Prenatal and postnatal neuroimmune interactions in neurodevelopmental disorders

Abstract

The intricate relationship between immune dysregulation and neurodevelopmental disorders (NDDs) has been observed across the stages of both prenatal and postnatal development. In this Review, we provide a comprehensive overview of various maternal immune conditions, ranging from infections to chronic inflammatory conditions, that impact the neurodevelopment of the fetus during pregnancy. Furthermore, we examine the presence of immunological phenotypes, such as immune-related markers and coexisting immunological disorders, in individuals with NDDs. By delving into these findings, we shed light on the potential underlying mechanisms responsible for the high occurrence of immune dysregulation alongside NDDs. We also discuss current mouse models of NDDs and their contributions to our understanding of the immune mechanisms underlying these diseases. Additionally, we discuss how neuroimmune interactions contribute to shaping the manifestation of neurological phenotypes in individuals with NDDs while also exploring potential avenues for mitigating these effects.

Full text

Nature Immunoogy
nature immunology
https://doi.org/10.1038/s41590-024-01797-xReview article
Prenatal and postnatal neuroimmune
interactions in neurodevelopmental
disorders
Eunha Kim 1,2 , Jun R. Huh 3 & Gloria B. Choi 4
The intricate relationship between immune dysregulation and
neurodevelopmental disorders (NDDs) has been observed across the stages
of both prenatal and postnatal development. In this Review, we provide a
comprehensive overview of various maternal immune conditions, ranging
from infections to chronic inammatory conditions, that impact t he n eu-
ro de ve lo pment of the fetus during pregnancy. Furthermore, we examine
the presence of immunological phenotypes, such as immune-related
markers and coexisting immunological disorders, in individuals with NDDs.
By delving into these ndings, we shed light on the potential underlying
mechanisms responsible for the high occurrence of immune dysregulation
alongside NDDs. We also discuss current mouse models of NDDs and their
contributions to our understanding of the immune mechanisms underlying
these diseases. Additionally, we discuss how neuroimmune interactions
contribute to shaping the manifestation of neurological phenotypes in
individuals with NDDs while also exploring potential avenues for mitigating
these eects.
NDDs typically manifest in early childhood and are characterized by
impairments in various aspects of neurological and psychological func-
tioning. Common examples of NDDs include autism spectrum disorder
(ASD), attention-deficit/hyperactivity disorder (ADHD), schizophrenia
and specific learning disorders
1
. Core features of NDDs include dif-
ficulties with cognitive abilities, social interaction, communication,
motor coordination and adaptive behaviors, and the symptoms and
severity of these disorders can vary widely among individuals. NDDs
often have a genetic basis, but environmental factors also play a role
in their development1.
In recent years, there has been a growing interest in the interactions
between the nervous and immune systems, both in homeostasis and in
the context of diseases. It has been observed that an atypical immune
response in a mother during pregnancy can have detrimental effects
on the neurodevelopment of her offspring. Moreover, individuals
with NDDs often display abnormalities in their immune function. For
instance, ASD is frequently accompanied by immune-related condi-
tions, such as dysregulation of cytokines and immune cells, as well as
inflammatory disorders. In this Review, we first provide an overview
of prenatal immune conditions contributing to the development of
NDDs. Subsequently, the Review will explore the known immuno-
logical signatures and frequently associated immune disorders in
individuals with NDDs and discuss potential factors contributing to
the co-occurrence of NDDs and immune dysfunctions. Finally, we
describe recent studies that investigate the interactions between NDDs
and immunological disorders, highlighting the potentially beneficial
effects of immune-primed characteristics. By examining these aspects,
this Review seeks to advance our understanding of the intricate con-
nections between the immune system and the development of NDDs
and highlight areas for future studies.
Received: 3 July 2023
Accepted: 15 February 2024
Published online: xx xx xxxx
Check for updates
1BK21 Graduate Program, Department of Biomedical Sciences, Korea University College of Medicine, Seoul, Republic of Korea. 2Department of
Neuroscience, Korea University College of Medicine, Seoul, Republic of Korea. 3Department of Immunology, Blavatnik Institute, Harvard Medical School,
Boston, MA, USA. 4The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology,
Cambridge, MA, USA. e-mail: eunha_kim@korea.ac.kr; gbchoi@mit.edu

Nature Immunoogy
Review article https://doi.org/10.1038/s41590-024-01797-x
(S1DZ)
22
. These IL-17A-dependent effects are causally related to the
behavioral abnormalities observed in offspring exposed to MIA. These
data overall suggest that inflammatory factors in the mother, rather
than infectious agents themselves, may predominantly contribute to
the risk of NDDs.
Emerging evidence from studies in mouse models also highlights
the influence of the maternal gut microbiome in the development
of ASD-like behaviors in MIA offspring. Notably, the presence of
segmented filamentous bacteria in the maternal gut, which promotes
the generation of IL-17A-expressing type 17 helper T (TH17) cells, con-
tributes to the manifestation of the behavioral phenotypes observed in
MIA offspring23,24. Studies using rodent models have provided insight
into the potential mechanisms and factors that contribute to the risk
of NDD development. MIA-induced neurodevelopmental abnormali-
ties observed in nonhuman primate models further support the broad
applicability and utility of this model25,26.
Maternal autoantibodies
Maternal autoantibodies, which exhibit reactivity to brain proteins,
have been regarded as both a causative factor and a potential biomarker
for ASD-like phenotypes induced by maternal immune system activa-
tion
27
. Maternal antibodies (IgG) can be actively transferred to the fetus
through the Fc receptor, FcRn, expressed in the placenta
28
. In children
with ASD, maternal autoantibodies were shown to be associated with
proteins in the fetal brain, including lactate dehydrogenase A and B,
cypin, stress-induced phosphoprotein 1, collapsin response mediator
proteins 1 and 2, Y-box-binding protein
29
and contactin-associated
protein-like 2 (CNTNAP2)30. In addition, maternal autoantibodies
against folate receptor alpha were shown to block folate transfer to
the fetus and increase the risk of neural tube defects31. Additionally, a
recent study using a cDNA phage display library to conduct an unbiased
screening identified novel autoantibody targets expressed in the human
fetal brain, such as ribosomal protein L23, glyceraldehyde-3-phosphate
dehydrogenase and calmodulin-regulated spectrin-associated protein
3 (ref. 32). Identifying maternal autoantibodies that contribute to NDDs
can aid in the development of diagnostic tools and novel prevention
and treatment strategies.
Maternal autoimmune disorders
Maternal autoimmune disorders have emerged as a notable risk factor
for NDDs33,34. The potential association between maternal autoimmune
conditions and the risk of ASD in offspring was first suggested by Money
et al.33 in 1971, a correlation that has been supported by subsequent
studies. For instance, a familial study revealed that 16% of mothers of
children with ASD had autoimmune disorders, including type 1 diabe-
tes, adult rheumatoid arthritis, hypothyroidism and systemic lupus
erythematosus, compared to only 2% of mothers of neurotypical indi-
viduals, resulting in an odds ratio (OR) of 8.8 (ref. 35). Furthermore, a
meta-analysis of five different studies reported an association between
maternal autoimmune diseases (such as type 1 diabetes, hyperthyroid-
ism or psoriasis) and ADHD in children36.
Croen et al.
37
identified psoriasis as the most prominent mater-
nal autoimmune condition associated with an increased risk of ASD.
Furthermore, an independent study reported that a maternal history
of psoriasis, but not a paternal history, was linked to an elevated OR of
ASD in children38. Notably, IL-17A, a major cytokine implicated in pso-
riasis pathogenesis39,40, has been identified as a critical factor driving
neurodevelopmental phenotypes in the poly(I:C)-induced MIA mouse
model
17,24
. These observations suggest that psoriasis-induced IL-17A
may contribute to the increased risk of ASD in children.
Similarly, a nationwide population-based cohort study conducted
in Sweden revealed associations between parental inflammatory bowel
disease (IBD) and ASD in children41. Specifically, the polygenic risk score
for IBD, particularly in mothers, was found to be associated with ASD
traits in children.
Prenatal immune environment and NDDs
Elevated immune responses during pregnancy are associated with an
increased risk of NDDs in children. In this section, we discuss various
inflammatory conditions in pregnant women, including infection,
autoimmune disorders, allergies and asthma, which have been impli-
cated as risk factors for NDDs in offspring.
Maternal infection during pregnancy
Over the past two decades, severe infections during pregnancy have
been suggested to elevate the likelihood of having a child with NDDs.
To date, numerous correlations between various modes of infection in
pregnant women and the risk of developing NDDs have been reported.
Here, our discussion will mostly focus on ASD, an NDD whose core
symptoms include impaired communication, altered social interaction
and restricted repetitive stereotypical behaviors.
In the mid-1960s, the United States experienced an outbreak of
rubella. Following this epidemic, a behavioral study conducted on
children with congenital rubella revealed a notable occurrence of
symptoms associated with ASD and schizophrenia
2,3
. These findings
prompted further investigations, and since then, numerous epide-
miological studies have established a connection between NDDs and
maternal infections caused by various pathogens during pregnancy.
For example, in the early 2000s, Brown et al.
4–6
reported a three- to
seven-fold increase in the risk of schizophrenia in the offspring of mothers
who experienced respiratory infections in the second trimester.
A separate study focusing on birth cohorts from 1984 to 2007 within
the Swedish population found a correlation between maternal hospi-
talization due to respiratory infections and a heightened risk of ASD
in the offspring7. A relationship between infection during pregnancy
and the increased risk of NDDs has been reported for various other
infectious conditions, including viral (for example, cytomegalovirus,
measles, mumps, chickenpox and polioviruses), bacterial (for example,
Escherichia coli) and parasitic (Toxoplasma gondii) infections8. These
results strongly suggest that various infections during pregnancy
are risk factors for NDDs. A recent study investigating the impact of
asymptomatic or mild severe acute respiratory syndrome coronavirus
2 (SARS-CoV-2) infection during pregnancy found no link between
prenatal exposure to SARS-CoV-2 and neurodevelopmental outcomes
in infants aged 5 to 11 months9. However, another study provided
preliminary evidence suggesting that maternal SARS-CoV-2 infection
may be associated with increased neurodevelopmental diagnoses in
the affected offspring10. Additional research is required to evaluate the
impact of severe SARS-CoV-2 infection and to determine the long-term
consequences on the neurodevelopment of offspring11.
Mouse models of maternal immune activation (MIA) using viral
or bacterial infection mimetics, such as poly(I:C) and lipopolysaccha-
rides (LPS), serve as valuable tools for investigating the fundamental
mechanisms through which MIA contributes to neurodevelopmental
abnormalities in offspring
12,13
. MIA mouse models also recapitulate
one of the key features of ASD, the male bias, which refers to the higher
prevalence of ASD in males, with a three to four times greater occur
-
rence compared to females
14–16
. In these models, pro-inflammatory
cytokines induced in pregnant dams upon MIA, such as interleukin
(IL)-6, type I interferons (IFN-α and IFN-β) and IL-17A, have prominent
roles in inducing neurodevelopmental defects in the offspring
12,17–19
.
For example, prenatal IL-6 induction causes a long-lasting increase in
excitatory synapses and disrupts hippocampal connectivity by activat-
ing signal transducer and activator of transcription 3 (STAT3) and its
downstream gene, regulator of G-protein signaling 4 (Rgs4)20. Mater-
nal IL-6 levels during pregnancy in humans influence newborn brain
organization and future executive function
21
. Maternal IFN-β interferes
with microglia development and increases susceptibility to postnatal
stress19. Maternal IL-17A promotes an integrated stress response in the
developing brain16 and leads to cortical hyperexcitability primarily
in the dysgranular zone of the adult primary somatosensory cortex

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Maternal asthma and allergies
A history of maternal immune conditions related to hyperimmune
sensitivity, including asthma, allergies and eczema, has been found to
increase the risk of ASD in children42. Notably, maternal asthma has been
identified as the most prevalent immune condition among mothers of
children with ASD, and it is more commonly observed in mothers of
male children with ASD compared to female children with ASD37,42. An
independent case study also revealed a correlation between maternal
asthma and allergies, particularly during the second trimester, and
the risk of ASD in children, while the association with paternal asthma
was weaker43.
To further investigate the connection between maternal
allergies and NDDs, a mouse model mimicking maternal allergic asthma
(MAA) was developed
44
. This model involved priming female mice with
ovalbumin before pregnancy and exposing them to aerosolized ovalbu-
min during pregnancy. The MAA mouse model successfully exhibited
neurodevelopmental behavioral traits, including repetitive behaviors
and reduced sociability, making it a promising tool for unraveling
the underlying causal mechanisms linking MAA and NDDs. Further
investigation into potential allergic immune pathways and related
cytokines, using this mouse model, might be a worthwhile avenue for
future studies in the field.
Postnatal immunological comorbidities in
individuals with NDDs
Children diagnosed with NDDs often display distinct immune-related
characteristics. Postmortem examinations of individuals with ASD
have uncovered evidence of chronic inflammation, elevated levels
of pro-inflammatory cytokines, the presence of autoantibodies
targeting brain proteins, and an increased population of cytotoxic
adaptive immune cells
45,46
. Similarly, individuals with schizophrenia
exhibit heightened microglial density in the brain and upregulation
of pro-inflammatory genes47. In this section, we describe immune
dysregulations observed in individuals with NDDs, encompassing
cytokine dysregulation, alterations in immune cell profiles, and the
presence of circulating antibodies targeting brain proteins. Further-
more, we describe possible mechanisms of why individuals with NDDs
have a greater likelihood of experiencing immunological disorders
compared to those with typical development.
Cytokine and chemokine signatures in NDDs
Cytokine dysregulation is a prominent feature observed in
individuals with NDDs, although some discrepancies exist among
the findings along with the variations in measurement methods and
sample types (Table 1). A cohort study published in 2011 compared
plasma cytokine levels among children with ASD, typical development
and developmental disabilities other than ASD (total n = 223, 97 with
ASD, 87 with typical development, 39 with developmental disabilities,
median age of 3.4 years)
48
. The study found that children with ASD
displayed elevated levels of pro-inflammatory cytokines, includ-
ing IL-1β, IL-6, IL-8 and IL-12p40, with a more pronounced increase in
those with regression compared to early-onset ASD. Furthermore,
the levels of certain cytokines correlated positively with the sever-
ity of clinical outcomes, such as impaired social interaction and
nonverbal communication. Additional studies observed elevated
IFN-γ, IL-6 and IL-1RA cytokine production from culture supernatants
of peripheral blood mononuclear cells (PBMCs) from individuals with
ASD
49
, and elevation of IL-4 and IL-13 from PBMCs upon stimulation
with phytohemagglutinin-L50. Whereas tumor necrosis factor (TNF)
is elevated in the brain lysates of individuals with ASD51, it is lower in
plasma levels in children with ADHD and negatively correlates with
symptoms of ADHD52. Conversely, IL-16, IL-13 and IFN-γ levels are
higher in ADHD and correlate positively with hyperactive–impulsive
symptoms, inattention and response time variability, respectively53.
The same study reported that the lower serum TNF levels also relate
to response time variability. For schizophrenia, increased cytokine
levels, including IL-6, TNF, IL-1β, IL-12 and transforming growth factor
(TGF)-β, were reported
54
, and elevated IL-6 levels were particularly
associated with disease phenotypes, such as insidious psychosis
onset, illness duration and cognitive impairment55.
Differential regulation of IL-17A has also been documented
in children with ASD. A 2012 study reported elevated serum levels
of IL-17A in children with ASD compared to neurotypical con-
trols56. Another study showed higher production of IL-17A from
phytohemagglutinin-L-stimulated PBMCs in children with ASD com-
pared to those with typical development57. Additionally, a study focused
on high-functioning individuals with ASD found that they exhibit higher
serum levels of IL-17A compared to matched controls58.
In addition to cytokines, elevated plasma levels of chemokines
were reported in children with ASD, such as monocyte chemoattract-
ant protein (MCP)-1 and macrophage inflammatory protein (MIP)-1β,
regulated upon activation of normal T cell expressed and secreted
Table 1 | Immunological signatures coexisting with NDDs
Human immune
signatures Mouse immune signatures
Cytokine and
chemokine
imbalance
ASD
Plasma: IL-1β, IL-6,
IL-12p40↑48, MCP-1,
MIP-1β, IL-8, RANTES,
eotaxin↑59 ; serum:
IL-17↑56,58;
PBMCs: IL-1RA, IL-6,
IFN-γ↑49, IL-4, IL-
13↑50, IL-17↑57;
brain lysates: TNF↑51
Mouse models with
ASD-like behavior
-MIA mouse model
Plasma: IL-6, IFN-γ, IL-17A↑
(LPS administration)61
Splenocyte stimulation:
IL-6, IL-17A↑62
-BTBR mouse model
Brain lysates: IL-1β, IL-6,
IL-12p40↑60
ADHD
Plasma: TNF↓52
Serum: IL-16, IL-13,
IFN-γ↑53
Schizophrenia
Serum: IL-1β, IL-6, IL-12,
TNF, TGF-β↑55
Immune cell
changes ASD
T cells↓64, Treg cells↓66
TH1, TH2 and TH17
signatures↑65
CD57+ NK cells↓70,71,
monocytes↑74
Mouse models with
ASD-like behavior
-MIA mouse model
Treg cells↓62,TH17↑67
- BTBR mouse model
Thymus: CD4+, CD8+
T cells↑68; spleen and
blood: TH1, TH2, Treg cells↑68
Schizophrenia
NK cells↑72,
monocytes↑73
Autoantibodies in
the brain ASD
Brain protein-speciic
antibodies↑76–78
Schizophrenia
α-NCAM1↑81
Immune disorders ASD
Skin, respiratory
allergies↑82, food
allergies (sensitivity)↑82,87,
atopic dermatitis↑84,85,88,
asthma↑84,85,88, allergic
rhinitis↑88, Crohn’s
disease, ulcerative
colitis↑92,93
Mouse models with
ASD-like behavior
IBD-related phenotypes
-SHANK3 knockout
(dextran sulfate
sodium-induced colitis) ↑98
-MIA mouse model
(C. rodentium-induced
colitis, anti-CD3-
induced colitis)↑67
ADHD
Psoriasis, allergies,
asthma,
allergic rhinitis, atopic
dermatitis↑88

Nature Immunoogy
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(RANTES) and eotaxin
59
. Particularly, RANTES, eotaxin and MCP-1 levels
positively correlated with behavioral symptoms.
In line with human observations, BTBR T
+
Itpr3
tf
/J (BTBR) mice, an
idiopathic mouse model with ASD-like phenotypes, displayed elevated
expression of cytokines in the brain, including IL-1β, IL-6 and IL-12
(ref. 60). In addition, MIA offspring exhibited increased levels of plasma
IFN-γ, IL-6 and IL-17A when exposed to low-dose LPS administration61
and increased IL-6 and IL-17A upon splenocy te stimulation62. These find-
ings suggest that dysregulated levels of cytokines and chemokines are
frequently observed in patients with NDDs and certain mouse models
of NDDs. However, further studies are needed to gain a more explicit
understanding of the contribution to NDD phenotypes.
Immune cell signatures in NDDs
Several reports indicate that children with ASD exhibit atypical
compositions of immune cell subsets compared to children with typical
development50,63. These immune cell dysregulations include changes
in the number of T cells64 and distinctive immune responses and tran-
scription patterns. For instance, PBMCs from individuals with ASD
exhibit elevated mRNA levels of signature transcription factors for the
T
H
1, T
H
2 and T
H
17 subsets of T cells, namely T-bet, GATA3 and RORγ
65
.
Additionally, there is a reduction in CD4
+
CD25
hi
regulatory T (T
reg
) cells,
which play a crucial role in maintaining immune homeostasis
66
. These
alterations may contribute to the persistent elevation of inflammatory
cytokines observed in individuals with ASD.
Similar immune cell changes have been observed in the MIA mouse
model of NDDs, including a reduction in CD25+ and FOXP3+ Treg cells62.
Furthermore, naive CD4
+
T cells in MIA offspring were found to be
epigenetically primed toward a pro-inflammatory state
67
. In addition,
BTBR mice showed an increase in the number of CD4
+
and CD8
+
T cells
in the thymus, as well as T
H
1, T
H
2 and T
reg
cells in the spleen and blood
68
.
The dysregulated activity of natural killer (NK) cells has long been
recognized in ASD69. NK cells are a subset of innate immune cells crucial
for immune surveillance and cytotoxicity. Interestingly, NK cells from
individuals with ASD exhibit heightened basal cytolytic activity but
reduced responsiveness upon stimulation along with decreased expres-
sion of NK cell receptors70,71. By contrast, individuals with schizophrenia
or bipolar disorder display an increased number of NK cells expressing
the activation marker HLA-DR, as well as elevated levels of activating
receptor expression, compared to controls
72
. Higher monocyte counts
have also been reported in peripheral blood samples both from indi-
viduals with ASD and schizophrenia73,74. Moreover, upon stimulation
with LPS and lipoteichoic acid, peripheral blood monocytes from
children with ASD exhibited increased expression of genes involved in
immune responses, such as nuclear factor-κB (NFKB1), FAS cell surface
death receptor (FAS), C-type lectin domain family 4 member E (CLEC4E)
and TGF beta kinase 3 (TAB3)75. These findings indicate that immune cell
dysregulation in NDDs extends beyond specific subsets, encompassing
both innate and adaptive immune cells.
Autoantibodies in the brains of individuals with NDDs
Multiple studies have indicated elevated levels of circulating autoanti-
bodies against brain protein lysates in individuals with ASD, including
lysates derived from humans and monkeys
76–78
. Moreover, the serum
levels of these brain protein-specific antibodies positively correlate
with the severity of ASD and cognitive impariment
79,80
. For instance,
whereas 25% of children with mild-to-moderate ASD exhibited
anti-neuronal antibodies in their circulation, the prevalence increased
to 87.5% among children with severe ASD, indicating a strong associa-
tion between antibody presence and disease severity79.
A recent study described the presence of autoantibodies against
neural cell adhesion molecule (NCAM1) in patients with schizophre-
nia81. This study demonstrated that anti-NCAM1 autoantibodies
disrupt interactions involving NCAM1, such as NCAM1–NCAM1 and
NCAM1–glial cell line-derived neurotrophic factor (GDNF) interactions.
Additionally, the delivery of anti-NCAM1 into the subarachnoid space
of the frontal cortex in mice induced behavioral abnormalities, further
implicating their role in the pathogenesis of schizophrenia.
Immunological disorders in individuals with NDDs
Apart from the previously discussed immunological characteristics,
patients with NDDs also exhibit a higher incidence of immune-related
disorders. In this section, we discuss the correlation between NDDs and
the development of specific immune disorders.
Children with ASD and ADHD have a higher likelihood of having
allergies, including food, skin and respiratory allergies, compared to
children without these disorders
82,83
. For instance, a cross-sectional
study involving 199,520 children who participated in the US National
Health Interview Survey from 1997 to 2016 revealed an increased
prevalence of food (OR, 2.29; 95% confidence interval (CI), 1.87–2.81),
respiratory (OR, 1.28; 95% CI, 1.10–1.50) and skin allergies (OR, 1.50;
95% CI, 1.28–1.77) among children with ASD compared to those
without
82
. Other studies have also reported a correlation between aller-
gic conditions, such as atopic dermatitis and asthma, and the diagnosis
of ASD84,85. By contrast, a separate meta-analysis that consolidated
findings from various epidemiological studies has proposed that there
is no apparent association between asthma and ASD
86
. A Childhood
Autism Risk from Genetics and the Environment (CHARGE) study
observed a higher prevalence of food allergies and food sensitivities
in children with ASD but a comparable prevalence of asthma and over-
all allergies when compared to children with typical development
87
.
A recent study based on Taiwan’s Maternal and Child Health Database,
which included over a million children with ASD and ADHD, revealed
a strong association between allergies, asthma, allergic rhinitis and
atopic dermatitis with both ASD and ADHD. However, psoriasis was
specifically associated only with ADHD88. According to one study,
the co-occurrence of asthma and ASD has particularly been linked to
elevated levels of IL-17A
57
. Collectively, these studies point to a connec
-
tion between NDDs and the occurrence of immunological disorders.
The noted discrepancies observed among these studies also emphasize
the need for more comprehensive and prospective research, as well
as relevant animal studies, to better understand the causality and
underlying mechanisms.
Gastrointestinal problems are frequently observed as comorbidi-
ties in children with ASD
89
. Studies have indicated a higher prevalence
of IBD in individuals with ASD or vice versa90,91. Separate studies also
reported a higher prevalence of both Crohn’s disease and ulcerative
colitis in individuals with ASD compared to controls92,93. Notably, the
ASD risk gene CNTNAP2 has been identified as one of the susceptibility
loci for IBD
94
. Additionally, in a model-driven comparative comorbidi-
ties simulation, an ASD-associated gene, autophagy related 7 (ATG7)
95
,
was found to be associated with IBD96.
Mouse models for NDDs also show increased susceptibility
to IBD-like phenotypes. Consistent with the role of ATG7 in ASD in
humans, an independent study demonstrated that mice with ATG7
deficiency exhibit more severe colitis phenotypes following Citrobacter
rodentium infection—a bacterial-induced colitis model
97
. In another
model, SHANK3-knockout mice demonstrated heightened suscep-
tibility to dextran sulfate sodium-induced colitis due to a compro-
mised intestinal barrier98. Moreover, the MIA mouse model displayed
increased susceptibility to C. rodentium-induced and anti-CD3-induced
gut inflammation. This enhanced susceptibility observed in MIA off-
spring is attributed to the priming of CD4
+
T cells, which preferentially
differentiate into the TH17 subset67.
Key factors contributing to the interaction
between immune disorders and NDDs
Thus far, we have explored the role of prenatal immune environ-
ments in the development of NDDs. Additionally, we have dis-
cussed the co-occurrence of postnatal immune conditions and

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neurodevelopmental phenotypes. Although numerous studies have
established an association between immunological phenotypes and
neurodevelopmental abnormalities, the underlying mechanisms link-
ing these conditions remain incompletely understood. In this section,
we explore potential mechanisms at play.
Immunogenetic traits in NDDs
Most NDDs, including ASD, have complex genetic etiologies99,100.
A recent systematic literature review of immunogenetic research in
ASD analyzed 29 studies published between 2010 and 2022, of which
11 identified specific immune gene polymorphisms, and analyses on
genome-wide single nucleotide polymorphism-based association
of ASD. Furthermore, 18 of these studies indicated an enrichment of
immune-related genes or pathways in the blood and postmortem brain
tissues of individuals with ASD
101
. A recent comprehensive study inte-
grated multiple levels of biological data, including genome-wide associa-
tion studies, expression quantitative trait loci analyses, spatial genome
organization and protein–protein interactions. This study revealed
that single nucleotide polymorphisms associated with ASD impact
immune pathways both during fetal development and in the adult cor-
tex
100
. Although a recent genome-wide association study identified five
common genetic risk variants for ASD without direct evidence of the
involvement of immune-related genes
102
, the overall findings suggest
a potential association between genetic traits related to the immune
system and ASD and underscore the need for further investigation.
Common maternal factors driving both NDDs and immune
disorders
Numerous studies have provided evidence that immunological factors
in mothers contribute to the development of both NDDs and immune
disorders, underscoring their shared influence on these systems. For
instance, maternally induced IL-6 has been shown to contribute to the
development of ASD-like behaviors
12,17,18,21
, while also impacting intestinal
immune homeostasis
103
, intestinal permeability and compositions of gut
microbiota
104
in the offspring. An MIA-induced rodent model was also
shown to display increased gut permeability and intestinal inflammatory
responses along with increased anxiety and cognitive impairment105.
We have recently shown that offspring prenatally exposed to MIA
exhibit both primed immune responses and neurodevelopmental phe-
notypes
67
. More specifically, we showed that while neurodevelopmental
abnormalities were prenatally determined by maternally induced IL-17A
acting directly on the fetal brain, the immunological phenotypes of the
offspring were postnatally determined by MIA-induced alterations in
maternal gut bacteria. This was demonstrated through a fecal material
transfer experiment conducted on germ-free females. The offspring
born to females who received fecal material transfer from stool samples
of MIA dams exhibited immunological phenotypes comparable to those
of MIA offspring but did not display behavioral abnormalities. Con-
versely, offspring born to MIA dams mono-colonized with segmented
filamentous bacteria exhibited MIA behavioral phenotypes without dis-
playing the immunological phenotypes. These findings suggest that the
immunological and neurodevelopmental phenotypes of MIA offspring
can be dissociated, despite both being driven by exposure to prenatal
inflammation. It is worth noting that differences in the gut microbiome
have been documented in mothers with ASD106, and recent human
studies have also highlighted the substantial influence the maternal
microbiome has on the children’s microbiome107. Together, these mouse
studies indicate that prenatal exposure to MIA plays a causative role in
generating both immunological and neurodevelopmental phenotypes.
Interactions between NDD phenotypes and
immune dysfunction
An interesting observation, which might stem from the interactions
between the immune and neurodevelopmental phenotypes of NDDs,
is the marked behavioral improvements seen in a subset of children
with ASD during episodes of fever, a classic symptom of immune
activation108. This fever effect stands as one of the most striking
episodes where the core symptoms of ASD are mitigated109.
To understand the mechanisms underlying the alleviation of ASD
symptoms during a fever, we recapitulated the phenomenon in an MIA
mouse model. We showed that behavioral abnormalities in offspring
exposed to MIA could be temporarily rescued by the inflammatory
response elicited by LPS administration
61
. We further demonstrated
that behavioral rescue is mediated by IL-17A, which engages its cognate
receptor (IL-17Ra) in the brain to reestablish a homeostatic balance of
the dysregulated cortical neural activity. Therefore, elevated IL-17A
levels in MIA offspring are critical for rescuing behavioral deficits dur-
ing an immune challenge. By contrast, monogenic models for autism
displayed no discernable increase in IL-17A production or rescue of
behavioral deficits upon an LPS-induced immune insult. However,
direct delivery of IL-17A into the cortex mitigated behavioral abnor-
malities in these monogenic mouse models for autism, irrespective
of their specific genetic mutations61.
Subsequent investigations revealed that MIA offspring, but not
the monogenic lines, exhibited a significant increase in the levels of
IL-17A when challenged with LPS
61
. Intriguingly, the CD4
+
T cells of
MIA offspring were epigenetically primed to readily differentiate into
effector T cells that produce elevated levels of IL-17A
67
. These findings
Alteration of maternal gut microbiota
(dysbiosis)
Poly (I:C)/
maternal immune activation
IL-17A
Low-grade inflammation
Improved
sociability
Ospring
Pregnant dam
Epigenetic changes
in T cells (priming)
Fig. 1 | Potential interactions between neurological and immunological
phenotypes in MIA offspring. The schematic depicts the potential impact of the
immune-primed phenotype on the neurological features observed in offspring
affected by MIA. When the pregnant dam experiences immune activation, it
leads to changes in maternal gut bacteria and epigenetic modifications in naive
CD4+ T cells of the offspring towards a pro-inflammatory state. These primed
CD4+ T cells in the MIA offspring have a higher propensity to differentiate into
effector T cells that produce elevated levels of IL-17A when faced with secondary
inflammatory challenges. Importantly, the increased levels of IL-17A have been
causally associated with the alleviation of ASD-like behavioral abnormalities.

Nature Immunoogy
Review article https://doi.org/10.1038/s41590-024-01797-x
collectively suggest that prenatal exposure to MIA epigenetically
primes the immune cells of MIA offspring to readily produce IL-17A
upon secondary inflammatory challenges, and increased IL-17A levels
are causally linked to the mitigation of ASD-like behavioral abnormali
-
ties (Fig. 1).
Similar observations appear to hold relevance in humans as well.
A recent data-driven study indicated that children with ASD who exhib-
ited behavioral improvements during febrile episodes were more likely
to have experienced prenatal maternal infection and were reported
to suffer from various gastrointestinal dysfunctions, including diar-
rhea, bloating and severe abdominal pain. Moreover, family members
of these fever-responding children reported a higher prevalence of
autoimmune disorders110.
Together, the collective evidence indicates that individuals with
NDDs, who display primed immune phenotypes and experience
fever-induced behavioral improvement, might have encountered
prenatal inflammation. This primed immune system in individu-
als with NDDs could potentially contribute to a higher incidence
of immune-related disorders. However, simultaneously, having
an immune-reactive potential might enable them to alleviate their
core neurological symptoms when exposed to fever-associated
immune insults.
Conclusion
In this Review, we provided an overview of studies examining the role of
maternal inflammation and immune-related disorders in the develop-
ment of NDDs. We have also explored the co-occurrence of immunologi-
cal symptoms in individuals with NDDs. Animal models, particularly MIA
rodent models, have been instrumental in uncovering the mechanisms
through which prenatal immune environments impact fetal neurode-
velopment and the simultaneous presence of immune dysfunctions
and neurodevelopmental abnormalities. Ongoing studies to enhance
our understanding of how prenatal immune conditions affect fetal
neurodevelopment have the potential to advance targeted therapeutics
and preventive strategies for NDDs. Moreover, unraveling the inter-
play between underlying immune conditions and neurological symp-
toms may facilitate the identification of novel biomarkers. Exploring
these pathways may eventually lead to the development of innovative
approaches that leverage the innate capabilities of the immune system
to address symptoms associated with various neurological disorders.
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Acknowledgements
E.K. was supported by the National Research Foundation of Korea
(RS-2023-00209464), the Technology Innovation Program (20023378)
funded by the Ministry of Trade, Industry & Energy (MOTIE, Korea),
and a Korea University grant (K2225821). J.R.H. was supported by
the Jeongho Kim Neurodevelopmental Research Fund, the Simons
Foundation Autism Research Initiative and a National Institute of

Nature Immunoogy
Review article https://doi.org/10.1038/s41590-024-01797-x
Mental Health grant (R01MH119459). G.B.C. was supported by a
National Institute of Mental Health grant (R01MH115307), The Simons
Foundation Autism Research Initiative, The JPB Foundation, The Carol
and Gene Ludwig Family Foundation and The Nancy Lurie Marks
Family Foundation.
Author contributions
E.K. wrote the initial draft, conceptualized the igures and revised
the manuscript. J.R.H. edited and enhanced the manuscript.
G.B.C. supervised the writing and edited the manuscript.
Competing interests
E.K. declares no competing interests. J.R.H. and G.B.C. are consultants
for CJ Cheiljedang and Interon laboratories.
Additional information
Correspondence and requests for materials should be addressed to
Eunha Kim or Gloria B. Choi.
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