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,**
*
Department of Anthropology, Northwestern University, Evanston, IL 60208-1310; Departments of
Pediatrics and
**
Nutrition and
Carolina Population Center, University of North Carolina, Chapel Hill, NC; and
Department of Anthropology, Emory University, Atlanta, GA
2To whom correspondence should be addressed. E-mail: t-mcdade{at}northwestern.edu.
 |
ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: • thymic factor • immune system • prenatal exposure delayed effects • growth and development • nutrition • humans
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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2
3)
. However, the
implications of early environments for the development and function of
the immune system in adulthood are not known. This study addresses this
question by investigating the long-term effects of prenatal and
early postnatal experience on thymic hormone production in adolescence.
We found recently that prenatal undernutrition is associated with
reduced antibody response to typhoid vaccination in adolescents from
the Philippines, whereas postnatal diarrheal morbidity and rapid weight
gain are positively associated with immunocompetence (4)
.
This prospective study provides evidence in support of early
programming of later immune function, complementing previous research
on programming of cardiovascular and endocrine systems, and suggesting
a possible mechanism for the recently reported association between
prenatal undernutrition and adult infectious disease mortality
(5
,6)
. This research also builds on previous work linking
pre- and postnatal undernutrition to deficits in several aspects of
immunity in infancy and early childhood (7
8
9
10)
.
A number of studies have drawn attention to the thymus as a potential
mediator of the immunological consequences of undernutrition. The
thymus is a primary lymphoid organ required for normal T-lymphocyte
development and function, and for the production of a number of thymic
hormones with peripheral immunoregulatory properties
(11
,12)
. Pre-T cells migrate from bone marrow to the
thymus where they differentiate and mature into competent T-lymphocytes
before their release into circulation. This process is critical for
minimizing the potential for self-reactivity, for establishing the
T-cell repertoire that populates peripheral lymphoid tissues and
for maintaining the balance between subsets of T cells
(13
,14)
. Protein-energy malnutrition in infancy and
early childhood has been associated with dramatic declines in thymic
weight, lowered thymic hormone levels, reduced numbers of maturing T
cells and alterations in the thymic microenvironment
(9
,15
16
17
18
19
20)
. The long-term consequences of early
undernutrition for thymic development and function are not known, but
the thymus has been hypothesized as a mediator of the associations
between fetal undernutrition and symptoms of adult atopic and
autoimmune disease (21
,22)
.
Thymic hormones play important roles in T-cell development and
peripheral T-cell function (23
,24)
, and a number of
studies have explored the clinical utility of thymic hormones as
treatments for immune deficiency (25)
. Thymopoietin, one
of the best characterized thymic hormones, is a 49–amino acid
polypeptide that is produced primarily by thymic epithelial cells. It
is involved in early T-cell differentiation, as well as the
coordination of lymphocyte subsets and the peripheral regulation of
mature T-cell function (26
27
28)
. It is also appears to
play an important role in cell cycle regulation in a number of tissues
(29
,30)
. Serum thymopoietin concentration correlates
roughly with thymus size; it is highest at 15–30 y of age and declines
in parallel with the age-related involution of the thymus
(31)
.
The immunoregulatory properties of thymopentin, a synthetic peptide
with the same biological properties as thymopoietin, have been
investigated extensively. In vitro studies report enhanced T-cell
differentiation, proliferation and cytokine production after
thymopentin treatment, and in vivo murine studies demonstrate reduced
tumor growth and restored T-cell activity after thymic involution
(28)
. In human clinical studies, thymopentin treatment has
been associated with increases in T-cell numbers, proliferation and
interleukin-2 production, improved delayed-type hypersensitivity
response to recall antigens, as well as improvement in the course of a
number of autoimmune, neoplastic and infectious diseases
(28
,32)
.
In this study, we hypothesized that prenatal and early postnatal environments would have implications for thymic hormone production in adolescence. We investigated this issue in an ongoing, longitudinal study of maternal and child health in the Philippines with detailed information on a range of potentially confounding factors. To the best of our knowledge, this is the first study to report the long-term effects of early environments on the thymus, providing support for the potential importance of early programming of adult immune function.
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SUBJECTS AND METHODS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The Cebu Longitudinal Health and Nutrition Study
(CLHNS)3
is an on-going population-based survey of maternal and
child health in the Philippines that began in 1983 with the recruitment
of 3327 pregnant women (33)
. In-home interviews were
conducted before and immediately after birth, and every 2 mo for 2 y to collect in-depth data on child and maternal health,
anthropometry, patterns of breast-feeding, dietary intake, rates of
diarrhea and respiratory disease, household socioeconomic status and
demographics, and environmental quality. Follow-up surveys were
conducted in 1991, 1994–1995, and 1998–1999. The prospective design
of this study provides a unique opportunity to explore a range of
direct and indirect pathways through which early environments may
affect later immune function.
In 1998–1999, 2089 CLHNS participants, 14 or 15 y old at the
time, were contacted for follow-up data collection. From these
remaining participants, a subsample of 103 individuals was selected for
evaluation of the relationships between early environments and immune
function in adolescence. Due to cost considerations and the nature of
the protocol, a limited number of participants were recruited according
to the following criteria: full-term birth (= 37 wk), currently
healthy, and small-for-gestational age (SGA: defined as <10th
percentile of birthweight for gestational age) vs.
appropriate-for-gestational age (AGA: 
10th percentile)
(34)
.
SGA and AGA individuals were selected randomly from their respective populations in the CLHNS cohort; we intentionally oversampled SGA individuals to evaluate the effects of intrauterine growth retardation (IUGR). We eliminated the potentially confounding effects of premature delivery by restricting our sample to full-term births, and focused on the small size assumed to be related to prenatal undernutrition. The subsample of SGA individuals recruited for this study is representative of SGA individuals in the larger CLHNS cohort, except that the average birthweight of 2347 g is significantly lower than the average of 2494 g for all SGA individuals in the CLHNS (P < 0.001).
Gestational age was determined from maternal recall of the date of her
last menstrual period or by clinical(35)
assessment of the
newborn for those mothers who could not recall their last menstrual
period, for low birthweight infants and for those who had pregnancy
complications. As in many countries in the developing world, IUGR is
common in the Philippines due to high rates of maternal undernutrition
during pregnancy. In the CLHNS, the prevalence of IUGR is 20.9%
(36)
.
Thymopoietin concentration was analyzed in blood samples collected as
part of a protocol investigating antibody response to vaccination
(4)
. Upon enrollment in the antibody study, 
5 mL of
EDTA plasma were collected and immediately frozen, followed by
vaccination against typhoid fever. Follow-up blood was drawn 2 wk
and 3 mo later. Thymopoietin concentration was assayed in samples
collected 2 wk after vaccination. The study protocol was conducted as
approved by the University of North Carolina School of Public Health
Institutional Review Board for research involving human subjects.
Thymopoietin ELISA.
Samples were shipped on dry ice to the United States and stored at -20°C before analysis. Thymopoietin concentration was assayed using a commercially available high sensitivity solid-phase ELISA kit (R&D Systems, Minneapolis, MN). Microtiter plate wells were precoated with a polyclonal antibody specific for the first 19–amino acid sequence of human thymopoietin. Samples, standards and controls were added to wells in duplicate along with biotinylated monoclonal antibody (specific for amino acid sequences 29–50) and incubated at room temperature for 2.5 h. Wells were washed, followed by the addition of streptavidin-alkaline phosphatase. Wells were washed again, and an amplifier solution was added to facilitate color development. Sulfuric acid was added to stop the reaction, and absorbance was read at 490 nm (Dynatech MR5000, Chantilly, VA). The intensity of color development is directly proportional to the quantity of thymopoietin, and unknown values were determined on the basis of the standard curve constructed from thymopoietin calibrators (Statlia, Brendan Scientific, Grosse Point Farms, MI).
Data analysis.
Four individuals with excessively high values due to sample hemolysis were excluded. Complete nutritional, anthropometric, morbidity and sociodemographic data were available for 96 individuals.
The distribution of thymopoietin was positively skewed, and values were
log-transformed to normalize the distribution before multiple
linear regression analysis (Stata, College Station, TX). Intrauterine
growth retardation was the primary independent variable of interest,
but aspects of the prenatal environment (maternal nutritional status
during pregnancy and parity), postnatal environment (household
socioeconomic status, pattern of breast-feeding, pathogen exposure
and infectious morbidity) and growth (length and weight), and current
status (pubertal status and nutritional status) were also considered as
potential predictors of thymopoietin concentration (Table 1
).
|
The morbidity variable provides a measure of diarrheal and/or respiratory disease during y 1 of life. At each of the six bimonthly home visits after the birth of their infant, mothers were asked whether the infant had experienced diarrheal or respiratory symptoms in the week preceding the visit. The potential effects of diarrheal and respiratory disease were considered separately, as well as together in the summary variable.
Current nutritional status was assessed through standard anthropometric measures, as well as hemoglobin concentration. Hemoglobin was considered as a continuous variable, and as a dichotomous variable for which anemic individuals (hemoglobin <110 g/L) were compared with nonanemic individuals. Nine participants were identified as anemic.
Previous research suggests that thymic activity may be influenced by
progression through puberty (12)
. Because participants in
this study were peripubertal, an attempt was made to control for
developmental status. Boys were classified as being in early or late
puberty according to self-ratings of pubic hair growth, and girls
were classified according to the stage of breast development.
We hypothesized that SGA individuals would have lower thymopoietin
concentrations than AGA individuals. We used the model-building
approach advocated by Lucas et al. (37)
to increase our
confidence in concluding that any association between IUGR and
adolescent thymopoietin concentration was due to the quality of the
prenatal environment rather than correlated aspects of postnatal
experience. Our approach was as follows: 1) evaluate the
crude association between SGA and thymopoietin; 2) add
variables representing aspects of postnatal growth, morbidity and
environment to multivariate models including
birthweight-for-gestational-age; and 3) consider the effect
of these variables without SGA in the model. Interaction terms were
included when appropriate. P < 0.05 was taken as the
criterion for statistical significance.
If the effect of SGA was reduced after adjusting for postnatal factors, we concluded that postnatal rather than prenatal environments were more likely to be causally related to adolescent thymopoietin production. However, we recognize that prenatal and postnatal effects may not be entirely independent, particularly with respect to growth, and that adjustment for postnatal factors may underestimate the importance of prenatal environments. If adjustment for postnatal factors amplified the effect of SGA, we concluded that both prenatal and postnatal influences were relevant. Significant interactions between SGA and postnatal factors were assumed to indicate that SGA modified the effect of later environments.
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RESULTS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. Proportion of females, pubertal status, gestational age, postnatal
growth in length and episodes of morbidity during y 1, the duration of
exclusive breast-feeding and current age did not differ
significantly between the two groups. As expected, SGA individuals had
significantly lower birthweight, as well as lower body mass index (BMI)
at age 14–15 y. They also gained significantly more weight in y 1 and
were more likely to be born to mothers without a prior pregnancy and
with lower BMI at the time of birth.
|
Next, variables representing aspects of the prenatal environment,
postnatal environment, size at age 10 or 11 y and current status
(Table 1)
were added to models including sex and
birthweight-for-gestational-age. The interaction between
birthweight-for-gestational age and exclusive breast-feeding
duration emerged as a significant predictor of adolescent thymopoietin
concentration, as well as growth in length during y 1 of life
(Table 3
). Other variables (Table 1)
did not approach statistical significance
(P > 0.15), nor did they modify the effects of
birthweight, breast-feeding or growth.
|
). Each additional centimeter of infant growth corresponded to 7.5%
increase in untransformed thymopoietin concentration, and adolescents
who were 1 SD above the mean in 1-y length increment (23.4
cm) had thymopoietin concentrations that were 1.5 times higher than
adolescents who were 1 SD below the mean (18.0 cm).
|
. The results for birth to 6 mo are
significant, whereas those for 6 to 12 mo are only marginally so.
Although these differences are small, they suggest that the first 6 mo
of life may be particularly important for thymic development.
The main effect of birthweight-for-gestational-age became significant
(ß = 0.12, P = 0.044) when length increment was
added to the model. The adjusted R2
for this model was 0.29. In addition, the duration of exclusive
breast-feeding (<51 vs. > 51 d) also emerged as an important
predictor of adolescent thymopoietin production. The main effect of
exclusive breast-feeding duration did not approach significance
(ß = 0.047, P = 0.42). However, the interaction
between birthweight-for-gestational-age and duration of exclusive
breast-feeding was significant, and the model including this term
had a substantially higher adjusted R2
value (Table 3)
, indicating that the effect of
birthweight-for-gestational-age depended on the duration of exclusive
breast-feeding.
Appropriate-for-gestational age individuals who were exclusively
breast-fed for >50 d stood out with elevated thymopoietin
concentrations in adolescence (Fig. 2
). Small-for-gestational age individuals had lower concentrations
regardless of exclusive breast-feeding duration, and short
breast-feeding, AGA individuals had comparably low concentrations.
The mean untransformed thymopoietin concentration of AGA, long
exclusively breast-fed individuals was 50–90% higher than the
thymopoietin concentration of individuals in the other three groups.
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|
DISCUSSION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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,39)
. Nonetheless, our findings are consistent
with research in this population documenting relationships among IUGR,
breast-feeding and weight velocity on adolescent antibody response
to vaccination (4)
. Limitations of this study include the relatively small sample size and its associated reduction in statistical power. In future research, we hope to take full advantage of the comprehensive CLHNS dataset. Furthermore, the possibility exists that the subsample chosen for this study was not representative of the CLHNS cohort and that findings reported here cannot be generalized. Participants were selected randomly from the pool of full-term SGA and AGA individuals, and, with the exception of birthweight, no significant differences were found between the subsample and the full cohort. In this study, the mean birthweight for SGA individuals was 147 g lower than the mean for remaining SGA individuals in the cohort, allowing for the possibility that results reported above may overestimate the effect of birthweight. In addition, this study cannot evaluate the significance of low birthweight combined with premature delivery because only full-term births were considered.
The study is also limited by challenges in the interpretation of
thymopoietin concentrations. The absence of reference values prevents
assessment of the clinical significance of our findings, even though
the relative differences in thymopoietin concentration associated with
birthweight-for-gestational-age, breast-feeding and growth in
length demonstrate the importance of these variables. In addition,
recent work has shown that thymopoietin is a ubiquitously expressed
nuclear protein that is found in a range of tissues with high levels of
proliferative activity (40)
. This raises the possibility
that differences in thymopoietin concentrations do not reflect
differences in activity of the thymus as assumed. However, even though
thymopoietin production is not limited to the thymus, the highest
levels of mRNA are found in the thymic cortex (29)
, and
circulating thymopoietin is generally believed to be of thymic origin
(28
,41)
. Future studies should consider evaluating
additional thymic peptides (e.g., thymosins, thymulin, thymic humoral
factor) as well as recent thymic emigrants (42)
for a more
complete picture of thymic activity.
Previous research on the thymus suggests that undernutrition and
progression through puberty are negatively associated with thymic
function (11
,12
,15)
, but in this study, only events early
in life were found to be significantly related to adolescent
thymopoietin production. This supports the hypothesis that early
environments are important for later thymic function, and suggests a
causal role for these environments rather than correlated aspects
of childhood and adolescent environments. Additional research in a
larger sample will be required to confirm and elaborate these findings.
Results presented here also differ from those of our study on
adolescent vaccine responsiveness in which current undernutrition was
significantly related to a lower likelihood of mounting a positive
antibody response in interaction with prenatal undernutrition
(4)
.
Mature T cells are released from the thymus by wk 14 of
gestation, and the rate of thymic tissue development increases
dramatically during the last trimester, followed by rapid postnatal
growth (13)
. As such, the prenatal and early postnatal
periods are critical for the thymus, and insults during these periods
may have more serious consequences than those experienced later in
life. Growth in length during y 1 of life may provide a proxy for organ
growth in general and thymic growth in particular. Concordantly, recent
sonographic assessments of thymic volume have reported positive
associations with birthweight and body length in infancy
(43
,44)
. An infant who grows slowly during this critical
period of thymic development may also grow a smaller thymus, with fewer
epithelial cells for thymic hormone production in adolescence.
Impaired thymus growth may also account for the lower
thymopoietin production in adolescents born SGA. This is consistent
with previous research documenting lower thymus weights in SGA newborns
(19)
and reduced thymic hormone activity at 1 mo of age in
SGA infants (9)
. The positive association between
thymopoietin production and the duration of exclusive
breast-feeding is also consistent with previous research reporting
an association between exclusive breast-feeding through 4 mo of age
and increased thymic volume at 10 mo (44)
. In addition to
the macro- and micronutrients that minimize the likelihood of
malnutrition, and the passive immunity that lowers the risk of
infection, breast milk contains a number of molecules that facilitate
immunological development in the newborn (45)
. Prolonged
breast-feeding may promote thymic development directly or
indirectly by improving the quality of the infant’s postnatal
environment. Breast-feeding was found to interact with prenatal
growth such that AGA, long exclusively breast-fed individuals had
the highest concentrations of thymopoietin in adolescence, suggesting
that AGA infants are better prepared to benefit from prolonged
exclusive breast-feeding. However, it is possible that analysis of
a larger sample would reveal an additive, rather than interactive
relationship between breast-feeding and
birthweight-for-gestational-age.
Reduced thymopoietin production could also be the result of early
programmed effects on the hypothalamic-pituitary-adrenal (HPA) axis.
The thymus is sensitive to HPA activity, i.e., in clinical populations,
the excessive glucocorticoid production of Cushing’s syndrome and the
large doses of adrenocorticotropic hormone for ipsarythmia both result
in thymic atrophy (15)
, and episodes of malnutrition,
infection and psychological stress, all associated with HPA activation,
appear to be causally related to transient thymic involution and
reduced thymic hormone production (15
,17
,46)
. Inhibition
of HPA activity and glucocorticoid production attenuates these effects
(47
,48)
. Birthweight has recently been associated with
alterations in glucocorticoid production in 9-y-old children
(49)
, and a number of primate studies have documented
lasting irregularities in HPA and immune function in offspring of
mothers stressed during pregnancy (50
51
52
53)
.
The association between early environments and adolescent thymic
hormone production may provide a mechanism for recent reports linking
fetal growth to symptoms of autoimmune and atopic disease in adults.
Phillips et al. (22)
discovered a negative association
between birthweight and the proportion of women producing antibodies
against thyroglobulin and thyroid peroxidase, whereas Godfrey et al.
(21)
found increased immunoglobulin E concentrations in
men and women with disproportionate fetal growth of the head relative
to the trunk and arms. Both groups speculate that impaired development
of the thymus after fetal undernutrition may be responsible for these
associations. Findings from this study support this hypothesis, but
also emphasize the importance of the early postnatal environment to
later thymic activity.
Additional research is required to establish the relevance of programming to the development and function of the immune system, and to explore the implications for atopic, autoimmune, infectious and neoplastic disease risk in adulthood. Although high rates of IUGR may make marginally nourished populations particularly vulnerable, the possibility of early programming of immune function will have important ramifications for other populations as well. Future studies should explore the moderators of early environment effects, the physiologic processes that link early environments to thymic development and function, and their specific immunologic consequences.
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FOOTNOTES |
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3 Abbreviations used: AGA, appropriate-for-gestational age; BMI, body mass index; CLHNS, Cebu Longitudinal Health and Nutrition Study; HPA, hypothalamic-pituitary-adrenal; IUGR, intrauterine growth retardation; SGA, small-for-gestational age.
Manuscript received October 23, 2000. Initial review completed November 9, 2000. Revision accepted December 21, 2000.
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