Antineural antibody in patients with Tourette’s syndrome and their family
Chin-Bin Yeh1, Ching-Hsing Wu2, Hui-Chu Tsung2, Chia-Wei Chen2, Jia-Fwu Shyu1,2,*
& James F. Leckman3
1Department of Psychiatry, Tri-Service General Hospital, Taipei, Taiwan;
Anatomy, National Defense Medical Center, National Defense University, No. 161, Sec. 6, Minquan E. Rd.,
Neihu District, Taipei City, Taiwan, 114;
Department of Pediatrics, Yale University, New Haven, CT, USA
2Department of Biology &
3Child Study Center, Children’s Clinical Research Center,
Received 24 March 2005; accepted 8 September 2005
? 2005 National Science Council, Taipei
Key words: antineural antibody, first-degree family, Tourette’s syndrome
It has been proposed that antineural antibodies were present in patients with Tourette’s syndrome (TS) and
other neuropsychiatric disorders. The purpose of our study was to investigate the presence of antineural
antibodies in the individuals with Tourette’s syndrome and the family members of TS patients. The sera of
four TS patients with no current streptococcal infection, their tic-free family members including father,
mother and sibling, and a age-matched control group who were tic free were assayed for antineural anti-
bodies directed against rat tissue and neurons in primary cell culture. There were prominent antineural
antibodies present in TS patients and their first-degree family members, but not in the control group.
Western blotting showed proteins of about 120 kDa in their sera that were not present in the sera of controls.
The preliminary results of our study suggest the importance of genetic vulnerability in the immunological
pathophysiology of tic disorders. Future studies should investigate the interactions of genetics, environment,
infectious agents, and immunity on symptom expression in families with tic disorders.
Previous studies have proposed that antineural
antibodies in patients with tic disorders and
related conditions, such as obsessive-compulsive
disorder [1–7]. Swedo and colleagues proposed the
existence of a group of patients with pediatric
antoimmune neuropsychiatric disorders associated
with streptococcal infection, or ‘‘PANDAS’’ .
This hypothesis was based on the observation that
some patients with Sydenham’s chorea (SC)
present with tics, obsessive-compulsive disorder
(OCD), and/or attention-deficit hyperactivity dis-
order (ADHD) [2, 9–11]. SC is thought to be a late
autoimmune sequela of streptococcal infection [12,
13]. Swedo and colleagues  suggested that these
neuropsychiatric symptoms may share a common
etiology. Some case reports and cross-sectional
antineuronal antibodies in patients with SC, tic
disorders, and obsessive-compulsive disorder. It
was thought that the autoantibody was induced by
streptococcal infection, and that this antibody
attacked the basal ganglion, resulting in the above
mentioned neuropsychiatric symptoms [6, 14, 15].
the presence of
*To whom correspondence should be addressed. Tel: +886-2-
87922484; Fax: +886-2-26479981, E-mail: firstname.lastname@example.org
This study was supported in part by the C.Y. Foundation for
the Advancement of Education, Science and Medicine, and
National Health Research Institutes (NHRI-EX94-9008SC),
Journal of Biomedical Science (2006) 13:101–112
Contrary to the above findings, several studies
have investigated the controversial concept of
PANDAS [5, 7, 16–19]. The existence of an
autoimmune mechanism underlying those neuro-
psychiatric disorders has not yet been proven,
although a novel treatment based on this theory
produced dramatic effects . In the first longi-
tudinal prospective study , there was no
association between streptococcal infection and
patients with tic or obsessive-compulsive disorder
over a 2-year follow-up period. These observations
confound the theory of a relationship between
infections and antibodies in the pathogenesis of TS
and related neuropsychiatric disorders. These
days, the etiologies of many diseases, including
diabetes and multiple sclerosis, point to an auto-
immune mechanism [22–25]. Moreover, the results
of previous studies indicate that both genetic and
environmental factors play important roles .
As we know from the biopsychosocial model of
the etiology of neuropsychiatric disorders, genetic
vulnerability seems to be the nexus for the inter-
action of biological and psychological factors .
Family studies are designed to explore genetic vul-
nerability to autoimmune-related disorders and/or
heritable diseases. In the past, research has focused
on the manner of inheritance, or the genetic
linkage, with very few contributions coming from
association studies. There is growing evidence that
both autoimmune and genetic factors are involved
in the pathogenesis of TS [28–32] although a study
tried but failed to identify such a marker by
investigating choline in the red blood cells of TS
twins and their parents . Therefore, it is
considered a trait marker that is indicative of a
genetic susceptibility to Tourette’s syndrome [33,
34]. Instead of a single approach or multiple
genetic approaches to test the theory of autoim-
mune stimulation by infections, the investigation
of proteins and their interactions should be the
next step upon which to focus. In the meantime,
the immunological deficits underlying these dis-
eases are gradually being identified. Therefore, we
are more interested in the underlying etiology as a
‘‘trait marker’’, such as the immunological mech-
anism that might be inherited and explained as the
vulnerability factor. The hypothesis we proposed
is that genetic vulnerability is crucial for the
pathogenesis of tic-related disorders. The aim
of our study was to investigate the role of
antineuronal antibodies among the family mem-
bers of patients with Tourette’s syndrome.
Methods and materials
Four outpatients were recruited and met the DSM-
IV criteria for TS. The children and their parents
gave their informed consent after the explanation
of the process of study andwere evaluated for acute
respiratory tract infection. The antistreptolysin O
antibody titer was monitored if any infection was
suspected in the previous 2 months. The ASO titer
was assayed with Rate Nephelometry (Beckman;
Conneticut, US). The patients were interviewed by
an experienced psychiatrist to evaluate the severity
of their tics and obsessive-compulsive symptoms.
Comorbid neuropsychiatric disorders were also
identified with DSM-IV based on the information
from the interviews with children and their parents.
We also asked the parents to complete the parents’
report version of the Yale Global Tic Severity Scale
(YGTSS) before the interview. We then arranged
another session to interview the parents with the
and DSM-IV, and their sibling with Kiddi-SADS.
At the same time, we collected blood samples from
the patients and their parents and/or siblings. The
samples were sent for further assay to a laboratory
where the laboratory personnel were unaware of
the patients’ background data. No comparisons
were made until all investigations were completed.
The control group was four healthy young adults
and four age matched children with no current or
past history of tics or other neuropsychiatric
disorder. They were also evaluated had no family
history of tics and related problems.
Brain sections and protein preparations from rats
The brains of male Wistar rats were sectioned into
the striatum, cortex, midbrain, hippocampus, cer-
ebellum, spinal cord, brain stem, olfactory bulb, etc
(Figure 1). After the addition of lysis buffer (10%
sodium dodecyl sulfate (SDS), Na3VO4, Tris–HCl;
Sigma Chemical Co., St Louis, MO, USA), the
samples were grounded, heated to 100 ?C for
5 min, centrifuged at 16,000 ? g for 30 min, and
then the upper layer was removedfor proteinassay.
Equal amounts of protein from different brain
areas were resolved by SDS-polyacrylamide gel
(8%) electrophoresis (PAGE), and then trans-
ferred to nitrocellulose (NC) membrane. After the
transfer process was completed, the NC membrane
was carefully dyed with Ponceau S. Skimmed milk
powder (10%, w/v) was used to inhibit non-
specific binding at room temperature. After 6 h,
primary antibody (serum samples taken from TS
patients) was added at a dilution of 1:2000, and the
membrane incubated at 4 ?C overnight. The NC
membrane was then washed three times with a
(TBST) for 10 min each time, before the addition
of the secondary antibody (mouse anti-human IgG
conjugated with horseradish peroxidase (HRP)
and diluted 1:7500; Jackson Company, West
Grove, Pennsylvania, USA) and incubated at
room temperature for 90 min. The membrane
was then washed three times with TBST, for
10 min each time. Finally, the membrane was
added into enhanced chemiluminescence (ECL)
solution and sandwiched between two plates for
Wistar rats weighing 250 g were perfused with
0.9% normal saline to clean out the blood. The
tissues of the rats were fixed with 2% PLP (lysine,
8% paraformaldehyde, m-periodate). The rat
brains were immersed in 30% sucrose solution
and stored at 4 ?C until the tissue sank to the
bottom. The brain tissues were placed on a block
made from aluminum foil, and the tissue was
embedded with a cryomatrix (OCT compound) for
instant freezing for cryotomy (Leica 3060). The
brain tissue was cut into thicknesses of 30 lm and
washed with TBS (Tris–base, NaCl) three times,
for 10 min each. The tissue was then washed in
PBS with 1% H2O2for 30 min. Samples were then
washed thrice with TBS, each time for 10 min, and
then transferred to a solution of 10% normal
horse serum containing 0.1% Triton X-100 for
Figure 1. Brain sections of rats.
10 min at room temperature. Primary antibody
(sera of Tourette’s syndrome patients diluted
1:100) was added, and the samples were incubated
at 4 ?C overnight. The next day, the tissues were
washed three times, each for 10 min, before the
addition of secondary antibody. The secondary
antibody (rabbit anti-human IgG conjugated with
fluorescein isothiocyanate (FITC) and diluted
1:200; Sigma Company) was added and the
samples incubated at room temperature for
60 min, then washed with TBS three times, each
for 10 min, and observed with a fluorescence
microscope (Leica DMIRE2).
Primary neuronal cell culture
Striatal tissue was dissected from the fetal gangli-
onic eminence of 14-day-old Sprague-Dawley rat
embryos. The striata were carefully dissected out
under a dissecting microscope, according to the
procedures described by Smart and Sturrock [32,
35]. They were then placed into another dish
(PBS) to thoroughly remove blood vessels and
membranes from the striatal tissues.
The tissues were cut into approximately 1 mm2
pieces and then incubated in sterile PBS containing
0.25% trypsin for 30 min at 37 ?C. The tissues
cells were resuspended in RPMI 1640 medium
containing 10% fetal bovine serum, 5% penicillin/
streptomycin, 5% L-glutamine. The cultures were
incubated at 37 ?C in 5% CO2.
Deionized water was used to prepare RPMI
1640 medium (Biochrom KG, Germany); 4 g
NaHCO3was added and the pH adjusted to 7.2–
7.3, before the solution was sterilized through a
0.2 lm filter. Before the experiment was com-
menced, the following were added to the medium:
(1) 10% fetal calf serum and the solution incu-
bated at 56 ?C for 30 min to inhibit any interfer-
ence by complement; (2) 1% L-glutamine; and (3)
1% penicillin and 0.1 mg/ml streptomycin, which
were mixed heterogeneously before use.
5 minat 600?g. The
Immunocytochemical staining of primary neuronal
The cultured cells were fixed immediately onto
discs with )20 ?C methanol for 5–10 min (the cells
were not allowed to dry out). The methanol was
then removed and the cells washed briefly, with the
addition of blocking buffer containing 10% nor-
mal goat serum for 40 min at room temperature.
The cells were then incubated with primary anti-
bodies (sera from patients with TS or healthy
controls; or anti-MAP-2 antibody (Chemicon
International, Temecula, CA, USA) or 24 h at
4 ?C. Samples were washed thrice for 10 min each
with PBS, then reacted with secondary antibody
(anti-human IgG conjugated with FITC, or goat
anti-mouse IgG conjugated with Cy3) (Jackson
Company, West Grove, Pennsylvania, USA) for
1 h at room temperature. Samples were again
washed thrice for 10 min each with PBS, and
then reacted with 4¢,6-diamidino-2-phenylindole
(DAPI) for 15 min at room temperature. The cells
were then examined with a confocal laser scanning
microscope (Zeiss, LSM510).
Patients with TS were diagnosed as comorbid with
either OCD or ADHD. There was an identical
twin pair in our study and both were diagnosed
with TS and comorbid ADHD. Their family
members had no current and past history of tics
or other neuropsychiatric disorders. All the sub-
jects recruited into our study were not currently
infected with Streptococcus. The demographic
data are shown in Table 1.
Selective binding of TS serum was observed in
specific brain regions of rats. There was no specific
binding of sera from normal healthy controls to
the cerebral cortex or striatum. In contrast,
binding of the sera from patients with Tourette’s
syndrome and their family members was observed
in pyramidal and dendrite neurons, forebrain,
midbrain, hypothalamus, and cortex. However,
sera did not bind to the corpus callosum
(Figure 2). Staining of similar density was seen in
the brain sections when treated with sera from the
family members of TS patients. However, there
was almost no staining in these brain regions when
treated with sera from the control group.
A protein of about 120 kDa was identified in
various regions of the rat brain using sera from TS
patients but not in normal control (Figure 3). A
similar banding pattern was also observed with the
sera of the family members of TS patients, The
Western blot showed that the high molecular
weight proteins were identified in various regions
of rat brain using serum from the individuals with
Tourette’s syndrome and their family members but
not in normal control group, but not with that of
the control group (Figure 5 and Table 1).
Primary neuronal cell culture
In vitro immunocytochemical staining showed
immunofluorescence in neuronal cells treated with
the sera of TS patients and their family members.
This neuronal cell straining was confirmed by
double immunofluorescence labeling with neuron-
specific anti-MAP2 antibody (Figure 4). We also
added dopamine-neuron-specific tyrosine hydrox-
ylase and choline acetyltransferase to detect cho-
line, but neither showed significant staining.
The results of our study show that antineural
antibodies run in the families of patients with TS.
The molecular weights of the proteins visualized on
western blots probed with the sera of TS patients
and their families were above 110 kDa, whereas
those visualized with the sera of normal controls
were about 60 kDa . Western blot analyses
were designed to identify possibly relevant antigen.
Previous studies mentioned that antibodies to heat
Table 1. Demographic data and summary of the analysis of patients with Tourette’s syndrome and their family members com-
pared with a control group.
Age of tic
120, 150, 170
120, 170, 180
100, 170, 180
P, F, M, and S denote patients, father, mother, and siblings of patients with Tourette’s syndrome, respectively; C denotes the control
group. P2 and S2 are twin brothers with Tourette’s syndrome comorbid with ADHD.
Figure 2. Selective binding of TS sera to rat neurons is observed in specific regions of rat brains. There was no specific binding of
sera from normal healthy controls to the cerebral cortex (a) or striatum (b). In contrast, binding of the sera from patients with
Tourette’s syndrome and their family members was observed in the following rat brain sections: pyramidal and dendrite neurons
(c, d), forebrain (e), midbrain (f), hypothalamus (g), and cortex (h). However, sera did not bind to the corpus callosum (cc) in (e).
shock protein 60 are known to be present in
virtually all individuals  in Western blot anal-
yses. Anti-60 kDa binding of seroreactivity against
neuronal antigen was found significantly just above
threshold more frequently in tic disorder patient
when compared to healthy control, autistic disor-
der . Thus, it suggested that the anti-60 kDa
might be not a specific pathogentically relevant
Figure 3. The Western blot showed that a protein of about 120 kDa was identified in various regions of rat brain using serum
from a Tourette’s case (b) but not in the normal control (a).
Figure 4. In vitro immunocytochemical staining further confirmed the selective binding of TS serum to striatal neurons. (a) DAPI
stain showing the nuclear labeling of the culture neuron cells. (b) Using serum from Tourette’s patient as the first antibody and
FITC conjugated secondary goat antibody. (c) Using neuron specific anti-MAP antibody as first antibody and rhodamine conju-
gated secondary goat antibody. (d) Overlay of figure (b) and (c).
autoantigen in the individuals with Tourette’s
syndrome. In immunohistochemical studies, the
antineuronal antibodies identified proteins in the
neuronal tissues of rats, and these were distributed
more specifically in the striatum than in the brain
stem, cortex, or paraventricular regions. In con-
trast to the sera of TS patients and their families,
there was very limited staining in the rat neuronal
tissue with the sera of the control group. We also
used a neuron-specific antibody to confirm that the
antibodies present in the sera of TS patients and
their families were directed against neuronal cells in
primary striatum neuronal cell cultures. Compared
with previous studies, our results indicated that
there were antineural antibodies in the sera of TS
patients, even in the absence of significant anti-
streptolysin O antibody titers or other signs of
Husby and colleagues were the first to describe
antineuronal antibodies that putatively arise in
acutely ill SC patients in response to group A
b-hemolytic streptococci (GABHS) infection .
In 1993, Swedo and colleagues, using similar
methods, showed that 91% (10/11) of SC patients
tested positive for antineuronal antibodies, but
50% (9/18) of healthy controls were also positive.
This technique was also used to study individuals
with acute, chronic, or remote rheumatic chorea,
compared with 40 controls; antineuronal antibod-
ies were found in 100%, 93%, and 44% of the SC
patients, respectively . Most studies involving
antineuronal antibodies have been in those pa-
tients with tics with Streptococcus-related symp-
toms. There were very few studies which have
considered antineuronal antibodies in patients
with Tourette’s syndrome, the clinical symptoms
of which do not correlate with streptococcal
infection.The most recent study compared the
PANDA group and the uncomplicated active
Group A streptococcal infection children and
found that the presence of antibrain antibody
could not be explained merely by the history of
GABHS infection . The sera from clinical
OCD cases showed antibodies directed against
caudate and putamen at a rate significantly higher
than that of clinical controls, providing evidence
of basal ganglia involvement in OCS without
Streptococcus infection . Anti-basal ganglia
antibodies were positive in 65% of a group of 65
patients with atypical movement disorders, but
were very rare in healthy adults and adults with
idiopathic dystonia. An autoimmune mechanism
was suggested underlyng the cases of atypical
movement disorders . Anti-60 kDa binding
occurred significantly more frequently in unse-
lected patients with tic disorders (67.1%) than in
those with autistic disorders or OCD, or in healthy
controls . There was also no significant corre-
lation between antineuronal antibody and anti-
streptolysin O antibody titers . Compared with
those studies, the preliminary results of our study
suggest the presence of antineuronal antibodies
among TS patients and their families, even in the
absence of streptococcal infection. In comparison,
no control subject was positive for antineuronal
antibodies. The relationship between antineuronal
antibodies and streptococcal infection warrants
Our study demonstrates the presence of an-
tineuronal antibodies not only in TS patients, but
also in their family members. These family mem-
bers either lacked lifelong tic symptoms or were in
remission from tic symptoms at the time of the
study. The molecular weights of the proteins
detected by TS sera on Western blots were
consistently higher than that detected by control
sera. These results suggest that these antineuronal
antibodies occur in the sera of TS patients and
their families, but not in the sera of the control
group, and detect a protein with a molecular
weight of about 120 kDa. Antineuronal antibodies
were also found in patients’ families, which is
consistent with our hypothesis. To the best of our
knowledge, no other study has previously investi-
gated the presence of antineuronal antibodies in
the families of TS patients. However, we did not
know any reason that both mother and father of
patient should have binding if genetic susceptibil-
ity. Possibly family members share some sort of
environmental trigger for pathology with only
those with lack of resistance genes showing clinical
symptoms. It is hard to make conclusion that the
family members of the case with TS shared the
same constitution with the cases of TS by
the results of our study since they might have the
similar exposure at home. The antineural antibod-
ies might be secondary to the factors including
unknown infection, toxin although there was no
among them. This finding emphasizes the impor-
tance of genetic and immunological vulnerability
in the pathogenesis of tic symptoms.
Figure 5. Western blotting analysis of a patient with Tourette’s syndrome and his family members. The high molecular weights of
the proteins (about 120 kDa) were identified in various regions of the rat brain by using the sera of the individuals with Tourette’s
syndrome and their family members (P1–patient with TS, F1–Father of the TS patient, M1–Mother of the TS patient, S1–Sibling
of the TS patient), but not in the sera of normal control (control).
The antineuronal assay used in previous studies
was performed with either human brain sections 
or a neuroblastoma cell culture . The IgG
antibody fraction from the sera of TS patients was
isolated by protein A affinity chromatography .
The postmortem human brain might have been
exposed to a hypoxic process or medication. It
complicated the identification of the specific anti-
gen in the brain. Moreover, the neuroblastoma cell
culture might not contain the pathogenic neuronal
antigenic structure in the brain of the individuals
with TS. In our study, we used two separate
substrates including rat brain tissue from several
brain areas, and cultured neuronal cells from rat
embroyos. Also, both Western blotting and fluo-
rescence microscopy has been done. The proteins
used in the Western blotting and immunohisto-
chemical studies were extracted from the brains of
adult male Wistar rats. Primary neurons were
cultured from striata dissected from 14-day-old
Sprague-Dawley rat embryos . The results of
the cell culture study showed good resolution, even
without image analysis. Compared to the human
basal ganglia they used in the previous studies, it
suggests that the fresh striata of rat embryos and
the brains of rats are reactive to the antineuronal
antibodiesof TSpatients, whenour method isused.
Interestingly, the family members of TS patients
exhibited antineuronal antibodies in their sera, but
had no tic symptoms. In a large family study,
almost 40% of patients with PANDAS had one or
more first-degree relatives with a history of motor
or phonic tic . However, in our study, no family
member had a history of tic. Our sample may not
represent the general population of individuals
with tic-related disorders. Meanwhile, the number
of our patient and their family was relatively small.
We did not assay the family member of the children
in the control group for the antineural antibody
although they was evaluated no tic history or
related problem. Using longitudinal and family
studies, future research should address the interac-
tions between genetics, environment, infectious
agents, stress, immunity, and symptom expression
in children with tics or obsessive-compulsive dis-
orders. The molecular characterization of antigens
should also be undertaken in future studies.
We believed that the occurrence of antineuro-
nal antibodies in the sera of TS patients and their
families strengthens the view that immune-medi-
ated mechanisms are involved in the development
of Tourette’s syndrome. To explore the role of
antibodies in the sera of TS patients, animal
models of TS have been established in which the
antibodies of TS patients are transferred into the
brains of rats by microinfusion . The involun-
tary movements seen in rats treated with intrastri-
immunoglobulins (IgG) are similar to those
observed in TS. Another immunohistochemical
analysis also confirmed the presence of IgG
selectively bound to striatal neurons in TS .
The preliminary results of our study should
provide a basis for future directions in research
into the underlying pathophysiology of TS, in a
model of genetic susceptibility to autoimmune
conditions, and their relationship to environmen-
TS seraor gamma
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