Autoantibodies in Autism Spectrum
SHARIFIA WILLS,aMARICEL CABANLIT,aJEFF BENNETT,b
PAUL ASHWOOD,b,cDAVID AMARAL,bAND JUDY VAN DE WATERa
aDivision of Rheumatology, Allergy and Clinical Immunology, UC Davis, Davis,
bThe MIND Institute, UC Davis, Davis, California, USA
cDepartment of Medical Microbiology and Immunology, UC Davis, Davis,
of neurodevelopmental disorders defined behaviorally by abnormalities
in social, verbal, and nonverbal communication. The etiologies of ASD
are unknown, likely to be the result of a variety of numerous genetic,
neurological, environmental, and immunological interactions that lead
on the various immune system anomalies, in particular, autoantibodies,
which have been reported in subjects with ASD. In addition, we will
discuss recent studies performed by our group concerning the presence
of autoantibodies directed against neural antigens, which are observed
in patients with ASD.
KEYWORDS: autism; ASD; immunity; autoantibodies; immune system;
nonverbal communication. They include Asperger’s syndrome, autism, child
disintegrative disorder, and pervasive developmental disorder, not otherwise
specified (PDD–NOS).1Stereotypic and restricted behaviors and/or interests
are often found in patients with ASD. Patients are diagnosed typically before
the age of 36 months, males at a rate four times that of females.2The current
prevalence is estimated at 1:150 in the total population.3There are likely to be
Address for correspondence: Judy Van de Water, Division of Rheumatology, Allergy and Clinical
Immunology, 451 E. Health Sciences Drive, Suite 6510 GBSF, UC Davis, Davis, CA 95616, USA.
Voice: 1-530-752-2154; fax: 1-530-752-4669.
Ann. N.Y. Acad. Sci. 1107: 79–91 (2007). C ?2007 New York Academy of Sciences.
80ANNALS OF THE NEW YORK ACADEMY OF SCIENCES
numerous etiologies for ASD, commonly resulting in a spectrum of disorders
infection, metabolic disorders, and perinatal hypoxia.4This review will focus
on the various changes noted in the immune system of subjects with ASD,
in particular the presence of autoantibodies directed against neural antigens,
described by both our laboratory as well as others.
ASD has been associated with approximately 15 genes, and is thought to
be the product of multiple weak gene interactions. When a broad definition
of ASD is taken into account, the concordance rate for monozygotic twins is
approximately 60–92%, while in dizygotic twins, this number falls to between
0% and 10%.5Familial risk is estimated at 5–10 times higher than the general
it was discovered that in lymphoblastoid cell lines from monozygotic twins
discordant in the severity of autism, the most differential gene expression
profiles were in genes important to the function, maturation, and structure of
the nervous system.7Moreover, genes involved in the patterning and growth
of the central nervous system (CNS) and its components as well as genes
involved in biochemical pathways have been proposed to be involved in the
that there is a genetic component in the etiology of ASD. Notably, of the genes
analyzed in ASD, a number of immune system-related genes have been linked
to this disorder. These include the null allele of the C4B gene, a complement
component, as well as the extended HLA haplotype B44-S30-DR4, and more
recently, A2.10–12Recently, Campbell and colleagues discovered that a certain
allele resulted in a twofold decrease in the promoter activity of the MET gene
and modification in binding of specific transcription factor complexes.13This
MET signaling is not only involved in neocortical and cerebellar development
but also immune system functioning and gastrointestinal development and
repair, findings all associated with symptoms found in subsets of individuals
with ASD. Overall, the genes associated with ASD to date demonstrate an
association between the CNS and immune systems and are key in unraveling
the etiology of ASD. Future studies must involve a clearly defined subject
population with a comparable set of behavioral phenotypes to better draw
conclusions regarding the target genes in ASD.
NEUROANATOMICAL OBSERVATIONS IN ASD
The most consistent neuroanatomical alterations observed in patients with
ASD involve the cerebellum and the limbic system, though other brainregions
WILLS et al. 81
have been observed to be abnormal, including the cerebral cortex, corpus col-
losum, brain stem, and the basal ganglia.14–17In the limbic system, small cell
in patients with ASD compared with controls.14In the cerebellum, the num-
ber of purkinje cells have been found to be reduced in patients with ASD.14
Altered brain growth has also been observed in patients with ASD compared
with control groups. The pattern of growth observed is an early, increased rate
of growth followed by a reduced growth rate, when compared with controls.18
alteration in the development of the CNS, resulting in permanent anatomical
changes likely to reflect or be the genesis of functional alterations.
IMMUNE SYSTEM OBSERVATIONS IN ASD
Immune findings in various studies regarding patients with ASD are often
inconsistent due to many factors, most notably the use of inappropriate con-
trol groups and heterogeneous, ill-defined subject groups. The interpretation
of results may be further complicated due to comorbidities, such as men-
tal retardation, epilepsy, sleep disorders, and gastrointestinal symptoms often
found in ASD. Various immune system components and mediators including
cytokine and immunoglobulin levels, cellular numbers and responsiveness,
monocytes/macrophages, and natural killer cells have all been investigated in
ASD.20–24Despite the lack of consensus, it is widely agreed that a subset of
patients with ASD demonstrate abnormal or dysregulated immunity. Further-
more, it has been proposed that autoimmunity may play a role in the pathogen-
esis and/or maintenance of ASD in some patients. The presence of antibodies
to “self” tissue, or autoantibodies, to various proteins has been observed in a
subset of patients with ASD (see TABLE 1).
The connection between autoimmunity and ASD was first recognized by
Money et al.25Children with ASD were found to be more likely to have a
family member with an autoimmune disease than normal controls. In 1982,
using the macrophage migration inhibition factor test in 13 of 17 patients with
ASD.26In 1990, Warren et al. observed that 6 of 11 mothers of children
with autism had antibodies that were reactive to lymphocytes of their autistic
child.27These studies demonstrate that the neuroimmune connection may be
of primary importance in a subset of subjects with ASD and warrants further
investigation in relation to this spectrum of disorders.
82ANNALS OF THE NEW YORK ACADEMY OF SCIENCES
TABLE 1. Autoantibodies reported in Autism spectrum disorders (ASD)
Studies in conflict
Myelin basic protein (MBP)
Connolly 2005,65Singh 199866
Silva 2004,44Zimmerman 200667
Brain-derived neurotrophic factor (BDNF)
Endothelial cells (EC)
Myelin basic protein
Heat shock protein 90 (HSP90)
Gliadin and cerebellar peptides
Todd and Ciaranello 198535
Singh 1997 (inhibition assay)37
Cook 1993,68Yuwiler 199236
Brain endothelial cells and nuclei
Neuron-axon filament protein (NAFP)
Glial fibrillary acidic protein (GFAP)
Singh and Rivas 2004∗∗39
Myelin basic protein (MBP)
Connolly 2005,65Singh 199338
Silva 2004,42Zimmerman 200667
Myelin-associated glycoprotein (MAG)
WILLS et al. 83
TABLE 1. Continued
Studies in conflict
Myelin oligodendrocyte protein
Neuron-axon filament protein (NAFP)
Myelin basic protein (MBP)
Neuron-axon filament protein (NAFP)
Unknown ∼20 kDa protein
B lymphocyte antigen increased in patients
with Sydenham’s Chorea, some obsessive-
compulsive patients, Tourette’s syndrome
patients with repetitive behaviors (D8/17)
∗study used bovine spinal cord as target, plasma used at dilution at 1:50.
∗∗sera used at dilution of 1:25.
∗∗∗controls used up to 50 years of age (15 adults).
HC = healthy controls; NNI = nonneurological illness; LKSV = Landau–Kleffner Syndrome Variant; HHV-6 = human herpes virus 6; MR = mental retardation;
DS = Down’s syndrome.
84ANNALS OF THE NEW YORK ACADEMY OF SCIENCES
with children with ASD differentially recognized fetal rat brain proteins when
with ASD displayed a pattern separate from their siblings and from typically
developing control children, although there was no clear delineation of pat-
terns between children with ASD and children with other neurodevelopmental
disorders. The presence of such antibodies possibly denotes a previous expo-
sure, perhaps the result of injury or abnormal development, to certain brain
antigens at an increased rate in subjects with ASD compared with typically
developing controls. In another study, Singer et al. investigated the reactivity
of serum autoantibodies to various areas of human brain in sera of children
with ASD, siblings of children with ASD, and healthy controls by Western
blot and ELISA.28Children with ASD had greater reactivity than controls to
basal ganglia and frontal lobe at 100 kDa molecular weight. The intensity of
reactivity in cingulate gyrus and cerebellum deep nuclei at 73 kDa was greater
in children with ASD than in controls. Reactivity was also found to be higher
in the siblings of patients with ASD.
Vargas et al. recently reported findings of an ongoing immune cytokine
activation in the postmortem brains of patients with ASD.29Areas affected
included the cerebral cortex as well as the cerebellum. Both microglia and
profiles were present in brain tissue as well as in cerebrospinal fluid (CSF).
Lymphocytes and antibody were found to be absent from the brain tissue,
but an accumulation of perivascular macrophages and monocytes were noted,
indicative of a possible predominating innate immune activation. The absence
of lymphocytic infiltration and antibody deposition may have been due to the
small patient numbers (11), which may not be inclusive of the full autistic
spectrum. In addition, subsets of patients with immune system dysfunction,
represented by autoantibodies, may have been inadvertently omitted. Of note,
many of these specimens were from older subjects and thus, these findings
could be reflective of downstream changes. The role of maternal immunity
during gestation has also been investigated with respect to autism. Dalton et
al. injected serum from a mother of three: a typically developing child, a child
with autism, and a child with a severe language impairment into gestating
mice.30The offspring of the injected mice demonstrated behavioral changes
as well as antibody deposition on purkinje cells and other neurons, in contrast
to the offspring of gestating mice injected with sera from mothers of typically
sera of mothers of children with ASD, which is able to alter neurodevelopment
and cause behavioral changes. Additionally, Shi and colleagues used a mouse
model to demonstrate that a maternal inflammatory response during gestation
was sufficient for the generation of behavioral alterations in the offspring
including changes in exploratory behavior, sensorimotor coordination, and
gating as well as in social behavior.31More recently, Croen et al. reported no
WILLS et al. 85
the development of ASD in the offspring. However, mothers diagnosed with
asthma or allergy during the second trimester were twice as likely to have a
child with ASD than mothers without asthma or allergy.32
The effect of the maternal immune response on the developing immune and
extensively in various psychiatric disorders, including autism and schizophre-
nia through the use of animal models.33,34A study by Meyer et al. showed
environmental exposures at two critical periods of fetal development resulted
in differential effects on future behavioral modifications, neuropathology, and
fetal brain cytokine responses.33The effects of environmental agents on the
immune system were suggested to be dependent on the period of exposure,
leading to disturbed postnatal immune functions in genetically susceptible in-
dividuals. This research supports the hypothesis that early immune/nervous
system disturbances are capable of permanently altering either/both
Various antibodies to self-proteins have been reported in patients with ASD
in the past.35–45However, it must be emphasized that these autoantibodies
have not been associated with pathology, are also found in diseases other than
ASD, and are not present in all subjects with ASD. It is not abnormal to detect
been associated with pathogenic states of disease, possibly representative of
ongoing immune activation. Factors acting in concert with autoantibodies,
such as genetics and environmental, may be at play in such a heterogeneous
spectrum of disorders.
To explore the possibility of autoantibodies to a conformational epitope
or a protein of low abundance in the brain, our lab performed immunohisto-
chemistry studies using brain slices from the nonhuman primate cynomolgus
monkey (Macca fascicularis). Sera were tested from patients with ASD (n =
(n = 11), and siblings of patients with ASD (n = 18; both typically developing
and with other disorders). Observations thus far have been restricted to the
cerebellum. Various levels of reactivity were observed across all groups. Of
importance, preliminary results have shown 20% of patients with ASD were
observed to have intense staining of what has been proposed to be the golgi
cell of the cerebellum, compared with 0% of typically developing controls
and 0% of subjects with developmental delay (FIG. 1). These autoantibod-
ies have not been shown to be pathogenic, though they may help delineate
which period(s) during neurodevelopment may have been impacted in geneti-
cally susceptible individuals with ASD. As the multiple processes involved in
86 ANNALS OF THE NEW YORK ACADEMY OF SCIENCES
FIGURE 1. Immunohistochemistry of monkey brain cerebellar sections stained with
plasma of a patient with ASD (left) and from a typically developing control (right). Scale
bar, 10 ?m.
specific processes that may occur in some patients with ASD.46
To be capable of a pathogenic effect, the neural-specific antibodies would
first have to enter the brain. Elegant studies performed by Diamond and
colleagues have shown that with blood–brain barrier abrogation, achieved
with the use of epinephrine and lipopolysaccharide, anti-DNA autoantibod-
ies associated with systemic lupus erythromatosus (SLE) were able to cause
changes in emotional behavior and memory via excitotoxic death caused by
cross-reactivity with NMDA (N-methyl d-aspartate) receptors in an animal
model.47,48Furthermore, additional research has demonstrated that antibodies
directed against DNA and other nuclear proteins are capable of entering living
cells, binding their intracellular targets, and causing apoptotic death.49–54
Several studies have investigated the interdependent relationship between
the central nervous and immune systems. Beginning early in development, the
relationship between the immune and nervous systems is exceedingly com-
plex, continuing into adulthood mediated mainly through the hypothalamus-
pituitary-adrenal (HPA) axis.55–57Immune system factors, such as major his-
tocompatibility complex I, cytokines, and chemokines are important in many
Several proteins associated with the nervous system, such as neuropeptides,
have a broad range of effects on the development of the immune system and
WILLS et al. 87
its function (suppression as well as activation), including the innervation of
immune system-associated organs, such as the lymph nodes and spleen.58–63
A carefully established equilibrium and timing of the previously mentioned
parameters is vital for normal immune and CNS functioning. Changes in-
curred during development could cause alterations that are lifelong, such as
alterations in receptor distribution and/or number in both systems as well as
during and following neurodevelopment. However, outside of cytokine induc-
tion, autoreactive lymphocytes are an essential element in the generation of
autoimmunity. Studies by Schwartz and Cohen have shown that in the nervous
system, autoreactive T lymphocytes specific for neural antigens were capable
of causing disease as well as conferring neuroprotection by promoting repair
of these autoreactive cells are in fact also necessary for protection follow-
ing tissue damage. It is possible that disruption of this balance, such as in
the dysregulated immune system noted in patients with ASD, a shift toward
autoimmunity may occur.
It is important to remember that ASD are a large, heterogeneous group of
immunological factors. Also important is to reiterate that the mere presence of
autoantibodies is not abnormal and can be found in normal, healthy controls.
However, elevated levels, such as those seen in patients with ASD, may be
representative of a continuous cycle of immune activation and antibody pro-
duction, potentially resulting in the generation of pathogenic autoantibodies.
Alternatively, these autoantibodies may be an epiphenomenon, possibly corre-
sponding to a period in neurodevelopment that may have been altered. Future
research must employ extensive group classification to correlate such find-
ings with a behavioral phenotype. Exploration into neuroimmune crosstalk,
particularly during development, will be an essential factor in deciphering the
complexity of ASD.
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