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Different Distribution of HLA Class II Alleles According to Response to Corticosteroid Therapy in Sudden Sensorineural Hearing Loss
Sang W. Yeo, MD, PhD;
Shi-Nae Park, MD;
Yong-Soo Park, MD;
Byung-Do Suh, MD, PhD;
Hoon Han, MD, PhD;
Hee-Baeg Choi, PhD;
Tai-Gyu Kim, MD, PhD
Arch Otolaryngol Head Neck Surg. 2001;127:945-949.
ABSTRACT
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Objective To investigate the association of HLA class II alleles with the susceptibility
to sudden sensorineural hearing loss and with the results of corticosteroid
treatment in the Korean population.
Design HLA-DRB1, -DQA1, -DQB1, and -DPB1 genotyping by the sequence-specific
oligonucleotide probes method in 41 patients with sudden sensorineural hearing
loss and in 206 healthy control subjects. Initial hearing levels at the onset
of hearing loss and final hearing levels after treatment were evaluated for
the association with HLA class II alleles.
Setting Tertiary care referral center, ambulatory and hospitalized care.
Subjects Forty-one patients (24 men and 17 women; mean age, 49.2 years) were
compared with 206 controls. Patients were divided into 2 groups according
to their response to corticosteroid therapy (good response vs nonresponse).
Results The frequencies of HLA-DRB1, -DQA1, -DQB1, and -DPB1 alleles were not
significantly different between patients and controls (P>.05). When an association between the results of corticosteroid treatment
and the frequency of HLA alleles was evaluated, the frequencies of HLA-DRB1*14
(relative risk [RR] = 3.5, P<.02), -DQA1*03 (RR
= 4.2, P<.02), and -DQA1*05 (RR = 3.1, P<.03) were significantly increased, but HLA-DQA1*01 (RR = 0.2, P<.004) and -DQB1*06 (RR = 0.2, P<.009) were decreased in the group nonresponsive to corticosteroid
therapy, compared with the controls. The distribution of HLA-DQA1*01 (P<.04), -DQB1*06 (P<.02),
and -DQA1*03 (P<.003) was significantly different
between the responsive and the nonresponsive groups. HLA-DQA1 allelic combination
analysis showed that the frequencies of DQA1*03 and *05 had a high RR value
in patients with sudden sensorineural hearing loss (RR = 4.1, P<.003) and in patients in the nonresponsive group (RR = 8.9, P<.001), compared with the controls.
Conclusion The presence of HLA class II alleles may be a useful genetic marker
in forecasting a prognosis in Korean patients with sudden sensorineural hearing
loss.
INTRODUCTION
SUDDEN sensorineural hearing loss (SNHL) is a partial or complete, typically
unilateral hearing loss characterized by a rapidity of onset or a progression
that may occur within a few moments or for a few days. Sudden SNHL has numerous
possible causes, including viral infection, vascular occlusion, cochlear membrane
breaks, ototoxic drugs, and bacterial infection. Autoimmunity or immunologic
disorders have been suggested as possible causes of idiopathic progressive
SNHL; however, the role of genetic factors in the pathogenesis has not been
studied. Many patients with sudden and rapidly progressive SNHL have circulating
cross-reacting antibodies and benefit from glucocorticoid therapy.1 Treatment of sudden SNHL should be focused on its
cause, although when a cause cannot be found, the treatment regimen is much
more controversial. The specific mechanism of corticosteroid therapy in the
treatment of sudden SNHL is unknown; however, it may improve infectious, inflammatory,
and immune-mediated conditions.
Since autoimmune SNHL was first reported by McCabe2
in 1979, some of the previously ill-defined inner ear diseases, such as Meniere
disease,3 otosclerosis,4
and idiopathic progressive SNHL,5 have been
believed to be associated with autoimmunity. Some autoimmune diseases can
be affected by inherited HLA alleles. Identification of the exact locus within
the HLA responsible for suspected autoimmune disease susceptibilities has
become important in diagnosing and understanding the pathogenesis of the disease.
Several genes located within the major histocompatibility complex that are
potentially involved in the immunologic process of inner ear diseases have
been identified.6-9
Bowman and Nelson6 demonstrated a significantly
reduced frequency of HLA-DR4 without an alteration in other DR specificities
on serologic typing in patients with immune-related SNHL. Bernstein et al7 observed a significant increase in the percentage
of patients with inner ear disease displaying the A1-B8-DR3 haplotypes. High
resolution genotyping for HLA class II alleles at the DNA level using polymerase
chain reaction sequence-specific oligonucleotide reverse dot hybridization
revealed a significant increase in the frequencies of HLA-DRB1*0301, -DRB3*0101,
-DQB1*0201, and -DPB1*0401 and a significant decrease in -DQB1*0301 in patients
with idiopathic progressive SNHL, compared with the controls.8
However, most previously reported studies have focused on idiopathic SNHL
and Meniere disease in white populations, and studies attempting to correlate
HLA with sudden SNHL, particularly in Asian populations, are rare. This study
was designed to investigate the effect of HLA class II alleles on genetic
susceptibility to sudden SNHL and to evaluate the correlation between HLA
class II genotypes and recovery from hearing loss in sudden SNHL.
PATIENTS AND METHODS
PATIENTS
Forty-one patients with sudden SNHL were included in this study. Sudden SNHL was defined as hearing loss that is greater
than 30 dB in 3 contiguous frequencies, occurring within 3 days, and in most
cases within several hours. Patients underwent general physical and otologic
examinations; audiological testing, including pure tone audiometry, speech
audiometry, and auditory brainstem response; routine laboratory tests; and
magnetic resonance imaging studies of the auditory canal and temporal bone.
No cause for the hearing loss was identified.
These patients had been admitted to the otolaryngology department at
St Mary's Hospital in Seoul, Korea, between March 1995 and December 1998.
They consisted of 24 men and 17 women (mean age, 49.2 years; range, 21-74
years). Following the diagnosis of sudden SNHL, treatment was started with
oral corticosteroid therapy, low molecular weight dextran infusion, and oral
vasodilator. For corticosteroid therapy, 1 to 2 mg/kg of body weight per day
(usual dose, 60 mg) of prednisone was given for 6 days and then tapered for
another 4 to 6 days. Additional corticosteroid therapy in a similar manner
was recommended to patients who did not display beneficial results to initial
dosages. Administration of oral nicotinic acid was started in a daily dose
of 150 to 200 mg and increased until facial flushing appeared.
Audiometric examinations were performed every other day during hospitalization
and at subsequent visits. Two hundred six randomly selected Korean subjects
with no history of hearing loss, ear disease, or immune-mediated systemic
disorders and without a family history of hereditary hearing impairment were
used as controls. The control subjects consisted of 160 men and 46 women (mean
age, 25 years; range, 23-27 years).
HLA GENOTYPING
DNA was extracted from heparinized blood samples by the salting out
method, and class II typing was performed by the polymerase chain reaction
sequence-specific oligonucleotide probes method.10
The method was essentially the same as that described at the 12th International
Histocompatibility Conference (D. Charron and R. Frauchet, written communication,
June 1996), with minor modifications. For each locus, specific primers were
used to amplify products, which were then denatured and immobilized on a nylon
membrane and probed with a series of digoxigenin-labeled oligonucleotides
specific for the known hypervariable sequences. Stringent washing was performed
in the presence of tetramethyl ammonium chloride (Sigma-Aldrich Corp, St Louis,
Mo). The hybridized probe was detected according to the manufacturer's instructions
with the antidigoxigenin antibody conjugated with alkaline phosphatase, followed
by the addition of chemiluminescent substrate disodium 3-(4-methoxyspiro[1,2-dioxetane-3,2'(5'-chloro)tricyclo[3.3.1.1(3,7)]
decan]-4-yl)
phenyl phosphate (CSPD) (Boehringer Mannheim GmbH, Mannheim, Germany). Chemiluminescence
was detected by exposure to x-ray film. HLA-DRB1, -DQA1, and -DQB1 genotyping
was performed in 41 patients, with HLA-DPB1 genotyping performed in 40 patients
because of the absence of 1 patient's DNA.
HEARING LEVEL
The hearing level of patients was tested from 125 to 8000 Hz in pure
tone audiograms, and the result was recorded as the mean of the hearing thresholds
at three speech frequencies (500, 1000, and 2000 Hz). The improvement in hearing
was assessed at 4 weeks after the start of treatment according to the criteria
proposed by Siegel.11 Patients with no improvement showed less than a 15 dB gain in hearing. Those with slight improvement had more than a 15 dB gain and a final
hearing level poorer than 45 dB. Patients with partial recovery gained more than 15 dB in hearing and had a final hearing level between
25 and 45 dB. Patients with complete recovery had
a final hearing level better than 25 dB, regardless of the amount of gain.
STATISTICAL ANALYSIS
Comparisons between patients and controls were analyzed by means of
2-tailed Fisher exact tests. Relative risk (RR) was calculated using the method
of Woolf (Haldane's12 modification was used
in sets containing zero). An uncorrected P value
for the number of comparisons was used, and P<.05
was considered statistically significant. Three-locus haplotypes (DRB1, DQA1,
and DQB1) were assigned to all subjects on the basis of known associations.
The frequency of DRB1, DQA1, and DQB1 haplotypes was compared in the patient
and control groups using  2 tests.
RESULTS
INITIAL HEARING LOSS AND RECOVERY FROM HEARING LOSS
A mild hearing loss was considered to be in
the range of 25 to 40 dB; moderate loss, 41 to 55
dB; moderately severe loss, 56 to 70 dB; severe loss, 71 to 90 dB; and a profound loss
was indicated by a threshold greater than 90 dB. Of 41 patients, 7 (17%) were
classified in the mild hearing loss category, 6 (15%) in the moderate group,
16 (39%) in the moderately severe group, and 12 (29%) in the severe hearing
loss group.
Evaluated according to the criteria proposed by Siegel,11
the overall rate of recovery among our 41 patients with sudden SNHL was 17
(41%) with no improvement, 13 (32%) with complete recovery from hearing loss,
6 (15%) with partial recovery, and 5 (12%) with slight improvement. Overall,
24 patients (59%) achieved slight improvement of their hearing loss or better.
However, we did not find a significant correlation between the level of initial
hearing loss and recovery from hearing loss in patients with sudden SNHL.
ASSOCIATION BETWEEN HLA CLASS II ALLELES AND RESULTS OF TREATMENT
The results of HLA class II genotyping in the patients with sudden SNHL
and in the controls are shown in Table 1. The frequencies of HLA-DRB1, -DQA1, -DQB1, and -DPB1 alleles were
not significantly different between the patients and the controls (P>.05). The frequencies of HLA-DRB1*14 (RR = 2.6), -DQA1*04 (RR = 2.1),
-DQA1*05 (RR = 1.8), -DQB1*04 (RR = 2.2), -DPB1*0501 (RR = 2.0), and -DPB1*1701
(RR = 2.2) were higher in the patients, but these differences were not statistically
significant (P>.05). Although the frequencies of
HLA class II alleles were not significantly different according to severity
of initial hearing loss, they were significantly different according to the
degree of recovery from hearing loss (P>.05 for both).
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Table 1. Frequencies of Class II Alleles in Patients With Sudden SNHL
and in Healthy Controls*
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Among the 41 patients with sudden SNHL, 24 responded well to corticosteroid
treatment (RS group) and 17 did not respond to corticosteroid treatment (NRS
group). When an association between the results of treatment and the presence
of HLA alleles was evaluated, the frequencies of HLA-DRB1*14 (RR = 3.5, P<.02), -DQA1*03 (RR = 4.2, P<.02),
and -DQA1*05 (RR = 3.1, P<.03) were significantly
increased and the frequencies of HLA-DQA1*01 (RR = 0.2, P<.004) and -DQB1*06 (RR = 0.2, P<.009)
were significantly decreased in the NRS group, compared with the controls.
The frequencies of HLA-DQA1*01 (P<.04) and -DQB1*06
(P<.02) were significantly increased, and the
frequency of HLA-DQA1*03 (P<.003) was significantly
decreased in the RS group, compared with the NRS group. The frequency of the
HLA-DRB1*04 allele was higher in the NRS group compared with the RS group,
but it was not statistically significant (P>.05).
A significant association between HLA-DPB1 alleles and the results of corticosteroid
therapy in patients with sudden SNHL was not found (P>.05).
The frequency of HLA-DPB1*1701 was higher in the NRS group (RR = 4.6) compared
with the controls, although it was not statistically significant (P>.05) (Table 1). HLA-DQA1
allelic combination analysis revealed that the genotype frequencies of -DQA1*03
and *05 had a high RR value in patients with sudden SNHL (RR = 4.1, P<.003) and in the NRS group (RR = 8.9, P<.001), compared with the controls. In addition, the genotype frequencies
of -DQA1*03 and *05 were significantly different between the NRS group and
the RS group (P<.03) (Table 2).
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Table 2. Frequencies of DQA1*03 and *05 Alleles in Patients With Sudden
SNHL and in Healthy Controls*
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HAPLOTYPE
The frequency of the HLA-DRB1*14-DQA1*05-DQB1*03 haplotype was significantly
increased in patients with sudden SNHL (RR = 1.6, P<.04)
and in the NRS group (RR = 4.6, P<.03) compared
with the controls, but it was not increased in the RS group (P>.05). The frequency of the DRB1*04-DQA1*03-DQB1*03 haplotype was
significantly increased only in the NRS group (RR = 5.8, P<.002); however, the frequency of the DRB1*02-DQA1*01-DQB1*06 haplotype
was significantly decreased only in the NRS group (RR = 0.2, P<.04) compared with the controls. In a comparison of the RS group
and the NRS group, the frequency of the DRB1*02-DQA1*01-DQB1*06 haplotype
was significantly increased in the RS group compared with the NRS group (29.2%
vs 0%, P<.02), and the frequency of the DRB1*14-DQA1*05-DQB1*03
haplotype was significantly decreased in the RS group compared with the NRS
group (0% vs 23.5%, P<.03) (Table 3).
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Table 3. HLA Class II Haplotypes (HLA-DRB1, -DQA1, and -DQB1) Showing
Significant Association With Sudden SNHL*
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COMMENT
Wilkins and associates13 treated patients
with idiopathic sudden SNHL with a "shotgun" regimen consisting of corticosteroid,
vasodilators, carbogen inhalation, dextran, histamine, and diuretics. Despite
the inconsistent results of corticosteroid treatment seen in early studies,
corticosteroids in moderate doses have become the most widely accepted treatment
for idiopathic sudden SNHL. In the present study, patients received oral corticosteroids
and vasodilators for a 10- to 12-day course, and none showed serious harmful
effects from the drugs. Wilson et al14 reported
that 78% of patients treated with corticosteroid experienced complete or partial
recovery, and a similar study15 also showed
a significantly improved recovery rate in a group treated with corticosteroids
compared with a nontreated group. However, with the shotgun regimen, Wilkins
et al13 did not achieve better results than
the spontaneous recovery that is reported in the literature. Fifty-nine percent
of our patients showed slight improvement or better, and this is low compared
with the results described in earlier reports. Possible explanations why treatment
in this study was not as effective may be the older age of our patients (mean
age, 49.2 years) and the more severe levels of initial hearing loss (68% with
hearing levels poorer than 56 dB).
In the present study, low molecular weight dextran infusion and oral
vasodilators were given to patients to try to improve cochlear blood flow.
Redleaf et al16 noted that 74% of patients
with sudden SNHL showed improvement with dextran treatment, but hearing improvement
by oral vasodilator treatment alone was not reported. In this study, treatment
with oral corticosteroids, low-molecular-weight dextran, and vasodilators
did not show significant improvement of hearing, compared with corticosteroid
treatment alone or no treatment (P>.05).
Among the possible mechanisms of HLA class II alleles and disease association,
inner ear autoimmunity may be related to the phenomenon of molecular mimicry.
The shared structure between an individual pathogen and particular class II
molecules may serve as a cross-reactive autoantigen and lead to an immune
reaction in the inner ear. In this study, there was no significant alteration
in HLA class II alleles in the patients with sudden SNHL compared with the
controls. The association of HLA with the response to corticosteroid therapy
has been reported in some autoimmune diseases, including idiopathic thrombocytopenic
purpura, nephrotic syndrome, and giant cell arteritis.17-19
In Japanese pediatric patients with corticosteroid-sensitive nephrotic syndrome,
DQA1*0103 was significantly lower than in the controls (RR = 0.19, P<.04), whereas DQB1*0302 was increased.17
Our results suggest that the presence of HLA-DRB1*14, -DQA1*03, and -DQA1*05
alleles is associated with a poor recovery from sudden SNHL, and that the
presence of HLA-DQA1*01 and -DQB1*06 alleles forecasts a good prognosis in
Korean patients with sudden SNHL. HLA-DQA1*03 is the most prominent allele
associated with poor recovery from hearing loss in Koreans with sudden SNHL.
Significantly higher frequencies of HLA-DQA1*01 and -DQB1*06 and a significantly
lower frequency of -DQA1*03 were observed in the RS group, compared with the
NRS group. However, no significant association between HLA-DPB1 alleles and
the results of corticosteroid therapy in the patients was found. No association
with HLA-DP alleles was observed, which narrows the disease susceptibility
region that is genetically involved to the DR-DQ region. Interestingly, the
presence of DQA1*03 and DQA1*05 alleles in the NRS group showed the highest
RR values. In type 1 diabetes mellitus, which has been extensively studied
for HLA association, susceptibility or protection is known to be primarily
associated with given DQ heterodimers.20 In
this study, the HLA-DRB1*04-DQA1*03-DQB1*03 and DRB1*14-DQA1*05-DQB1*03 haplotypes
were associated with nonresponsiveness to corticosteroid therapy in the patients
with sudden SNHL. In particular, DRB1*04-DQA1*03-DQB1*03 showed more significant
and higher RR values than did DQA1*03 in the NRS group, whereas the DRB1*02-DQA1*01-DQB1*06
haplotype was not present in the NRS group. It is interesting that the distributions
of HLA alleles are different relative to the response to corticosteroid therapy
in patients with sudden SNHL. Rauzy et al21
studied 41 patients with giant cell arteritis and found it to be associated
with HLA-DRB1*04. Also, they reported that the association between giant cell
arteritis and HLA-DRB1*04 appears to be accompanied by corticosteroid resistance.
Therefore, our results suggest the existence of an immune-mediated response
in the inner ear as a possible etiopathogenic factor. In addition, these results
suggest that genetic studies of HLA can predict the response of some diseases
to corticosteroid treatment.
CONCLUSIONS
This study showed that genetically determined factors may affect the
course of sudden SNHL. However, our findings should be considered preliminary
because of possible differences in HLA status between Koreans and other ethnicities
with sudden SNHL. Further studies with a larger number of patients in different
populations may better reveal the immunogenetic background of sudden SNHL.
In addition to the high resolution typing of the HLA class II alleles, an
extensive molecular approach incorporating the gene scan method will provide
more useful information for defining the genetic factors associated with responsiveness
to corticosteroid therapy or the progression of sudden SNHL.
AUTHOR INFORMATION
Accepted for publication February 7, 2001.
This work was supported by grant HMP-96-M-2-1033 of the Good Health
Research and Development Project, Ministry of Health and Welfare, Republic
of Korea.
We thank the staff of the research laboratories of the Departments of
Otolaryngology and Microbiology and Immunology, The Catholic University of
Korea, Seoul.
Corresponding author and reprints: Tai-Gyu Kim, MD, PhD, Department
of Microbiology and Immunology, College of Medicine, The Catholic University
of Korea, Banpo-dong 505, Seocho-ku, Seoul 137-040, Korea (e-mail:
cbib{at}cmc.cuk.ac.kr).
From the Departments of Otolaryngology (Drs Yeo, S-N. Park, Y-S. Park,
and Suh) and Microbiology and Immunology (Drs Han, Choi, and Kim), College
of Medicine, The Catholic University of Korea, Seoul.
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