Rett syndrome and other autism spectrum disorders—
brain diseases of immune malfunction?
NC Derecki1,2, E Privman2,3and J Kipnis1,2,3
1Neuroscience Graduate Program, University of Virginia, Charlottesville, VA, USA;2Department of Neuroscience, University of
Virginia, Charlottesville, VA, USA and3Medical Scientist Training Program, University of Virginia, Charlottesville, VA, USA
Neuroimmunology was once referred to in terms of its pathological connotation only and was
generally understood as covering the deleterious involvement of the immune system in
various diseases and disorders of the central nervous system (CNS). However, our conception
of the function of the immune system in the structure, function, and plasticity of the CNS has
undergone a sea change after relevant discoveries over the past two decades, and continues
to be challenged by more recent studies of neurodevelopment and cognition. This review
summarizes the recent advances in understanding of immune-system participation in the
development and functioning of the CNS under physiological conditions. Considering as an
example Rett syndrome a devastating neurodevelopmental disease, we offer a hypothesis that
might help to explain the part played by immune cells in its etiology, and hence suggests that
the immune system might be a feasible therapeutic target for alleviation of some of the
symptoms of this and other autism spectrum disorders.
Molecular Psychiatry (2010) 15, 355–363; doi:10.1038/mp.2010.21; published online 23 February 2010
Keywords: Rett syndrome; neuroimmunology; T cells; immune system; neurodevelopment;
Function of the immune system in central nervous
The immune system and the central nervous system
(CNS) are characterized by more similarities than
differences. Both systems learn from experience. Both
communicate discrete pieces of information over very
short distances through synapses and over very long
distances through intricate chemical signaling net-
works. Although both systems are critical to an
organism’s survival, they are commonly regarded as
separate entities in terms of their ability to commu-
nicate with and influence one another. This systemic
segregation, which underlies the concept of the
brain’s ‘immune privilege,’ was long believed to be
almost absolute. It was only within the last couple of
decades that this particularly resilient scientific
dogma has been seriously challenged.
Initial steps were taken toward a more nuanced way
of thinking about the immune system in terms of its
function in relation to such ‘privileged’ parts of the
whole organism in pioneering work showing that a
well-controlled amplification of the autoimmune
response could be correlated with improved neuronal
survival in acute CNS injury.1,2Those studies were
followed by others from diverse groups, all implicating
the key to effective repair and maintenance of the
CNS.1,3–10Further studies showed the pivotal func-
tion of the innate immune system, implicating such
cells as CNS microglia11,12and peripheral myeloid-
derived cells13in CNS regeneration and neuroprotec-
tion.1,3,7,8Recent data point to even more complex
heterogeneity in innate immune activation and function
than was originally thought.14,15Thus, for example,
recognition of innate immune-cell phenotypes as pro-
inflammatory (M1) or anti-inflammatory (M2)15–17is
attracting increasing interest as the basis for a possible
downstream mechanism linking the action of T
lymphocytes to healthy CNS function.
Function of the immune system in higher brain
It is now generally accepted that the immune system
can be benign, even protective,18–20in the context of a
well-controlled response to CNS pathology. Acute
injury or inflammation, however, is an entirely
different entity from the physiological assembly and
maintenance of the complex neural circuits under-
lying higher brain functions. Thus, it was tantalizing
to discover that mice with severe combined immu-
nodeficiency showed marked impairment in beha-
and memory in the Morris Water Maze) and, as a
corollary, that injection of adult T-cell-deficient
Received 1 February 2010; accepted 3 February 2010; published
online 23 February 2010
Correspondence: Dr J Kipnis, Department of Neuroscience,
University of Virginia, Charlottesville, VA 229081, USA.
Molecular Psychiatry (2010) 15, 355–363
& 2010 Nature Publishing Group All rights reserved 1359-4184/10 $32.00
mice with wild-type splenocytes improved their
spatial learning and memory performance to a level
comparable with that of normal mice.21Transfusion
of T-cell-depleted splenocytes had no such effect on
cognitive function, indicating that the observed
improvement was dependent on the presence of
T cells.22A clue to the nature of the specific T cells
needed for such learning and memory was provided
by experiments with TMBP and TOVA transgenic
mice (respectively engineered to express T cells
specific for an epitope of either the myelin basic
protein (MBP) autoantigen or the irrelevant antigen
the Morris Water Maze was compared with that
of the wild-type control, the TMBP mice performed
no worse and even slightly better than the wild
type, suggesting that a single population of T cells
reactive to a CNS autoantigen was sufficient to
support spatial learning and memory functions. The
performance of the TOVA mice, whose T cells lack
the capacity to recognize and react with CNS
antigen, reflected significant learning impairment.
Taken together, the results showed that T cells
specific to CNS antigen were key supporters of spatial
learning and memory.
Although the function of the healthy brain is clearly
affected by the immune system,21,23no T cells or
peripheral myeloid-derived cells are found in the
CNS parenchyma under normal physiological condi-
tions. The brain is surrounded, however, by the
meninges, which provide a tripartite membranous
covering, under which flows cerebrospinal fluid
produced by the choroid plexus epithelium.24,25
The cerebrospinal fluid drains into cervical lymph
thereby allowing peripheral T cells to
respond to CNS antigens. Thus, whereas in the
healthy brain, access of immune cells to the CNS
parenchyma is restricted, this is not the case for their
access to the ventricular choroid plexus and the
meninges. These latter tissues are indeed densely
populated by myeloid-derived cells such as macro-
phages and dendritic cells,27,28and by substantial
numbers of T cells.29,30Therefore, it is reasonable to
learning and memory might originate in the meninges
and choroid plexus/ventricular areas rather than in
Indeed, recent work in our laboratory has shown
that immune changes within the meningeal milieu
surrounding the CNS have a significant impact on
CNS function (Derecki et al., unpublished observa-
tions). We showed that T-cell deficiency, either
chronic (in severe combined immunodeficiency mice)
or acute (pharmaceutically induced), skews menin-
geal myeloid immunity toward a pro-inflammatory
(M1) phenotype. We believe that this skewed pro-
inflammatory meningeal response could contribute
to the learning and memory impairment seen in the
abovementioned experiments on acute and chronic
T-cell deficiency. We further show that successful
performance of the Morris Water Maze task is
accompanied by the accumulation of interleukin
(IL)-4 producing (TH2) cells in the meninges, pointing
to a critical function for IL-4 in learning and memory
(Derecki et al., unpublished observations).
Function of the immune system in CNS development
The amazingly intricate network assembled in the
course of wiring the mammalian CNS testifies to the
ability of single genes to dictate multiple phenotypic
outcomes. Indeed, many genes that were once thought
to encode proteins relevant only to the immune
system—including cytokines, chemokines, major his-
tocompatibility complex (MHC), and complement
factors31–34—are now known to have major functions
in the CNS at all stages of development.
Signaling by cytokines is crucial for neural-tube
development and neural/glial specification. Expres-
sion of bone morphogenetic proteins—members of the
transforming growth-factor b superfamily—potently
suppresses neural induction unless these proteins are
themselves actively repressed.35This action is facili-
tated by the factors noggin and chordin,36and allows
Notch-dependent differentiation of neuroepithelial
cells into radial glial cells. In subsequent differentia-
tion steps, IL-6 and neuropoietic cytokines, such as
leukemia inhibitory factor, ciliary neurotrophic factor,
and cardiotrophin 1, turn on or off downstream genes
responsible for determining the fate of neuroepithelial
cells as radial glial cells, neurons, or glia by signaling
through glycoprotein 130 and the transcription-factor
STAT3.37STAT3 signaling is itself regulated by the
protein-tyrosine phosphatase SHP2. Interestingly,
both STAT3 and SHP2 are important in both the
developing and adult immune systems.38Numerous
other cytokines with clearly defined functions in the
immune system, including IL-1b, IL-2, -3, -4, -5, -7, -9,
and -11, are also expressed in the developing CNS.39
Although the spatial and temporal expression for
some of these cytokines are well defined,40,41insight
into their precise developmental functions will
require further elucidation.
Immune-derived chemokines in the periphery act
through gradients to attract cells bearing cognate
receptors. In the CNS, chemokines have been shown
to perform in a similar way, thereby regulating neural-
cell migration. Several chemokine receptors are
expressed in stereotypic patterns in the CNS,31but
for most of them, specific functions remain obscure.
This may be due to the promiscuity of most
chemokine ligands and receptors, as well as the fact
that individual neurons usually express multiple
chemokine receptors.42A notable exception is the
CXCL12/CXCR4 pairing, which shows strong mutual
and consequently, much is known
about their function in the CNS. Mutant mice lacking
either partner of this pair show significant defects
The reported finding that meninges are a primary
source of CXCL1246is particularly interesting in
view of recent results in our laboratory showing the
Rett syndrome: a neuroimmunological perspective
NC Derecki et al
importance of meningeal immunity for CNS function.
Onetheorypostulates that meningeal CXCL12,
secreted adjacent to brain parenchyma, maintains
cerebellar granule cells in proximity to mitogenic
sonic hedgehog before their migration.47In the mouse
hippocampus, meningeal CXCL12 attracts nascent
neurons into place in the dentate gyrus.48CXCL12
and CXCR4 also participate in axonal guidance,
interacting with canonical guidance molecules, in-
cluding semaphorins 3A and C, Robo, and Slit-2.49,50
Consequently, knockout mice show abnormalities in
Recent work has uncovered unexpected functions
in the CNS for MHC-I and complement-factor C1q.
MHC-I, a membrane-bound structure found in nu-
cleated cells, is active in the presentation of cytosolic
cells presenting foreign or unrecognizable polypep-
tides are eliminated by the immune system.32The
complement system comprises a family of some 25
small proteins that bind to extracellular immune
complexes or plasma-membrane components and
mediate the removal of unwanted cells and debris.52
In screening for changes in activity-dependent gene
expression in thedeveloping
nucleus, Shatz and coworkers noted that fluctuations
in neuronal MHC-I occur synchronously with the
synaptic refinement needed to establish visual cir-
cuitry in the CNS.34In line with that observation,
mutant mice deficient in MHC-I were found to show
significant aberrations in retinogeniculate axonal
refinement.53Accordingly, it was postulated that the
function of MHC-I in synaptic elimination may be
analogous to its function in the periphery as a
mediator of the removal of cells presenting ‘non-self’
antigen.33The complement-factors C1q and C3 were
subsequently identified by Barres and coworkers32
in a similar function in the same pathway. Most
recently, it was suggested that the two immune
proteins may actually partner one another in achiev-
ing synaptic refinement in the lateral geniculate
Immune factors occupy a prominent place in the
developing CNS, in which they regulate cellular
differentiation and migration, network formation,
and—as described above—even synaptic refinement.
Thus, immune dysfunction during pre- or post-natal
CNS development is likely to have serious ramifica-
tions in terms of emergent cognitive functions.
Immune mediators might have central or contributory
functions in both the etiology and the amelioration
of pathologies that manifest themselves during this
time—namely, pervasive developmental disorders,
such as Rett syndrome (RTT), for example, and other
autism spectrum disorders (ASD).
RTT is a pervasive developmental disorder that is
grouped with the ASD. RTT affects 1 in 8500
females;55in rare cases, males with X-chromosome
aneuploidy or somatic mosaicism have presented
with the classical RTT phenotype.56Patients with
RTT have normal psychomotor and head circumfer-
ence development up to the age of about 5 months,
followed by deceleration of head growth accompanied
by impaired language development, psychomotor
retardation, stereotyped motor deficits and behaviors,
and loss of social engagement before the age of 4
years.57Morphologically, RTT patients exhibit small
brains with no evidence of atrophy, a phenotype
consistent with a lack of proper development rather
than ongoing degeneration. Neurons in RTT patients
dendritic spines, and increased packing density.58
Magnetic resonance spectroscopy shows a progres-
sively increasing glia-to-neuron ratio in the white
matter, suggesting progressive axonal damage and
inflammatory astrocytosis indicative of mild white-
matter pathology. In addition, there are indications of
increased glutamine–glutamate cycling at the sy-
napse, pointing to increased excitatory neurotrans-
mission in younger RTT patients.59
In approximately 80% of cases, RTT is linked to a
mutation in the MECP2 gene on the X chromosome.
MECP2 encodes a methyl CpG-binding protein that
binds to methylated DNA and acts as either a
transcriptional activator or a repressor, depending
on genetic context.60Only one mutated X chromo-
some is necessary for the disease to manifest, so
differences in X-chromosome inactivation among
female patients partially explains the variability seen
in the disease phenotype.61
Immune system and RTT
The neurological abnormalities in RTT are accompa-
nied by fundamental immunological changes both in
the CNS and in the periphery. MECP2, apart from its
central function in the etiology of RTT, has been
shown to have a contemporaneous function in the
development and regulation of the immune system;62–64
notably, it was recently named as a candidate
order systemic lupus erythymatosus.65Nevertheless,
research into immune-system abnormalities in RTT
has been limited. In the few such studies conducted
to date, however, it has become increasingly clear that
mutations in MECP2 not only affect the CNS directly,
but also profoundly alter the expression of genes
influencing the functional capabilities, activation
states, cytokine profiles, and access to the CNS of
Gene expression profiles of T cells harboring the
MECP2 mutation reflect the complexity inherent in
predicting downstream effects of a transcriptional
mediator. As an example, T cell clones from RTT
patients showdecreased mRNAtranscripts for T-box 21.66
T-box 21 encodes T-bet, a master transcription fac-
tor that controls lineage commitment of CD4þ
T-helper cells thereby promoting TH1 differentiation
in part by allowing access to the interferon-g
Rett syndrome: a neuroimmunological perspective
NC Derecki et al
would indicate a marked TH2skew in RTT patients.
However, studies have also disclosed increased
transcript levels of L-RAP (leukocyte-derived arginine
aminopeptidase), an interferon-g-induced gene,68as
well as of CD6. The latter is transcriptionally
regulated by RUNX1/3,71which inhibits TH2commit-
ment.72Thus, the inflammatory skewing effects of
MECP2 require further clarification. Notably, CD6 is
also a co-stimulatory molecule that participates in
T-cell activation and differentiation,71and its ligand,
ALCAM (activated leukocyte cell adhesion molecule),
has a function in leukocyte migration across the
blood–brain barrier.66,73Thus, T cells in RTT patients
would probably have relatively readier access to the
CNS. This would emphasize the critical importance
of their cytokine profile, as the data support a
destructive function for supranormal levels of pro-
inflammatory cytokines in the CNS.74
Although there is general agreement that the total
numbers of circulating lymphocytes in RTT patients
are normal,69,70IL-2 receptor (CD25)-positive (canoni-
cally activated) T lymphocytes could not be detected
T lymphocytes were found to be increased.75Other
groups have reported a decrease in CD8þ T cells and
CD57þ natural killer cells and increased serum
levels of soluble IL-2 receptor.70Abnormally large
numbers of HLA-DRþT cells could indicate that a
component of RTT is immune dependent, and
possibly autoimmune in nature.76
Takenalone, T-bet downregulation
Possible immune etiology and therapeutic interven-
tion for RTT
Whereas initial studies strongly supported an exclu-
sively neuronal function for MECP2 in RTT pathol-
ogy, it has since been shown that other cells,
specifically glia, have a major function in the
disease.77,78Genetic manipulations in mouse models
were used to show that specific neuron-restricted
expression of wild-type MECP2 is insufficient for
rescue of the phenotype;77,79its pan-neural expression
is needed.80Later studies disclosed that MECP2 is
also expressed in glia, and that astrocytes expressing
a mutant form of the protein can confer a diseased
‘stunted’ phenotype in wild-type neurons in vitro;
the reciprocal experiment showed that wild-type
astrocytes could rescue stunted neurons and promote
normal neurite development.78As both astrocytes and
microglia provide support for neuronal development,
and because these two cell types represent a connec-
tion between the adaptive immune system and the
CNS parenchyma, it seems reasonable to suggest that
glial pathology is indicative of larger immune pro-
blems implicated in RTT.
Increased numbers of HLA-DRþT cells together
with a striking decrease in IL-2 receptor expression
could point to the presence of an autoimmune
component of RTT dysfunction and other ASD;76
alternatively, it could be indicative of an anergic
T-cell phenotype, which might similarly implicate
a potential function for T lymphocytes in RTT.
Preliminary data by our group, aimed at characteriz-
ing the meningeal immunity of MECP2 mutant mice,
are largely in agreement with the published data
indicating severe deficits in activation of T lympho-
cytes in human beings; we observed a similar lack of
IL2R expression in the meninges after training in
spatial learning and memory assays (Derecki et al.,
Furthermore, dysregulation of the expression of
brain-derived neurotrophic factor (BDNF) is a me-
chanism by which mutations of the MECP2 gene
might lead to the neuropathological findings and
developmental problems of RTT.81During experience-
dependent neuronal activation, calcium influx and
Ca2þ/calmodulin-dependent protein kinase II med-
iate selective phosphorylation of MECP2 in the brain.
This phosphorylation represses the ability of MECP2
to bind to the Bdnf promoter, thus blocking disin-
hibition of Bdnf transcription during times of neuro-
nal activity and affecting dendritic arborization and
spine formation.81This is particularly interesting in
view of the fact that BDNF production is not limited
to neurons. In fact, glial cells produce substantial
amounts, as do immune cells such as T and B
lymphocytes, and monocytes.82
Taking the above observations into consideration,
possible immune therapies for RTT might be directed
toward modification of glial phenotypes by manip-
ulation of meningeal immunity (Figure 1). The cells
most immediately affected by the meningeal cyto-
kines are likely to be astrocytes, which—because of
their interaction with the pia mater (the inner
membrane of the meninges)—are the neural cells
closest to the meninges.24,83Astrocytes have numer-
ous functions in the brain, including growth-factor
production, extra-synaptic glutamate buffering, and
water metabolism.84They also support brain plasti-
city and synaptogenesis in both the normal and the
diseased CNS.85,86Astrocytes express receptors for
most of the known cytokines and have been shown
to acquire a neurotoxic phenotype on stimulation
with pro-inflammatory cytokines such as IL-1b and
tumor necrosis factor-a.87,88Activation of astrocytes
by T cells or anti-inflammatory cytokines, such as
IL-4,89,90results in their better glutamate buffering
under normoxic conditions, and restores glutamate
buffering under oxidative stress conditions.89,90More-
over, microglia, which heavily populate the parench-
yma (and comprise approximately 25% of the glia
limitans, which lies immediately adjacent to the pia
mater), respond robustly to cytokine stimulation
and accordingly can acquire both protective and
destructive phenotypes.91,92Microglia activated by
IL-4 produce insulin-like growth-factor 1,93a factor
that supports cognitive function and neural growth,
whereas microglia activated by pro-inflammatory
cytokines express large amounts of inducible nitric
oxide synthase and other neurodestructive mole-
cules91,94that could indeed impair learning processes.
Rett syndrome: a neuroimmunological perspective
NC Derecki et al
Synaptic stripping, a neuronal phenotype seen in
RTT, was recently shown to be mediated by microglia.
One interesting suggestion was that synaptic strip-
ping may actually be a neuroprotective microglial
response to activation of the immune response in the
CNS;14,95thus, the pathology seen in RTT might be
the result of a dysregulated immune response rather
than simply neuronal in origin. Magnetic resonance
spectroscopy shows a progressively increasing glia-to-
neuron ratio in the white matter of RTT patients,
suggesting ongoing axonal damage and astrocytosis.
In addition, there are indications of increased
glutamine–glutamate cycling at the synapse, leading
to an excess of extracellular glutamate96in RTT,
which would also be consistent with microglial and
astroglial dysfunction. It may be that RTT is a disease
not of neurons, but rather of glia, a proposal that is
supported by recent evidence.77,78,80If this is indeed
the case, then manipulations at the level of the
immune system aimed at modifying microglial phe-
notype, rather than the neuronally directed therapies
considered up to now, might actually offer a better
chance of disease amelioration, and additionally
obviate a need for direct access to and genetic
manipulation of neuronal targets.
Another candidate therapy for amelioration of RTT
pathology is the oral administration of copolymer
(Cop)-1. Cop-1 is a synthetic polypeptide (4.7–
11.0kDa) comprising four amino acids, L-alanine,
L-lysine, L-glutamic acid, and L-tyrosine, in a defined
molar ratio. It was originally synthesized in an
attempt to mimic the activity of MBP in the induction
of experimental autoimmune encephalomyelitis in
laboratory animals.97Serendipitously, it was found to
be non-encephalitogenic and actually suppressive of
MBP-induced encephalomyelitis.98Presently, Cop-1
is the most frequently prescribed drug for the
treatment of multiple sclerosis. Recent results suggest
that Cop-1 induces an M2 phenotype in myeloid-
derived cells.99Strikingly, M2 monocytes in adoptive
transfermodels can provide
against encephalomyelitis.100Presumably, therefore,
by suitably shaping and regulating both microglial
and T-cell phenotypes in the context of neuroinflam-
mation, it might be possible to control CNS inflam-
mation in a location-specific and context-specific
In addition to manifesting anti-inflammatory prop-
erties in the CNS, Cop-1 also exhibits neuroprotective
activity in acute and chronic neurodegenerative
X-linked, because of X-inactivation, some cells in afflicted females express the mutant form of the gene, whereas others do
not. In the above illustration, mutant T cells are shown in an inactive or anergic state. Inactive T cells produce low levels of
cytokines, in particular IL4. Loss of T-cell modulation of meningeal immunity has been shown to lead to an M1 meningeal
myeloid skew. M1 myeloid cells produce high levels of pro-inflammatory neurodestructive cytokines (iNOS, TNF-a) as in
turn do reactive microglia. Reactive astrocytes buffer glutamate at reduced levels, and produce substantially diminished
levels of BDNF. All these factors combined lead to an environment in CNS impoverished in critical neuronal growth factors,
leading to massive dysfunction in mutant neurons (B), and diminished function in normal neurons (A). Amelioration of T-
cell function could return homeostasis to the meningeal immune milieu. Normal levels of IL4 would push meningeal
myeloid cells to an M2 fate, encouraging production of neuroprotective factors such as TGFb and arginase. T-cell-derived
interferon-g (not shown) and IL4 would also support improved glutamate buffering and improved BDNF production by
astrocytes as well as production of arginase and IGF-1 by microglia. An improved meningeal and glial environment would
lead to strong support for normal neurons (A) and mutant neurons (B) alike, thus improved neural function overall and
amelioration of RTT. Several immune-related genes (e.g. MHC) have been connected to ASD in linkage analysis studies, thus
some ideas expressed in this paradigm can be generalized.
Hypothesis—immune function in RTT. RTT is most often caused by a mutation in the MECP2 gene. As MECP2 is
Rett syndrome: a neuroimmunological perspective
NC Derecki et al
pathologies,101,102for example in models of Parkinson’s
and Alzheimer’s diseases, by driving the uptake of
cytotoxic compounds. Recent results in an optic
nerve crush injury model showed that Cop-1, when
delivered by dendritic cells loaded with the drug ex
vivo, exerts a direct neuroprotective effect on me-
chanically injured neurons.103Although prevented by
its size and charge from traversing the blood–brain
barrier on its own, Cop-1 is readily internalized by
the dendritic cells and is capable of enhancing
their ability to cross the blood–brain barrier and to
be released on the parenchymal side. It thus provides
a possible route for the entry of Cop-1 into the CNS
Recent discoveries, some of which are outlined in this
review, have altered traditional views of the function
of immune cells in the CNS and changed our
perception of neuroimmunology as a term that covers
pathological conditions into one that refers to phy-
siological interactions between the two systems.
There is general agreement by now that a well
controlled and properly functioning immune system
is a prerequisite for normal functioning of the brain.
It has yet to be established, however, whether the
function of immune cells is restricted to maintenance
of CNS homeostasis, or whether the immune system
is directly involved in brain function. Thus, for
example, in the case of cognitive function, it is not
yet known whether the immune system participates
actively in learning and memory processes or simply
helps the brain to cope with stress and thus allows the
learning process to be more efficient. Nevertheless,
as clearly shown by findings summarized in this
review, we can no longer ignore immune malfunction
as a potentially contributory or even causative factor
in the etiology of neurodevelopmental, cognitive, and
psychiatric diseases. We put forward here the hypoth-
esis that immune malfunction is responsible, at least
in part, for several manifestations of RTT. Were the
immune system of RTT patients intact (that is bearing
the wild-type MECP2 allele), the disease progression
might be slowed down and several of the symptoms
ameliorated. On the basis of this hypothesis, studies
should be aimed at deciphering the function of the
immune system in progression of the disease in
animal models of RTT, and on the consequent
development of immune-based therapies.
Here, we singled out one disease from a wide
spectrum of neurodevelopmental syndromes com-
monly called ASD. A central characteristic of ASD
patients seems to be autoimmune dysfunction, as is
suggested by several lines of evidence on the basis of
data indicative of abnormal T-lymphocyte activation,
the presence of CNS autoantibodies, and signs of
innate immune-system activation in the CNS. As
overall lymphocyte numbers are normal in these
patients, the CD4þ population (shown to specifically
support cognitive function21,23,105) is diminished.
Given the critical functions played in CNS develop-
ment, organization, and function by cytokines, chemo-
kines, macrophages, and Tcells, immune malfunction
might well have a function in ASD etiology and hence
serve as a future therapeutic target.
Our hypothesis, unlike theories suggesting that a
leading factor for ASD development and progression
is immune-system overactivation, proposes that ab-
normal neurodevelopment and function in ASD are
an outcome of the lack or malfunction of the relevant
T cells, probably autoimmune in nature. Once the
function of the immune system in the etiology of
these diseases is better understood, bone marrow
transplantation and vaccines aimed at boosting
immune function might be included in future
Conflict of interest
The authors declare no conflict of interest.
We thank Amber Cardani for her critical reading and
discussion of the manuscript and Shirley Smith for
editing the manuscript. This work was supported
in part by NICHD (R21HD056293) and NINDS
(R01NS061973) awards to JK, by Training in Neuro-
biology and Behavioral Development (T32HD007323)
award to NCD, and by Medical Scientist Training
Program (T32GM007267) award to EP.
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