats in these teenagers. Similar results were obtained by Vanto and Koivikko 63 who found that children who had had contact with a dog as a family pet when they were less than 1 year of age had more positive tests than children who were initially exposed later in life or children with no regular contact.
NUMBER 3, PART 1
M o n t h of b i r t h
A number of studies have suggested that the month of birth influences an infant's risk of subsequent inhalant allergy. 58~ The general theory developed from these studies is that the more intense an allergen exposure is during the first 6 to 12 months of life, the more likely an infant is to develop allergy to the allergen. 58~6 As the infant approaches a year of age, the risk of inhalant allergy appears to decrease. Studies from Finland demonstrate that the maximal risk of sensitization to birch pollen is found in infants born between February and April, just before the birchpollen season in May2 The maximal risk of grass and mugwort allergy was found in individuals born in April or May, corresponding to the later pollination seasons for grass and mugwort. 6t
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Infant feeding
The concept that infant feeding practices are related to the risk of allergy started with a study in 1936 by Grulee and Sanford 67 who reported that breast-feeding protects against eczema. In the following years, many studies have been performed to evaluate the protective effect of breast-feeding. Although most of these studies have focused on atopic dermatitis or food allergies, some studies have also considered inhalant allergy. A recent detailed review by Kramer 68 identified 22 studies evaluating breast-feeding as a method for reducing atopic dermatitis. Kramer68 evaluated all these studies with 12 standards to determine how adequately the study had been performed. Four standards related to exposure, including no reliance on prolonged maternal recall, blind ascertainment, and sufficient duration and exclusivity of breast-feeding. Similarly, four standards were applied to outcome measure and four standards were applied to the statistical analysis. Of the 22 studies dealing with breast-feeding and atopic dermatitis, seven studies found some protective effect and
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15 did not. None of the studies meet all 12 standards, and there was no clear evidence that studies reporting an effect of breast-feeding were more or less rigorously performed than studies demonstrating no effect. Kramer 68 also reviewed 13 studies examining the effect of breast-feeding on asthma. Seven of the studies reported some protective effect on asthma, whereas six studies did not. There were also seven studies evaluating breast-feeding and allergic rhinitis, with two of the seven studies reporting some protective effect. The major conclusion of Kramer's study was that there were no clear reasons for the inconsistent results reported by these studies, but given the negative results of some of the larger and relatively welldone studies, it was hard to believe that breast-feeding produced much of a protective effect. Kramer 68 also concluded that "future s t u d i e s . . , should improve both the biologic and methodologic aspects of their design and analysis." Other recent reviews have stated that on balance the current literature suggests some protective effect of diet limitation on the development of allergy. 69 A concern raised about studies of the protective effect of breast-feeding is the possibility that infants are sensitized in utero by the transplancental passage of food allergens or the passage of food allergens into breast milk and then into the infant. Several studies have sought to test this hypothesis. F~ilth-Magnusson and Kjellman 7~ prospectively studied 212 women from midpregnancy. All the women had a personal history of allergy. The mothers were randomized to a diet strictly excluding cow's milk and egg from the twenty-eighth week to delivery or to a regular diet. Dietary compliance was judged by measurement of IgG antibodies to egg and milk. After delivery, breast-feeding was advised along with delayed introduction of solid foods. When the infants were evaluated at 6 and 18 months, there was no evidence of any protective effect in the infants of the mothers on the low allergen diet. 68
Viral infections Viral respiratory infections have long been known to precipitate wheezing in children, but considerable debate has revolved around the question of whether viral infections lead to an increased risk of allergy or whether certain manifestations of viral infections only occur in children who are genetically predisposed to develop allergy. 71, 72 Frick et al.73 followed 24 infants with bilateral parental histories of allergy for the development of signs of allergic disease. The infants were evaluated at 3-month intervals. Included in the evaluation were blood samples for total serum IgE and for IgE specific for six common allergens. Allergic symptoms occurred in 21 of the 24 at-risk infants.
J. ALLERGY CLIN. IMMUNOL. SEPTEMBER 1990
Allergic sensitization, defined as the initial detection of allergen-specific IgE, occurred coincidentally with rising virus antibody titers in 62% of the children. 73 The rises in viral antibody titers in children developing allergic sensitization were not different from rises observed in an age-matched group of nonatopic children. In subsequent studies, Frick and Brooks 74 have demonstrated that, in dogs selected for a high risk of allergy, injection of pups with live attenuated distemperhepatitis vaccine, followed by injection of ragweed and grass pollen, resulted in more IgE than that found in litter mates administered only the pollen injections. Other animal models have also demonstrated that IgE production can be enhanced by concomitant viral infection and allergen exposure. 7s, 76 The mechanism responsible for the increase in IgE with viral infections is not known, but alterations in the interactions between helper and suppressor lymphocytes are believed to be important. 77 An additional microbial agent, not commonly considered in the pathogenesis of allergy is pertussis vaccine. Killed Bordetella pertussis organisms increase the sensitivity of rats and mice to histamine and increase the potential for IgE production. 78 Sen et a l . 79 compared the effects of DPT vaccine versus diphtheria-tetanus vaccine in healthy children. They found that when children receiving pertussis were compared to children not receiving the pertussis, children administered pertussis had a marked increase in histamine-induced skin whealing, a decrease in epinephrine-induced hyperglycemia, and a decrease in tachycardia induced by administration of isoproterenol. These effects were most marked the day after the DPT injection and persisted for up to 20 days. Since these effects of pertussis vaccine in children are similar to effects found in animal models, it appears likely that children receiving pertussis vaccination would be at increased risk of allergic sensitization for at least a few days after the injection. Unfortunately, no studies have examined allergic sensitivity in children in relationship to the months during which they received DPT immunizations.
Cigarette-smoke exposure As previously mentioned, maternal cigarette smoking has been associated with increased cord-blood IgE concentrations, 35 and there is evidence suggesting that passive exposure to cigarette smoke may increase allergic sensitization in children. 8~ 8, KjellmanSO reported modest increases in total serum IgE concentrations in children exposed to cigarette smoke. Weiss et al.8~ evaluated a large number of children for respiratory effects associated with exposure to parental smoking. Prick skin tests to several environmental
VOLUME 86 NUMBER 3, PART 1
Environmental factors versus genetic determinants
allergens were included in the evaluation. They found that the probability of a child having at least one positive skin test was doubled if the mother smoked, sl These data on the effects of passive smoking in children are in agreement with adult human and animal studies.3, 82, 83 Two studies of sensitization to occupational allergens have demonstrated that smoking workers have a significantly greater risk of allergy compared to similarly exposed but nonsmoking coworkers.8O. 81 A study with rats found that animals exposed to an aerosolized allergen concomitantly with cigarette smoke were significantly more likely to form IgE antibodies to the allergen than were control animals only exposed to the allergen, s2 The previously mentioned study by Horwood et a1.11 evaluated the risk of a child developing asthma in relationship to a large number of environmental influences, included parental smoking. In the cohort of 1056 children, boys were significantly more likely to develop asthma than were girls (14.3% versus 6.3%), but there was no association between the risk of asthma and either paternal or maternal smoking. O w n b y and McCullough 84 evaluated 191 children for a relationship between the presence and quantity o f IgE to a group of c o m m o n inhalant allergens and parental smoking. One hundred of the children were randomly selected from healthy children receiving well-child care, and the other 91 children were referred for allergy evaluations. No significant differences between either the frequency o f positive specific IgE tests nor the quantity o f specific IgE were found in either patient group in relationship to maternal, paternal, or parental smoking. The prevalence of maternal smoking was more than doubled in the children referred for allergy evaluation compared to the children receiving well-child care. This finding is consistent with other studies demonstrating increased respiratory symptoms in children exposed to cigarette smoke.
it may prime an infant for subsequent l g E production. Given the difficulties in trying to control human genetics, it is unlikely that genetic manipulation will be able to prevent allergy in the near future, but environmental controls may help reduce morbidity from allergy by delaying the onset of inhalant allergy and reducing the severity of symptoms.
CONCLUSION
Inhalant allergy develops in children as the result of multiple interactions between the immune system and the environment. Although the current state of knowledge does not permit precise identification of the relative importance of genetic and environmental influences, it appears that genetic control is most important in determining the overall risk of allergy. This is observed in the control of total serum IgE concentrations and the likelihood o f forming IgE after allergen exposure. Environmental influences are probably most important in determining the specific allergens to which a person will develop sensitivity. Early allergen exposure may be especially important because
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