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Early environments and the ecology of inflammation
Thomas W. McDade
1
Department of Anthropology and Cells to Society: The Center on Social Disparities and Health at the Institute for Policy Research, Northwestern University,
Evanston, IL 60208
Edited by Gene E. Robinson, University of Illinois at Urbana–Champaign, Urbana, IL, and approved August 21, 2012 (received for review February 13, 2012)
Recent research has implicated inflammatory processes in the patho-
physiology of a wide range of chronic degenerative diseases, although
inflammation has long been recognized as a critical line of defense
against infectious disease. However, current scientific understandings
of the links between chronic low-grade inflammation and diseases of
aging are based primarily on research in high-income nations with low
levels of infectious disease and high levels of overweight/obesity.
From a comparative and historical point of view, this epidemiological
situation is relatively unique, and it may not capture the full range of
ecological variation necessary to understand the processes that shape
the development of inflammatory phenotypes. The human immune
system is characterized by substantial developmental plasticity, and
a comparative, developmental, ecological framework is proposed to
cast light on the complex associations among early environments,
regulation of inflammation, and disease. Recent studies in the Philip-
pines and lowland Ecuador reveal low levels of chronic inflammation,
despite higher burdens of infectious disease, and point to nutritional
and microbial exposures in infancy as important determinants of in-
flammation in adulthood. By shaping the regulation of inflammation,
early environments moderate responses to inflammatory stimuli later
in life, with implications for the association between inflammation
and chronic diseases. Attention to the eco-logics of inflammation
may point to promising directions for future research, enriching our
understanding of this important physiological system and informing
approaches to the prevention and treatment of disease.
cardiovascular disease
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developmental origins of health and disease
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ecological immunology
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evolutionary medicine
These days, inflammation is much maligned. Several studies have
implicated inflammation in the etiology of a wide range of dis-
eases of aging, including diseases of the cardiovascular, metabolic,
musculoskeletal, nervous, and immune systems. Underscoring this
point, on its cover in 2004, Time magazine labeled inflammation
“The Secret Killer”(1). There is some irony in this label, because
inflammation comprises a critical line of defense against infection,
and without this protection, even minor injuries or infections can
become potentially life-threatening.
This paper attempts to reconcile these views by considering both
the costs and the benefits of inflammation from the perspective of
comparative human biology. Although typically studied under
controlled, circumscribed environmental conditions, the human
immune system shows considerable developmental plasticity and
functional variation across individuals and populations. In-
flammation is no exception, and attention to the eco-logics of in-
flammation—principles related to developmental plasticity and
ecological contingency that inform its organization and function—
may advance scientific understandings of the regulation of in-
flammation and its impact on human disease.
Contrasting Approaches to the Study of Inflammation and
Disease
C-reactive protein (CRP) is a prototypical acute-phase protein and
commonly measured biomarker of inflammation (2). The recent
advent of highly sensitive laboratory assays for CRP has led to
the discovery that chronic low-grade inflammation—levels of in-
flammation previously thought to be inconsequential—may con-
tribute to the pathophysiology of a wide range of diseases of aging,
including cardiovascular disease (CVD) (3), type 2 diabetes (4),
metabolic syndrome (3), and late-life disability (5) as well as all-
cause mortality (6). As a result, CRP is increasingly measured in
clinical and epidemiological settings, and recent consensus guide-
lines recommend CRP >3 mg/L as the cutoff point to identify
individuals at high risk for cardiovascular disease (7). These
guidelines, however, are based on data from European and Eu-
ropean-American populations, where approximately one-third of
adults have CRP >3 mg/L. The use of these guidelines for other
demographic groups is not well-established.
This conceptualization of inflammation as a chronic phenome-
non contributing to diseases of aging is relatively new. For nearly
2,000 y, since Celsus first articulated calor, rubor, tumor, and dolor
as the four cardinal signs of inflammation (8), inflammation has
been understood as a critical component of innate immune defenses
against infection and injury. Acute activation of inflammatory pro-
cesses after pathogen exposure is rapid—within hours—whereas
more specific adaptive immune processes (mediated by T and B
lymphocytes) take several days to come on line (9).
Biochemical mediators of inflammation like CRP play impor-
tant roles in activating complement, promoting phagocytic activity,
and opsonizing bacteria, fungi, and parasites (2). Trace amounts of
CRP are normally detectable in circulation, and concentrations
increase by several orders of magnitude as part of the acute-phase
response to infection. Because the acute-phase response is stim-
ulated by a wide range of pathogens, prior research has measured
CRP as a nonspecific indicator of clinical or subclinical infection,
with values above 5 or 10 mg/L commonly used to identify acute-
phase activity (10, 11). This line of thinking has been in place since
1930, when CRP was first described as a pattern recognition
molecule that reacted with C-polysaccharide of the cell wall of
Streptococcus pneumoniae bacterium (12).
Thus, we have two perspectives on the complex associations
among inflammation and disease (Fig. 1). The acute-phase ap-
proach emphasizes short-term elevations in inflammatory media-
tors like CRP as adaptive responses to pathogenic challenge that
are necessary to protect us from infectious disease. In contrast, the
chronic low-grade inflammation perspective assumes that in-
dividual differences in CRP levels are stable over time and that
elevated concentrations of CRP—above 3 mg/L but below levels
thought to be attributable to acute infectious events—contribute to
the development of diseases of aging like CVD. These perspectives
are typically applied in distinct epidemiological universes. A focus
on acute-phase responses has predominated in lower-income
nations to investigate inflammatory responses to endemic in-
fectious diseases, whereas the conceptualization of inflammation
as a chronic process that contributes to diseases of aging has
This paper results from the Arthur M. Sackler Colloquium of the National Academy of
Sciences, “Biological Embedding of Early Social Adversity: From Fruit Flies to Kindergart-
ners,”held December 9–10, 2011, at the Arnold and Mabel Beckman Center of the
National Academies of Sciences and Engineering in Irvine, CA. The complete program
and audio files of most presentations are available on the NAS Web site at www.nason-
line.org/biological-embedding.
Author contributions: T.W.M. designed research, performed research, analyzed data, and
wrote the paper.
The author declares no conflict of interest.
This article is a PNAS Direct Submission.
1
E-mail: t-mcdade@northwestern.edu.
www.pnas.org/cgi/doi/10.1073/pnas.1202244109 PNAS Early Edition
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emerged in affluent industrialized settings, where life expectancies
are relatively high and burdens of infectious disease are lower.
A more comprehensive understanding of inflammation may be
gained by bridging these perspectives. Although the acute-phase
and chronic low-grade approaches both focus on inflammation as
a critical physiological process with links to disease, they have
proceeded as parallel lines of research pursued by distinct teams of
investigators in different epidemiological settings with divergent
conceptual and empirical goals. Both lines of research have proven
productive, but a more convergent approach may castnew lighton
the range of variation in key inflammatory processes and reveal the
origins and implications of this variation.
Ecological Variation and Developmental Plasticity in the
Human Immune System
Inflammation is one part of a larger network of immune defen-
ses, the primary function of which is to provide protection from
the ubiquitous bacteria, viruses, and parasites that share our
world. The immune system is also centrally involved in cellular
renewal and repair, and thus, it plays critical roles in wound
healing and protection against cancer. Not unlike the nervous
system (13), central aspects of the immune system are relatively
undifferentiated early in development, with functional organi-
zation and complexity emerging over time through a process of
engagement with expectable inputs from the environment. Both
systems use developmental processes that learn about the ex-
ternal world, represent this information internally, and calibrate
somatic investments in ways that optimize functionality within
the constraints of a given environment (14, 15).
Ecological contingency in immune development is seen most
clearly in clonal selection, where the process of immune de-
velopment and maturation depends on interaction with antigens
from the environment to adapt an individual’s specific lympho-
cyte repertoire to the local disease ecology (9). However, the
context-dependent nature of immune development extends well
beyond clonal selection (15). For example, higher burdens of
infectious disease in infancy increase the strength of the antibody
response to typhoid vaccination in adolescence (16), suggesting
a higher overall level of investment in specific immune defenses in
high pathogen environments. In addition, low levels of infectious
exposure in infancy have been associated with increases in Th2
cytokine production and total IgE concentration (17–19), a pat-
tern of immune development that promotes allergic, atopic, and
autoimmune diseases later in life. Research on the hygiene hy-
pothesis has shown repeatedly that microbial exposures in infancy
shape the development of immune regulatory networks in ways
that are important for limiting immunopathological processes
(20, 21), with recent findings pointing to potentially important
roles for the human gut microbiota (22).
Prenatal and early postnatal nutritional environments also
have lasting effects on human immunity. For example, infants
born small for gestational age—indicating a relatively impov-
erished prenatal nutritional environment—are less likely to re-
spond to vaccination in adolescence, have higher total IgE, and
produce lower concentrations of thymopoietin, a thymic hor-
mone important for cell-mediated immunity (16, 18, 23). In
addition, slow rates of growth in infancy—likely indicative of
inadequate postnatal nutrition—are associated with reduced
vaccine responsiveness and thymopoietin production in adoles-
cence (16, 23). These findings build on early research with ani-
mal models, showing that undernourished rats give birth to
offspring with immune deficiencies that last into adulthood, al-
though the offspring had unrestricted access to food (24, 25).
Psychosocial factors are also an important part of the ecology of
human immune function (26, 27). The impact of stress on multiple
aspects of immunity is well-established, and it has been investigated
primarily in adulthood. The few studies conducted with children and
adolescents indicate significant adverse impacts as well (28–30),
whereas experimental research with nonhuman primates suggests
that maternal stress during pregnancy and maternal separation in
infancy have substantial effects on offspring immune function that
persist beyond infancy (31, 32). Recently, neglect or abuse in early
childhood has been associated with reduced cell-mediated immunity
and increased inflammation in adolescence and young adulthood
(33, 34). Similarly, low socioeconomic status early in life predicts
elevated CRP among adults (35) as well as increased proin-
flammatory and decreased antiinflammatory gene expression (36).
In sum, emerging evidence shows considerable variation and
plasticity in human immune development and function, and it
points to aspects of the nutritional, microbial, and psychosocial
ecology in infancy and early childhood as important determinants
of an individual’s immunophenotype. However, current research
in biomedical immunology focuses primarily on the cellular and
molecular mechanisms coordinating immune defenses using ani-
mal models and clinic-based patient populations, and it rarely
applies longitudinal, life-course research designs. In contrast, an
ecological, developmental approach recognizes that the immune
system—like other physiological systems—develops and functions
in whole organisms that are integral parts of their surrounding
environments (14, 37). To the extent that ecological factors are
relevant to inflammatory phenotypes, research on the regulation
of inflammation may benefit from such an approach.
Early Environments and the Eco-Logics of Inflammation
In terms of human history, people living in contemporary in-
dustrialized environments enjoy unprecedented access to calorie-
dense foods, low demands for physical exertion and energy expen-
diture, and regimens of sanitation and hygiene that have reduced—
by orders of magnitude—the frequency and diversity of microbial
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CRP (mg/L)
Days
ID1 ID2 ID3
0
5
10
15
20
25
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1 5 9 13172125293337414549535761
CRP (mg/L)
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Fig. 1. Hypothetical pattern of CRP production over 8 wk for three individuals according to the acute-phase (Left) and chronic low-grade (Right) approaches
to the study of inflammation and disease.
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www.pnas.org/cgi/doi/10.1073/pnas.1202244109 McDade
exposures (38, 39). In particular, saprophytic mycobacteria, lacto-
bacilli, and many helminthes common in rotting vegetable matter,
soil, and untreated water represent disappearing classes of micro-
organisms that have been part of the human and mammalian en-
vironment for millennia and are generally treated as harmless by
their hosts (40). Of course, there is substantial heterogeneity in
nutritional and microbial environments within contemporary in-
dustrialized nations, much of it structured by socioeconomic and
geographic factors. However, this heterogeneity is relatively cir-
cumscribed compared with the qualitative shifts that have, on av-
erage, led to substantial caloric surpluses and reductions in contact
with microorganisms.
Because the human immune system evolved in environments with
marginal nutritional status and substantially higher levels of microbial
exposure, it is reasonable to ask whether overnourished, under-
infected industrialized populations capture the full range of variation
that is necessary to understand the determinants of inflammatory
phenotypes (14, 41, 42). In light of the key role of inflammation in
antipathogen defenses and the importance of early environments in
shaping the development and function of the human immune system,
comparative research across different ecological settings is needed to
generate insights into the complex associations among early envi-
ronments, regulation of inflammation, and disease.
This logic has motivated us to conduct a series of studies in
environments with higher levels of infectious disease, including
the Philippines and lowland Ecuador. The Philippines is a lower
middle-income nation with relatively low but rising rates of
overweight/obesity, CVD, and metabolic syndrome (43, 44), and
we have drawn on data from the ongoing Cebu Longitudinal
Health and Nutrition Survey (CLHNS) to investigate the pre-
dictors of inflammation in this environment. Infectious disease
continues to account for more than 30% of all mortality in the
region, and respiratory infections rank beside ischemic heart
disease as the top causes of death (45). Despite an ongoing
legacy of infectious disease, one-quarter to one-third of Filipino
adults are now overweight or obese (43, 44).
The Ecuadorian Amazon is home to the Shuar, an indigenous
group living in small villages across scattered clusters of house-
holds that pursues a subsistence strategy based on horticulture,
hunting, and fishing (46). Electricity and running water are not
available, and the Shuar have very limited access to Western
medicines or healthcare. Acute respiratory infection, gastroin-
testinal illness, and vector-borne disease are the primary sources
of morbidity, with rates of mortality caused by infectious disease
that are more than five times higher than the United States and
Canada (47, 48). In contrast, the cardiovascular and metabolic
risk profiles of Shuar adults are relatively favorable compared
with adults in industrialized nations (49).
Among young adults in the Philippines (20–22 y), median CRP
is exceptionally low at 0.2 mg/L compared with 0.9 mg/L for age-
matched adults in the United States (50). Plasma samples were
analyzed in a clinical facility in the United States using a gold-
standard high-sensitivity CRP assay; therefore, differences in
laboratory protocols are not likely to account for this discrepancy.
Similarly, older women in the Philippines (35–69 y) have higher
median CRP at 0.9 mg/L, but this concentration is still sub-
stantially lower than 2.02 mg/L, the median CRP for older
American women (51). Additionally, in lowland Ecuador, median
CRP for adults ages 18–50 y is 0.5 mg/L, despite a prevalence of
infectious disease that is even higher than the Philippines (52).
Why do populations with higher burdens of infectious disease
seem to have lower baseline levels of CRP? Given that in-
flammation is an important component of innate immune defenses,
this association represents something of a paradox. In the Philip-
pines and Ecuador, adults are relatively thin compared with US
adults, and because visceral adipose tissue is an important source of
proinflammatory cytokines like IL-6 (53), lower levels of body fat-
ness could account for lower inflammation. This does not seem to
be the case. In our Cebu cohort, median waist circumference for
women is 66.5 cm compared with 85.0 cm for young adult women
in the United States. However, when we restrict our analysis to
womenwithwaistcircumferencesbetween70and80cm—arange
of values with substantial overlap across the populations—median
CRP for women in Cebu is only 0.3 mg/L compared with 0.7 mg/L
for US women (50). We found similar differences in the association
between skin-fold thickness and CRP in men across the two pop-
ulations (skin-fold thickness was the only adiposity variable signifi-
cantly associated with CRP among men in Cebu). As such, low CRP
in the Philippines cannot be explained away by the lower levels of
overweight/obesity relative to populations like in the United States.
Rather, these results suggest that the relationship between body fat
and inflammation may differ across populations.
Similarly, genetic differences are another potential source of
variation in CRP within and between populations (54), but they
cannot account for lower concentrations of CRP in the Philippines.
We recently reported that the frequency and pattern of associa-
tions between several SNPs and CRP in young and older adults in
the Philippines are consistent with prior research in populations of
European ancestry (55, 56). The proportion of explained variance
in CRP attributable to direct genetic influences was small (4.8–
5.6%), with evidence that the level of microbial exposure in the
household environment moderated the effects of some of these
genes. These results suggest that similar geneticinfluences operate
across populations, their influences on inflammation are environ-
mentally contingent, and differences in genetic background are not
likely to be primary determinants of low CRP in the Philippines.
Rather, converging lines of evidence point to the potential im-
portance of early environments in shaping inflammatory pheno-
types, with implications for population differences in patterns of
CRP production in adulthood. Based on prior research showing the
importance of nutritional and microbial exposures to immune de-
velopment in particular, one might hypothesize that these factors
0.00
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0.25
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0.35
0.40
Diarrhea in
infancy
Animal feces
exposure
Born in dry
season
Probability of elevated CRP
Low/no High/yes
Fig. 2. Association between microbial exposures in infancy and probability
of elevated CRP in young adulthood in the Philippines. Results are based on
predicted probabilities from the fully adjusted logistic regression models
reported in ref. 57. Low and high values for predictors were set as follows:
diarrhea (zero to three or more episodes), animal feces exposure (zero to
three or more intervals), and born in dry season (no or yes). Original values
were retained for other variables in the model.
McDade PNAS Early Edition
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are significant predictors of inflammation in adulthood. We find
support for this hypothesis within the Philippines, where birth
weight is negatively associated with CRP in young adulthood (57),
similar to results from other cohorts outside the Philippines (58,
59). However, birth weight is not likely to account for popula-
tion differences in average CRP concentration between the Phil-
ippines and the United States. Because average birth weights in our
sample were almost 400 g lower than average birth weights in the
United States in 1983 (60), CRP concentrations should be, with all
other factors being equal, higher in the Philippines than in the
United States.
When the CLHNS began collecting data in the early 1980s,
Filipino families in Cebu lived in a wide range of settlements,
including rural towns and remote outlying areas as well as dense
urban areas with affluent neighborhoods and poorly constructed
squatter camps (61). Approximately one-half of the homes in the
study had electricity, more than three-quarters of families col-
lected water from an open source, less than one-half of families
used a flush toilet, and more than one-half of families had ani-
mals (e.g., dogs, chickens, goats, or pigs) roaming under, around,
or in the house. The level and intensity of exposure to infectious
microbes were relatively high, and episodes of diarrhea were
frequent when the cohort was in infancy (62, 63). There was also
significant variation in exposure within the sample, because
participants were drawn from households across settlement types
and the full range of socioeconomic conditions in Cebu. Fur-
thermore, because there is substantial seasonal variation in
rainfall that is associated with pathogen transmission and in-
fectious morbidity in Cebu (62, 63), month of birth contributes to
additional variation in infectious exposures in infancy. These
factors make CLHNS an ideal dataset with which to test the
hypothesis that infectious exposures in infancy may have lasting
effects on the regulation of inflammation in adulthood.
Support for this hypothesis comes from three distinct meas-
ures of infectious exposure in infancy (Fig. 2). Higher levels of
animal feces in the home, more frequent episodes of diarrhea,
and birth during the dry season each predicted lower CRP as
a young adult (57). The magnitude of these associations was
substantial. Moving from the highest to the lowest levels of di-
arrhea morbidity and exposure to animal feces, the probability of
elevated CRP increased by a factor 1.4, whereas individuals born
in the dry season were one-third less likely to have elevated CRP
as a young adult. Births in the dry season were followed by
a higher frequency of infectious disease in the first 12 mo than
births during other parts of the year, indicating higher levels of
microbial exposure in early infancy.
Negative associations between microbial exposures in infancy
and inflammation in adulthood are broadly consistent with the
hygiene or old friends hypothesis, in which low levels of microbial
exposure early in life bias immune development and regulatory
processes in ways that increase the likelihood of inflammatory
conditions such as allergy, asthma, and autoimmune disease later in
life (64–66). Frequent but transient encounterswith microbes in the
local environment may be important in this process, and/or local
environments may influence the structures of resident microbial
communities in the human gut and on mucosal and skin surfaces
that have lasting effects on immune development (22, 67). The
cellular mechanisms underlying these processes are not clear, but
they likely involve regulatory T cells and the balance of pro- and
antiinflammatory cytokine production and related intracellular sig-
naling pathways (40, 65). Epigenetic modifications to genes involved
in these processes represent a viable molecular mechanism through
which microbial exposures in infancy may have a durable impact on
inflammatory phenotypes (68, 69), particularly because prior re-
search has documented substantial between-individual variation in
the methylation status of genes involved in inflammation (70). The
developmental and environmental factors contributing to this var-
iation have yet to be explored.
Conceptually, one might hypothesize that microbial exposures
play important roles in the establishment of effective regulatory
networks during sensitive periods of immune development in
infancy. Less hygienic environments increase the frequency and
diversity of microbial inputs, which result in more frequent bouts
of acute inflammation (Fig. 3). Repeated activation and de-
activation of inflammation promotes the development of more
competent regulatory pathways, which can effectively turn in-
flammation on when it is needed and off when it is not needed.
To the extent that these pathways become established and car-
ried forward, inflammatory stressors in adulthood are handled in
a similar manner. Inflammatory responses ramp up quickly, and
antiinflammatory processes keep the responses under control.
Conversely, more hygienic environments minimize the fre-
quency and intensity of microbial exposures in infancy, limiting
opportunities for the activation and deactivation of inflammatory
pathways during critical periods of immune development. The
result is a more proinflammatory phenotype. When inflammatory
stressors are encountered in adulthood, proinflammatory path-
ways are readily activated, but effective counterbalancing antiin-
flammatory regulatory networks are not in place to prevent
overblown, lingering, or chronic levels of activity.
It seems reasonable to conclude that a tightly regulated in-
flammatory system would confer substantial advantages over a less
responsive system. Infectious threats to self are confronted quickly
and effectively with a robust response, but collateral damage to self is
minimized by actively down-regulating responses after resolution.
Like many other experience-based neural and physiological systems
(13, 71, 72), active engagement with the environment during critical
stages of development is necessary to achieve this functional state. In
thecaseofimmune/inflammatory systems, microbial exposures seem
to be important, expectable inputs that have been a normal part of
the human environment for millennia. Natural selection could not
anticipate the highly sanitized, low-infectious disease environments
currently inhabited by humans in affluent industrialized settings, and
apoorlyeducatedimmunesystemmaybetheresult.
Support for an Eco-Logical Model of Inflammation
Is there an eco-logic to inflammation? Do principles related to
developmental plasticity, ecological contingency, and experience-
matory activity
↓ chronic
inflammation
infancy adulthood
↑↑↑↑ ↑
Higher microbial exposure
Inflamm
↑ chronic
y
↑ chronic
inflammation
Inflammatory activity
↑↑
Lower microbial exposure
Fig. 3. Conceptual model of the association between microbial exposure in
infancy and regulation of inflammation in adulthood. The arrow from in-
fancy through adulthood represents developmental time. Upper applies to
environments with higher levels of microbial exposures; Lower describes
low-infection, highly hygienic environments.
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based biology help resolve the paradox of low baseline CRP
concentrations in high infectious disease environments? Might our
understanding of how inflammation is regulated and how in-
flammation provides protection against some diseases but con-
tributes to others be advanced by a comparative, developmental
perspective that foregrounds ecological factors as drivers of
functional variation?
Our findings from the Philippines point to early environmental
factors as critical determinants of the dynamics of inflammation
in adulthood, and circumstantial evidence for the importance of
early microbial environments in shaping inflammatory pheno-
types also comes from rising rates of allergic and autoimmune
diseases over the past three decades, particularly among lower-
income nations, where rates of these diseases tend to increase
after economic development (40, 42). One might also interpret
the divergent patterns of association between body fat and CRP
discussed above in this light. If effective antiinflammatory net-
works are in place in environments like the Philippines, then
perhaps they provide a counterbalancing influence when proin-
flammatory pathways are activated by excess body fat.
However, more research on the levels and regulatory dynamics
of inflammation across ecological and epidemiological settings is
needed. To that end, we have conducted three additional studies
in the Philippines and Ecuador that highlight variability in key
inflammatory processes and provide additional support for the
hypothesis that early environments shape the regulation of in-
flammation in adulthood.
Vaccine Responsiveness in Adolescence Predicts CRP in Young
Adulthood. In 1998–1999, when members of the Cebu cohort
were 14–15 y old, we administered a typhoid vaccine to a subset
of study participants to investigate the long-term effects of early
environments on immune function. We measured the antibody
response to vaccination as a functional marker of immunocom-
petence, and we found that prenatal undernutrition and low
infectious morbidity in infancy were both associated with re-
duced responses to vaccination (16).
Parallels between this study and our more recent analysis of
the early-life predictors of CRP suggest that microbial and nu-
tritional exposures may initiate a more fundamental shift in the
development and regulation of immunity. We explored this
possibility by investigating whether antibody response to vacci-
nation in adolescence was associated with CRP measured 7 y
later in young adulthood. The results were striking: median CRP
was more than four times higher in 2005 among individuals who
did not respond to the vaccine in 1998–1999 (73). For non-
responders, median CRP was 0.8 mg/L compared with 0.2 and
0.1 mg/L for mild and robust responders, respectively.
These results suggest that the same set of early-life nutritional
and microbial exposures that promote the development of more
robust antibody-mediated immune defenses also influence the
pathways involved in the regulation of inflammation, resulting in
lower levels of chronic low-grade inflammation in adulthood. An
alternative possibility is that early environments have a direct
effect on adaptive immune defenses only, with secondary con-
sequences for inflammation, or that the negative association
between vaccine responsiveness and CRP production represents
a tradeoff in the allocation of resources to different subsystems
of immune defenses during development (14).
Regardless of the particular pathways involved, these results
underscore the role that environments in infancy play in shaping
multiple aspects of an individual’s immunophenotype, and they
point to the importance of microbial exposures in promoting
more robust specific immune defenses as well as lower levels of
chronic inflammation. Conversely, nutritional deprivation during
sensitive periods in infancy may impede these processes, aside
from the level of microbial exposure.
No Evidence for Chronic Low-Grade Inflammation in Lowland Ecuador.
The hypothesis that chronic inflammation contributes to diseases
of aging depends on a model of inflammation in which individuals
reliably differ in their level of inflammatory activity. Prior research
on the biovariability of CRP has largely validated this assumption,
with some individuals showing consistently higher CRP levels than
others across multiple time points (74, 75). This pattern is apparent
in the United States, but is a similar pattern evident in environ-
ments with higher levels of infectious disease? Are inflammatory
pathways constantly activated because of a lifetime of exposure to
infectious microbes, or have these exposures led to the de-
velopment of more tightly controlled inflammatory responses?
We sought to answer these questions by documenting the pattern
of CRP variability in lowland Ecuador (52). We collected blood
samples from 52 adults over four weekly intervals, and during this
time, almost two-thirds of the participants reported at least one
episode of infectious disease. Several individuals had CRP >3mg/L
at one time point, indicating high risk for CVD based on current
consensus guidelines (7). However, no individual had CRP >3mg/L
across two or more sampling intervals, and all but one individual
produced CRP values <1.5 mg/L during the course of the study.
This pattern provides a striking contrast to prior analyses in the
United States, where a subset of individuals has been shown to
reliably produce clusters of high CRP values (74, 75).
These findings underscore the critical importance of multiple
CRP measures across time in determining the prevalence of
chronic inflammation, particularly in environments with high levels
of acute inflammation caused by infectious exposures. A study in
this environment measuring CRP at only one time point would be
justified in concluding that several individuals had high-risk levels
of inflammation, but it would have failed to observe that these
same individuals would be categorized as low risk the next week.
The implications for study design are clear, but these results also
provide compelling evidence for a distinct pattern of regulation
that challenges some assumptions of the chronic low-grade in-
flammation perspective. Most importantly, we found no evidence
for stable between-individual differences in chronic inflammation:
Individuals who produced high CRP at one observation also pro-
duced exceptionally low values of CRP at other observations. This
is a remarkable finding. Of the 52 adults in our study, prior research
would lead us to predict that 17 individuals (approximately one-
third) would have CRP >3 mg/L across all observations (7). How
can it be that not a single individual had CRP >3 mg/L across even
two or more time points?
IL-6 and perhaps other proinflammatory cytokines are likely
involved in up-regulating CRP in response to acute challenges in
lowland Ecuador. However, the results bring into relief what
seems to be an efficient set of antiinflammatory pathways that
turn these responses off and reduce CRP concentrations to very
low baseline levels—levels not commonly observed in the United
States. We speculate that this distinct pattern of CRP variability
traces back to environmental exposures early in life during sen-
sitive periods of immune development. In particular, infectious
exposures during these periods may promote the development of
regulatory networks—involving antiinflammatory cytokines and/
or intracellular signaling pathways—that can effectively down-
regulate inflammation to very low levels of activity.
Inflammatory Cytokine Concentrations Differ Across Populations.
Consistent with the finding that concentrations of CRP are low in
the Philippines, we have reported low concentrations of the proin-
flammatory cytokine IL-6 compared with prior research (76). The
median concentration of 1.0 pg/mL in our sample is among the lowest
on record for studies of healthy adults. Conversely and perhaps more
importantly, we found exceptionally high concentrations of IL-10:
the median concentration of 7.56 pg/mL is more than two times
higher than the average baseline value from other studies of healthy
adults. This antiinflammatory cytokine suppresses IL-6 production as
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well as other proinflammatory pathways (77), and lower concen-
trations of IL-10 have been associated with increased risk for chronic
diseases (4, 78). This pattern of results provides additional evidence
for meaningful variation in key aspects of inflammation across pop-
ulations, and it suggests that the balance of pro- to antiinflammatory
signaling may differ in the Philippines, perhaps explaining the ex-
ceptionally low concentrations of CRP (50, 57).
Unanswered Questions and Directions for Future Research
If the main thesis of this paper is true, that environmental expo-
sures early in development influence the dynamics of inflammation
in adulthood, then the implications for scientific and clinical
understandings of the links among environments, inflammation,
and disease may be substantial. This section poses three questions
for future research that may represent particularly productive
applications of an eco-logical model of inflammation.
Do Early Environments Moderate the Effect of Inflammatory Stressors
in Adulthood? In the absence of inflammatory stimuli in adulthood,
individual differences in regulatory dynamics may have little con-
sequence. However, in the presence of activation, significant dif-
ferences in patterns or levels of response may emerge. Individual
differences in inflammatory phenotype may, therefore, be the key
outcome of early environmental exposures, with the level of in-
flammation and its consequences for health emerging in interaction
with inflammatory stimuli in adulthood. Analogous interactions
have been reported for other physiological systems, pointing to
a more generalized impact of environments early in development in
calibrating set points for later responsiveness and function (71).
If early environments moderate the impact of current environ-
ments on inflammation, then additional explanatory power may be
achieved by explicitly modeling these interactions. For example,
perceived psychosocial stressors and depressive symptoms have
been positively associated with CRP in the United States (79, 80).
Might the effect of stressors on inflammation be modified by
prenatal nutritional environments or the intensity of microbial
exposure in infancy? Interaction terms or stratified analyses could
be applied to test these hypotheses, and based on our results from
the Philippines and Ecuador, one might expect that the association
between psychosocial stressors and chronic inflammation would be
strongest for individuals with lower birth weights or lower levels of
microbial exposure in infancy. Recent studies indicating that
childhood adversity modifies inflammatory responses to stressors
later in life suggest that this life-course approach may be a partic-
ularly productive direction for future research (81–83).
Is Inflammation Associated with CVD in High-Infectious Disease
Environments? The hypothesis that chronic inflammation contrib-
utes to CVD as well as other diseases of aging is not without its
skeptics (84, 85), but it has generated considerable empirical sup-
port (3–5). However, the vast majority of this support comes from
research conducted in affluent settings, where rates of infectious
diseases are low and levels of overweight and obesity are high. To
the extent that environments like lowland Ecuador and the Phil-
ippines represent an infectious disease ecology that was more
common globally in the past than today, chronic inflammation
might be labeled a disease of affluence, a problem thatis unusual by
historical standards and has only emerged recently in post-
epidemiologic transition populations like the United States. Fur-
thermore, if microbial exposures represent normative ecological
inputs that guide the development of several immune processes,
including the regulation of inflammation, then it is reasonable to
hypothesize that rising rates of CVD and diabetes globally are not
just a product of the nutrition transition, but also caused, in part, by
regimens of hygiene and changes in lifestyle that have reduced the
intensity and diversity of microbial exposures to levels not experi-
enced previously in the history of the human species. The work by
Raison et al. (86)—drawing on the cytokine theory of depression—
has proposed a similar framework for explaining recent increases in
major depressive disorder in high-income nations.
It remains to be seen if a pattern of frequent but acute activation of
inflammation—similar to the pattern that we documented in Ecua-
dor—is associated with elevated CVD risk. However, given that
acute spikes in CRP were followed by very low levels of CRP, it seems
possible that the regulatory dynamics of this inflammatory phenotype
are distinct and do not contribute to the initiation or progression of
CVD. Consistent with this interpretation, a recent study in rural
lowland Bolivia failed to detect a significant cross-sectional associa-
tion between CRP and atherosclerosis, despite high concentrations
of CRP (87). It will be important for future research in international
settings to collect multiple measures of CRP (as well as other in-
flammatory mediators) across time to differentiate acute from
chronic inflammation, and to determine whether inflammation con-
tributes to diseases of aging only when it transitions to a more chronic
state. These studies should also reveal the ecological and lifestyle
factors that bring on this transition in inflammatory phenotype.
Is Inflammation During Gestation a Mechanism Involved in the Intergener-
ational Transmission of Health? Inflammatory processes are a norma-
tive part of human reproduction, playing important roles in ovulation,
implantation, gestation, and parturition. For example, CRP is ele-
vated slightly among healthy pregnant women, but dysregulated in-
flammatory states contribute to preterm delivery and fetal growth
restriction (88, 89). The regulation of inflammation during gestation
is, therefore, an important determinant of preterm delivery and birth
weight, which in turn, has implications for physiological function and
health of offspring that last into adulthood. Indeed, current research
on the developmental origins of health and disease focuses on the
prenatal environment as a critical determinant of cardiovascular and
metabolic disease risk in adulthood, and any factor influencing ma-
ternal physiology—and by extension, the earliest environment of the
next generation—has the potential to have effects that reach into that
next generation (90). Inflammation represents a plausible biological
mechanism contributing to this cycle, but the factors that influence
the regulation of inflammation during pregnancy are not known.
We and others have shown that individuals who were born small
have elevated inflammation as adults (33, 57–59). If early environ-
ments shape inflammation inadulthood, one might hypothesize that
the prenatal environment experienced by a woman will be an im-
portant determinant of how she regulates inflammation when she
becomes pregnant. Similarly, microbial exposures in infancy and
psychosocial stressors in childhood may shape the inflammatory
milieu during gestation, with potential effects on the developing
fetus. Together, these lines of research motivate additional in-
vestigation into inflammation as a potential mechanism for linking
environments and health across generations.
Conclusion
Is inflammation a silent killer? Perhaps. However, it is worth asking
when in human history and where around the world inflammation has
become implicated in the pathophysiology of chronic degenerative
diseases. A comparative human biological approach reveals sub-
stantial variation in the level and dynamics of inflammation within
and across populations, and it points to ecological factors during
development as key contributors to this variation. It also reminds us
that inflammation plays a central role in innate defenses against in-
fectious disease, even as current research tends to focus on chronic
inflammation and diseases of aging. Hopefully, consideration of the
eco-logics of inflammation will point to promising directions for fu-
ture research that advances our understanding of this important
physiological system and translates into novel approaches to the
prevention and treatment of disease.
ACKNOWLEDGMENTS. This work was supported by National Science Founda-
tion Grant BCS-1027687 and National Institutes of Health Grants R01 HL085144
and 5 R01 TW05596.
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