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Contribution of the Interleukin 4 Gene to Susceptibility to Subacute Sclerosing Panencephalitis
Takehiko Inoue, MD;
Ryutaro Kira, MD, PhD;
Futoshi Nakao, MD;
Kenji Ihara, MD, PhD;
Wafaa M. Bassuny, MD;
Koichi Kusuhara, MD, PhD;
Kenji Nihei, MD, PhD;
Kenzo Takeshita, MD, PhD;
Toshiro Hara, MD, PhD
Arch Neurol. 2002;59:822-827.
ABSTRACT
| |
Background Although the exact pathogenesis of subacute sclerosing panencephalitis
(SSPE) remains to be determined, both viral and host factors seem to be involved.
Objective To identify host genetic factors involved in the development of SSPE.
Methods We investigated the association of polymorphisms in the T helper (Th)1
and Th2 cytokine, and related genes (interferon [IFN]- ,
IFN- receptor 1 [IFN- R1], IFN-R2 [IRF-1], interleukin 12 receptor  1 [IL-12R1], IL-4, IL-4R, and IL-10 genes) with SSPE in Japanese subjects.
Results A significant association (P = .03) was observed
between SSPE and the T allele of the biallelic polymorphism
at position -589 in the promoter region of the IL-4 gene. The IRF-1 allele 1 tended to interact
with the IL-4 promoter -589
Tgenotype in the development of SSPE (P =
.06), as judged on logistic regression analysis. The frequency of the genotype
combination of IL-4 promoter -589
T and IRF-1 allele 1 (at least 1 allele) in
patients with SSPE was much higher than that in the controls (47.7% vs 22.0%; P = .003,  2 analysis). However, there was
no association between other polymorphisms and SSPE.
Conclusion To our knowledge, this study is the first to demonstrate the possibility
that the IL-4 promoter gene –589
T gene polymorphism with increased IL-4 synthesis in combination with IRF-1 allele 1 confers host genetic susceptibility to SSPE
in Japanese subjects.
INTRODUCTION
SUBACUTE SCLEROSING panencephalitis (SSPE) is a slowly progressive central
nervous system complication of measles. Although the exact pathogenesis of
SSPE remains to be determined, both viral and host factors seem to be involved
in it.1-2 As viral factors for
the development of SSPE, measles viruses (MVs) isolated from the central nervous
system of patients with SSPE are replication defective and have extensive
mutations within the envelope-associated genes. However, matrix gene mutations
thought to be characteristic of SSPE viruses have also been found in recent
clinical isolates.3 Therefore, it is unclear
whether these mutations are critical for the development of SSPE.
As a host factor, immaturity of the host immune system and central nervous
system has been suggested to play a role in the increased risk for SSPE development
among infants who have had measles before 2 years of age.1, 4
Although no universal abnormality has been identified in the immune system
of patients with SSPE, impairment of MV-specific cell-mediated immunity has
been observed in a significant proportion,5-6
while anti-MV antibody production is enhanced in serum and cerebrospinal fluid.
Thus, it is likely that the T helper (Th)1 function involved in cell-mediated
immunity is generally down-regulated and the Th2 function implicated in antibody
production is well preserved. In our previous study on live MV-specific Th1/Th2
cytokine production by peripheral blood mononuclear cells, most patients with
SSPE exhibited decreased MV-specific Th1 cytokine production and preserved
Th2 cytokine synthesis.7 Thus, it is possible
that a defect of the Th1 response and the preserved Th2 response toward MV
in most patients with SSPE might reflect the persistence of a relative dominance
of the Th2 response over Th1 at the time of the initial measles infection.7 Enhanced Th2 polarization at the time of the initial
measles infection may result in insufficient elimination of MV and a higher
frequency of MV persistence. In the murine model of experimental MV encephalitis,
MV-specific T cells from susceptible C3H mice produce smaller amounts of Th1
cytokines than those from resistant BALB/c mice.8
To determine the genetic background of the Th1/Th2 cytokine responses
in patients with SSPE, we have mainly investigated functional or disease-associated
polymorphisms of the Th1 and Th2 cytokine and related genes. The interleukin
4 (IL-4) promoter 589 C/T,9-11
IL-4 receptor  chain (IL-4R) codon 50 Ile/Val,12 IL-10 promoter 627 C/A,13
interferon- (IFN-) gene CA repeat,
and IFN regulatory factor-1 (IRF-1) gene GT repeat14 polymorphisms are associated with Th2-shifted cytokine
production or Th2-dominant disorders. In addition, the IFN- receptor 1 (IFNGR1) codon 14 Val/Met and IFNGR2 codon 64 Gln/Arg polymorphisms have also been examined, as their
combination has been associated with systemic lupus erythematosus, a disorder
of the Th1/Th2 balance.15 As Th1-inducing cytokine
receptors, the IL-12 receptor 1 chain (IL-12RB1)
codon 214 Gln/Arg, 365 Met/Thr, and 378 Gly/Arg polymorphisms were included
because of their association with mycobacterial infection, in the clearance
of which Th1 cytokines play a major role.16
To our knowledge, this study is the first to demonstrate the possibility that
the IL-4 promoter gene -589
T polymorphism with increased IL-4 synthesis in combination with IRF-1 allele 1 confers host genetic susceptibility to SSPE
in Japanese subjects.
SUBJECTS, MATERIALS, AND METHODS
SUBJECTS
Thirty-eight Japanese patients with SSPE (25 male and 13 female subjects)
and 100 healthy Japanese individuals composed the study population. All of
the patients with SSPE fulfilled the diagnostic criteria, for example, clinical
features, increased MV antibody titer in cerebrospinal fluid, and typical
electroencephalography showing periodic slow-wave complexes early in the disease.1, 4 The age of onset of SSPE in the study
population ranged between 2 and 15 years (mean, 8.0 years). Thirty-three patients
had natural measles occurring between the ages of 0.4 and 4 years (mean, 1.3
years), the measles history being unknown in the other 5 patients, including
1 with a history of live attenuated measles vaccination. The control subjects
were randomly selected from among healthy school children. The control group
was not age-matched for measles or measles vaccination. Informed consent was
obtained from the subjects and/or their parents.
MATERIALS AND METHODS
DNA Extraction and Polymerase Chain Reaction Amplification
Genomic DNA was extracted from peripheral blood using a commercially
available blood kit (QIAamp DNA Blood Kit; Qiagen, Tokyo, Japan). Each polymerase
chain reaction (PCR) reaction was carried out with 20 ng of genomic DNA, 12.5
pmol of each primer, 0.6 U of Taq DNA polymerase
(Promega, Madison, Wis), and 5 nmol of each deoxynucleoside triphosphate,
in a total volume of 25 µL, using a PCR thermal cycler (Thermal Cycler
MP; TaKaRashuzo Corp, Otsu, Japan). The sequences of the primers and probes
used in this study are given in Table 1.
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Table 1. Oligonucleotide Primers and TaqMan
Probes Used in Polymerase Chain Reactions (PCRs)*
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IL-4 Promoter –589
C/T Genotype Analysis
The C/T transition polymorphism at position –589 in the promoter
region of the IL-4 gene was analyzed by PCR-restriction
fragment length polymorphism (PCR-RFLP) as previously described.9
The PCR profile used was as follows: initial denaturation at 93°C for
5 minutes, followed by 36 cycles of 93°C for 1 minute, 48°C for 1
minute, and 72°C for 1 minute, with final extension at 72°C for 3
minutes. The PCR products were digested with AvaII
at 37°C for 1 hour, followed by separation in 3% agarose gels.
IL-4R Codon 50 Ile/Val Genotype Analysis
The IL-4R codon 50 Ile/Val genotype analysis
was performed using the allele-specific amplification method with a TaqMan fluorogenic probe (TaqMan-ASA).17 The Ile and Val alleles were detected with Ile- and Arg-specific primers, respectively,
with a common primer. A one-base mismatch was introduced at the 3' end
of each ASA primer. The PCR amplification was carried out, in a total volume
of 25 µL, with 2 sets of ASA primers in the presence of a TaqMan probe using a sequence detection system (PRISM 7700 Sequence
Detection System; PE Biosystems, Foster City, Calif), which detects fluorescence
emission from the reporter dye in each PCR cycle. The PCR conditions were
as follows: initial denaturation at 95°C for 10 minutes, followed by 40
cycles of 95°C for 15 seconds, and 60°C for 1 minute. The fluorescence
signal was monitored in real time to determine the threshold cycle at which
the fluorescence emission level exceeded the baseline. The Ile or Val allele could be clearly distinguished
based on the differences in the threshold cycles.
IL-10 Promoter –627 C/A Genotype Analysis
The genotypes for IL-10 promoter –627
C/A were determined by means of PCR–single-strand conformation polymorphism
(PCR-SSCP). The PCR conditions were initial denaturation at 94°C for 5
minutes, followed by 35 cycles of 94°C for 30 seconds, 60°C for 30
seconds, and 72°C for 30 seconds, with final extension at 72°C for
5 minutes. The PCR products were mixed with the same volume of deionized formamide,
denatured for 5 minutes at 95°C, and then run on GeneGel Excel 12.5/24
(Pharmacia Biotech, Uppsala, Sweden) at 25 mA and 15°C for 1 hours.
Subsequent silver staining revealed the variable mobilities of conformational
fragments, which corresponded to the
–627 C and A genotypes.
IL-12RB1 Gene Codon 214 Gln/Arg, 365 Met/Thr,
and 378 Gly/Arg Genotype Analyses
The genotypes for IL-12RB1 codons 214 Gln/Arg,
365 Met/Thr, and 378 Gly/Arg were defined by means of PCR-SSCP, TaqMan-ASA, and PCR–restriction fragment length polymorphism
(RFLP), respectively. The PCR profile used for codons 214 Gln/Arg and 378
Gln/Arg was: 94°C for 30 seconds, 60°C for 30 seconds, and 72°C
for 30 seconds, for 35 cycles, with final 5-minute extension at 72°C.
Initial denaturation was conducted at 94°C for 5 minutes. Single-strand
conformation polymorphism analysis was performed at 25 mA and 20°C for
75 minutes. For RFLP, the PCR products were digested with AvaII at 37°C for 1 hour. TaqMan-ASA was
performed as described above. The Met and Thr alleles at codon 365 were detected with Met- and Thr-specific primers,
respectively, with a common primer. A 1-base mismatch was introduced at the
3' end of each allele-specific primer.
IFNGR1 Gene Codon 14 Val/Met and IFNGR2 Codon
64 Gln/Arg Genotype Analyses
The IFNGR1 gene codon 14 Val/Met and IFNGR2 gene codon 64 Gln/Arg genotypes were defined by
means of PCR-SSCP, as described previously.14
The PCR conditions for IFNGR1 were initial denaturation
at 94°C for 5 minutes, followed by 40 cycles of 94°C for 30 seconds,
60°C for 30 seconds, and 72°C for 30 seconds, with final extension
at 72°C for 7 minutes. The amplification conditions for IFNGR2 were the same except for an annealing temperature of 50°C.
Single-strand conformation polymorphism analysis was performed at 25 mA and
20°C for 1 hours, and 10 mA and 5°C for 3 hours, respectively.
Analysis of the CA Repeat Polymorphism of the IFN- Gene
The region containing the CA repeat polymorphism within the first intron
of the IFN- gene was amplified by PCR, as
described previously.14 The 5' end of
the forward primer was fluorescently labeled with 6-carboxyfluorescein dye.
The PCR conditions were as follows: initial denaturation at 95°C for 5
minutes, followed by 30 cycles of 95°C for 30 seconds, 56°C for 30
seconds, and 72°C for 1 minute, with final extension at 72°C for 5
minutes. Genotyping was performed in a mixture of amplified products and an
internal size standard with a genetic analyzer (PRISM 310; PE Biosystems).
Analysis of the GT Repeat Polymorphism of the IRF-1 Gene
The GT repeat polymorphism of intron 7 in the IRF-1 gene was determined by PCR, as described previously.14
The 5' end of the forward primer was fluorescently labeled with hexachloro-6-carboxyfluorescein
dye. The PCR conditions were initial denaturation at 95°C for 5 minutes,
followed by 30 cycles of 95°C for 30 seconds, 56°C for 30 seconds,
and 72°C for 1 minute, with final extension at 72°C for 5 minutes.
Genotyping was performed as described above.
STATISTICAL ANALYSES
Differences between allele or genotype frequencies in the 2 groups were
evaluated by means of the 2 analysis with a 2 x 2 or
contingency table. Whole allele distributions were analyzed by means of the 2 test with a 2 x 7 contingency table. When at least 1 cell number
was not more than 5, the 2-sided Fisher exact test was used for the 2 value. Logistic regression analysis was performed to identify any
interaction among the polymorphisms. P<.05 was
considered to be statistically significant.
RESULTS
The frequencies of each allele in the 38 patients with SSPE and 100
healthy controls are given in Table 2
and Table 3. A significant difference
in the allele frequencies between patients and controls was found for the IL-4 promoter –589 C/T gene
polymorphism. The frequency (0.789) of the T allele
in patients with SSPE was significantly higher than that (0.655) in healthy
controls (P = .03).
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Table 2. Allele Frequencies of Th1/Th2 Cytokine-Related Gene Polymorphisms
in Patients With SSPE and Control Subjects*
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Table 3. Allele Frequencies of IFN-
Gene CA Repeat and IRF-1 Gene GT Repeat Polymorphisms
in Patients With SSPE and Healthy Control Subjects*
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There were no significant differences in the allele frequencies of the IL-4R 50 Ile/Val, IL-10 promoter –627 C/A, IL-12RB1214 Gln/Arg, IL-12RB1 365 Met/Thr, IL-12RB1378
Gly/Arg, IFNGR1 14 Val/Met, IFNGR2 64 Gln/Arg, IFN- CA repeat, and IRF-1 GT repeat polymorphisms.
As the IL-4 promoter –589
C/T gene polymorphism was associated with SSPE, interactions between
this polymorphism and the other 9 polymorphisms were evaluated by logistic
regression analysis. IRF-1 allele 1 tended to interact
with the TT genotype in the development of SSPE (P = .06). The frequency of the genotype combination of IL-4 promoter –589 T and IRF-1 allele 1 (at least 1 allele) in patients with SSPE
was much higher than that in controls (47.7% vs 22.0%; P = .003, 2 analysis). Among 5 patients with SSPE older
than 2 years (ie, 4, 2, 4, 3, and 3 years) at the time of the initial MV infection,
4 were homozygous for the IL-4 –589 T allele, and the other was heterozygous. The clinical characteristics
of each individual patient with SSPE along with his or her IL-4 promoter –589 C/Tgenotype are shown
in Table 4.
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Table 4. The Clinical Characteristics of Each Individual Patient With
SSPE Along With Their IL-4 Promoter-589 C/T Genotype*
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For this study, samples from 13 of the 15 patients with SSPE with low
or no MV-specific IFN- production in our previous
study7 were available. No correlation was observed
between MV-specific IFN- production or disease
progression and gene polymorphisms. In addition, MV-specific IL-4 production levels were below the detection limit in all patients
with SSPE except 1 in the previous study.
COMMENT
To our knowledge, in this study, we have first demonstrated that the IL-4 –589T allele is significantly
associated with SSPE. In addition, the association with SSPE was more significant
for the genotype combination of IL-4 promoter –589 T and IRF-1 allele 1.
Thus, it is possible that polymorphisms of the IL-4
promoter and IRF-1, as host genetic factors, contribute
to a predisposition to SSPE in Japanese subjects.
The Th1 and Th1-inducing cytokines such as IL-2, IL-12, IFN-,
and tumor necrosis factor preferentially induce cell-mediated immunity,
while Th2 cytokines such as IL-4, IL-6, and IL-10 primarily support antibody
production. Interleukin 4 is a key cytokine for the Th2 response, which induces
activation and maturation of B cells as well as differentiation of immature
Th cells into Th2 cells, while IL-4 inhibits the differentiation and function
of the Th1 phenotype, especially IFN- production. In its promoter region,
the IL-4 –589T allele is associated with increased IL-4 gene promoter activity,9-11,18
leading to a relative dominance of the Th2 response. Actually, the genotype
combination of IL-4 promoter –589
T and IRF-1 allele 1 might further promote
Th2 polarization, based on our recent observation that this combination is
significantly associated with atopic asthma, a Th2-dominant disorder.14 In addition, the IL-4 –589 T allele has been suggested to play a role in
the interaction between the host and virus.18
Measle virus infection itself influences concurrent and subsequent Th1
vs Th2 immune responses. Measles is associated with Th1 activation (increased
IFN- and IL-2 levels) before and during the rash phase, followed by
preferential Th2 activation (decreased IFN- and IL-2 levels, and increased
IL-4 level) during the convalescent phase.19-20
The Th1 response seems to be crucial for clearance of MV from the blood and
other tissues mostly within the first 1 to 2 weeks after the onset of the
rash. However, the Th2 response leading to anti-MV antibody production may
cause decreased recognition of infected cells by the immune system through
the reduction of viral antigen expression,21-22
and thereby result in the establishment of persistent MV infection. Therefore,
it is possible that the genetic predisposition to Th2 dominance in patients
with SSPE also plays a role in the persistence of MV and the development of
SSPE through reduction of the Th1 response and enhancement of anti-MV antibody
production.
In our previous study on 15 patients with SSPE, we showed that low or
no MV-specific IFN- production was associated
with rapid disease progression.7 Determination
of the cytokine-related gene polymorphisms in 13 of the 15 patients revealed
that there was no correlation between MV-specific IFN- production or disease progression and gene polymorphisms. Once SSPE
has developed, nongenetic and/or other genetic factors may play major roles
in the decreased MV-specific IFN- production
and disease progression.
An immature immune system at the time of the initial measles infection
is considered to play a role since MV infection in early infancy leads to
development of SSPE at a higher frequency than when measles occurs later in
life, as in the case of persistent hepatitis B virus infection.23
Neonatal tolerance is thought to play a role in the establishment of chronic
hepatitis B virus infection in children born to hepatitis B virus–infected
mothers. In animals with an immature immune system, selection of either the
tolerance or protective immunity pathway is determined in part by the dose
and form of antigen presented.24-26
Such tolerance is not simply the result of immunologic immaturity but rather
is correlated with the induction of a nonprotective Th2 cytokine response.
Our patients with SSPE older than 1 year at the time of the initial MV infection
showed a higher frequency of the IL-4 –589 T allele than those 1 year old or younger at the time of
measles infection, although the sample size was too small for statistical
analysis. Thus, Th2 polarization during and after MV infection might result
in insufficient elimination and persistence of MV in cases with an immature
immune system or Th2-shifted cytokine gene polymorphisms. Host genetic factors
for SSPE might be difficult to identify in such cases, as environmental factors
contributing to early MV infection greatly influence the risk of SSPE.27-28 Further investigation of host genetic
factors for SSPE is necessary in other countries with different environmental
and genetic backgrounds.
AUTHOR INFORMATION
Accepted for publication January 8, 2002.
Author contributions: Study concept and design (Drs Inuoe, Kira, Ihara,
Kusuhara, Takeshita, and Hara); acquisition of data (Drs Inuoe, Kira, Nakao,
Bassuny, Kusuhara, Nihei, and Hara); analysis and interpretation of data (Drs
Inuoe, Kira, Ihara, Ihara, Kusuhara, and Hara); drafting of the manuscript
(Drs Inuoe, Kira, Kusuhara, and Hara); critical revision of the manuscript
for important intellectual content (Drs Kira, Nakao, Ihara, Bassuny, Kusuhara,
Nihei, Takeshita, and Hara); obtained funding (Drs Kira, Ihara, Kusuhara,
Nihei, Takeshita, and Hara); administrative, technical, and material support
(Drs Inuoe, Kira, Nakao, Ihara, Bassuny, Kusuhara, Takeshita, and Hara); study
supervision (Drs Kira, Ihara, Kusuhara, Takeshita, and Hara).
This study was supported in part by grants from the Ministry of Health
and Welfare of Japan, and the Ministry of Education, Science, Sports and Culture
of Japan, Tokyo.
We thank H. Hattori, MD (Osaka City University Medical School), S. Yamashita,
MD (Kanagawa Children's Medical Center), N. Koide, MD (National Iwaki Hospital),
H. Aiba, MD (Shizuoka Children's Hospital), T. Okada, MD (Kochi Medical School),
F. Hamada, MD (Hosogi Hospital), N. Koyama, MD (Toyohashi Municipal Hospital),
Y. Hirata, MD (Hamamatsu Medical Center), C. Baba, MD (Red Cross Nagasaki
Atomic Bomb Hospital), A. Ono, MD (Saiseikai Izumio Hospital), A. Tomoda,
MD (Kumamoto University), M. Funahashi, MD (Tokyo Children's Rehabilitation
Hospital), T. Kurokawa, MD (National Nishi-Beppu Hospital), R. Sakuta, MD
(Dokkyo University Koshigaya Hospital), M. Miyazaki, MD (Tokushima University),
K. Shioya, MD (National Nichinan Hospital), N. Nagano, MD (Asahikawa City
Hospital), T. Ishizu, MD (National Saishunso Hospital), K. Gondo, MD and Y.
Tokunaga, MD (Kyushu University), and K. Watanabe, MD (Kagoshima Municipal
Hospital) for providing us with samples from their patients, as well as Dr
N. Kinukawa, PhD (Kyushu University) for the advice on statistical analyses.
Corresponding author and reprints: Ryutaro Kira, MD, PhD, Department
of Pediatrics, Graduate School of Medical Sciences, Kyushu University, 3-1-1
Maidashi, Higashi-ku, Fukuoka 812-8582, Japan (e-mail: kirari{at}mailserver.med.kyushu-u.ac.jp).
From the Department of Pediatrics, Graduate School of Medical Sciences,
Kyushu University, Fukuoka (Drs Inoue, Kira, Nakao, Ihara, Bassuny, Kusuhara,
and Hara), Division of Child Neurology, Institute of Neurological Sciences,
Faculty of Medicine, Tottori University, Yonago (Drs Inoue and Takeshita),
and the Division of Neurology, National Children's Hospital, Tokyo (Dr Nihei),
Japan.
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