Profiling Human Leukocyte Antigens in

Vogt-Koyanagi-Harada Syndrome

XiaoYan Zhang, M.D., X i u - M i n g Wang, M.D., and T i a n - S h e n g Hu, M.D.

Human leukocyte antigen typing was per­ in HLA-DR4-positive control subjects than in
formed in 32 consecutive Chinese patients the HLA-DR4-positive patients (P = .0308),
with Vogt-Koyanagi-Harada syndrome and 52 which indicated that HLA-DQwl was nega­
unrelated healthy Chinese individuals. Re­ tively associated with the disease. This pro­
sults indicated that HLA-DR4 was identified tective effect from HLA-DQwl was also stud­
in 24 of the 32 patients with Vogt-Koyanagi- ied.
Harada syndrome (75.0%), but only in 12
(23.1%) of the 52 control subjects (P = .0003;
relative risk, 10.0). Human leukocyte antigen-
VOGT-KOYANAGI-HARADA SYNDROME, a com­
DQw7, also correlated with the disease, was
mon type of uveitis in Japanese individuals, has
identified in 19 (59.4%) patients, and in 19
been reported throughout the world. Most of
control subjects (36.5%; P = .0230). The two-
the patients found in the United States have
haplotype association detection demonstrated
been of Oriental or American Indian descent. 1,2
that HLA-DR4 and HLA-DQw7 were related
In China, the incidence of Vogt-Koyanagi-
through linkage disequilibrium, suggesting
Harada syndrome has been found to be 9.2% to
that the disease was primarily associated with
14.2% at the uveitis service in two medical
only one of the antigens. The comparison
centers. 34 The immunologic mechanism of this
between HLA-DR4-positive and HLA-DR4-
syndrome has been studied since the 1970s
negative patients with Vogt-Koyanagi-Harada
when Tagawa and associates 66 found a close
syndrome in regard to clinical manifestations
association between Vogt-Koyanagi-Harada
has shown that the HLA-DR4-positive group
syndrome and either HLA-Bw22J (Bw54) or
had a lower visual acuity at the first visit than
HLA-LD-Wa (Dwl5) in Japan and suggested the
did the HLA-DR4-negative group. However,
possibility of a disease susceptibility gene.
both groups responded well to corticosteroid
Ohno 7 later identified HLA-DRw53, HLA-Dwa,
treatment. No other significant correlations
and HLA-DR4 as Vogt-Koyanagi-Harada syn­
between HLA-DR4 positivity and ocular fea­
drome-relevant antigens in Japanese individu­
tures, including complications or systemic
als. Recently, HLA typing on racially diverse
features, were found. Therefore, we concluded
American patients with Vogt-Koyanagi-Harada
that the presence of HLA-DR4 may represent
syndrome showed an increased frequency of
susceptibility to Vogt-Koyanagi-Harada syn­
HLA-DR4, HLA-DQw3, and HLA-DRw53; and
drome, but may not represent specific tissue
a higher percentage of patients with Vogt-
involvement or determine the prognosis. A
Koyanagi-Harada syndrome who were positive
decreased frequency of HLA-DQwl in the
with these antigens were of American Indian
patient group was also noticed. Further stud­
descent. 8 To investigate this association further,
ies showed a higher percentage of HLA-DQwl
we performed HLA-A, -B, -DR, and -DQ region
typing in 32 Chinese patients with Vogt-
Koyanagi-Harada syndrome.
Accepted for publication Feb. 10, 1992.
From the Department of Ophthalmology, Peking Un­
ion Medical College Hospital, Chinese Academy of Med­
ical Science (Drs. Zhang a n d Hu); a n d Basic Medical
Research Institute, China-Japan Friendship Hospital Material and Methods
(Dr. Wang), Beijing, People's Republic of China.
Reprint requests to Tian-Sheng Hu, M.D., Department
of Ophthalmology, Peking Union Medical College Hos­ Patients and control subjects—Thirty-two
pital, Beijing 100730, People's Republic of China. consecutive unrelated patients with Vogt-

©AMERICAN JOURNAL OF OPHTHALMOLOGY 113:567-572, M A Y , 1992 567

568 AMERICAN JOURNAL OF OPHTHALMOLOGY May, 1992

Koyanagi-Harada syndrome who had various TABLE 1

stages of disease (19 males and 13 females) FREQUENCIES OF HLA-A, -B, -DR, AND -DO. ANTIGENS
were examined in the uveitis service in the IN PATIENTS WITH VOGT-KOYANAGI-HARADA
Department of Ophthalmology, Peking Union SYNDROME AND CONTROL SUBJECTS
Medical College Hospital from 1986 through
1988. The detailed medical histories of uveitis CONTROL
symptoms and systemic changes were obtained PATIENTS SUBJECTS
(N=32) (N=52)
from each patient at the first visit. The patients HLA
underwent complete ophthalmic examinations. ANTIGEN* NO. (%) NO. (%)
Vogt-Koyanagi-Harada syndrome was diag­ A1 5(15.6) 1 (1.9)
nosed on the basis of criteria proposed by A2 14(43.6) 17(32.7)
Sugiura. 9 All patients received corticosteroids A3 2 (6.3) 1 (1-9)
either systemically or topically depending on A9 5(15.6) 17(32.7)
the severity of symptoms. The disease onset A24 4 (12.5) 15(28.8)
was between 14 and 61 years of age. Of these 32 A10 4(12.5) 8(15.4)
patients, 30 (93%) were from northern China A26 1 (3.1) 3 (5.8)
and all patients were of Han nationality. The Aw34 0 6(11.5)
Han Chinese represent almost 94% of the total A11 16(50.0) 17(32.7)
population in China and constitute the great A19 — —
homogeneous mass of the Chinese people. The A29 0 3 (5.8)
Han nationality also outnumbers the minority A30 3 (9.4) 5 (9.6)
nationalities in most provinces or autonomous A31 2 (6.3) 4 (7.7)
regions. Fifty-two unrelated healthy staff mem­ A32 3 (9.4) 0
bers and students from Peking Union Medical Aw33 1 (3.1) 4 (7.7)
College Hospital (24 men and 28 women), who A28 2 (6.3) 3 (5.8)
ranged in age from 19 to 62 years, were used as Blank 6(18.8) 13(25.0)
control subjects. Of these 52 subjects, 50 (96%)
were of Han nationality and 42 (81%) were B5 4(12.5) 8(15.4)
from northern China. The individuals with au­ B51 3 (9.4) 1 (2.0)
toimmune diseases or inherited diseases were B7 1 (3.1) 4 (7.7)
excluded before blood samples were collected. B8 1 (3.1) 0
Human leukocyte antigen typing—Human leu­ B12 3 (9.4) 0
kocyte antigen typing trays (Terasaki HLA-ABC B44 3 (9.4) 1 (1.9)
and DRw tray, One Lambda, Inc., California), B13 5(15.6) 11(21.1)
including a panel of 57 antisera (15 for HLA-A, B14 0 0
28 for HLA-B, ten for HLA-DR, and four for B15 6(18.8) 7(13.5)
HLA-DQ), were used. B-lymphocyte lympho- Bw62 4(12.5) 4 (7.7)
kwik (One Lambda, Inc., California) and rabbit B16 0 8(15.4)
complement for both HLA-A, -B, -C (class I), B17 3 (9.4) 4 (7.7)
and HLA-DR (class II) typing were from the Bw57 1 (3.1) 2 (3.9)
same source. Lymphocytes were isolated from B21 2 (6.3) 2 (3.9)
peripheral venous blood. The B-lympho-kwik Bw22 3 (9.4) 4 (7.7)
method was used for isolating B lymphocytes. Bw54 1 (3.1) 2 (3.9)
Human leukocyte antigen typing was per­ Bw55 1 (3.1) 1 (1.9)
formed by using a standard microlymphocyto- B27 4(12.5) 2 (3.9)
toxicity test.10 B35 5(15.6) 5 (9.6)
Statistical analysis—The results were exam­ B37 2 (6.3) 2 (3.9)
ined by the Chi-square test. Fisher's exact test B40 12 (37.5) 10(19.2)
with correction was used instead of the chi- Bw60 8 (25.0) 9(17.3)
square test when the sample number was less Bw41 0 2 (3.9)
than five.11 The relative risk was calculated by Bw42 0 0
using the method of Svejgaard and associates. 12 Bw53 0 3 (5.8)
The relative linkage disequilibrium under both
the autosomal recessive model and the rare Continued on following page.
autosomal dominant model was estimated us­ 'Indented entries are splits of the preceding entry.
ing the formulas of Porta and McHugh. 13
Vol. 113, No. 5 Vogt-Koyanagi-Harada Syndrome 569

TABLE 1 (Continued) occurrence of HLA-DR4 and HLA-DQw7 anti­

FREQUENCIES OF HLA-A,-B,-DR, AND-DQ ANTIGENS gens among patients with Vogt-Koyanagi-
IN PATIENTS WITH VOGT-KOYANAGI-HARADA Harada syndrome and control subjects was sta­
SYNDROME AND CONTROL SUBJECTS tistically analyzed to discriminate primary and
secondary disease haplotype association and
CONTROL was shown in the autosomal recessive model,
PATIENTS SUBJECTS Z = 0.2073; and in the rare autosomal dominant
(N=32) (N=52)
HLA model, Z = 1.4357, which indicated an insignif­
ANTIGEN* NO. (%) NO. (%) icant difference. Therefore, linkage disequilib­
Bw59 1 (3.1) 2 (3.9) rium existed between HLA-DR4 and HLA-
Bw67 0 3 (5.8) DQw7.
Blank 10(31.3) 15(28.8) The ocular and systemic clinical features of
DR1 0 2 (3.9) HLA-DR4-positive patients and HLA-DR4-
DR2 8 (25.0) 10(19.2) negative patients were compared. The ocular
DR3 3 (9.4) 3 (5.8) features during the active stage and the compli­
DR4 24 (75.0) 12(23.1) cations in relation to HLA-DR4 were deter­
DR5 2 (6.3) 11(21.2) mined (Table 2; the ocular features such as
DRw6 9(28.1) 9(17.3) exudative retinal detachment and neovascular-
DR7 7(21.9) 18(34.6) ization were not included in the database be­
DRw8 1 (3.1) 6(11.5) cause the clinical records of some patients were
DRw9 5(15.6) 12(23.1) unavailable). Although the HLA-DR4-positive
DRw10 1 (3.1) 3 (5.8) group had a higher percentage of vitreous opac­
Blank 3 (9.4) 15(28.8) ity than did the HLA-DR4-negative group, this
difference was not statistically significant. No
DQw1 11 (34.4) 29(55.7) other ocular signs were statistically significant­
DQw2 7(21.9) 7(13.5) ly different between the HLA-DR4-positive
DQw3 21 (65.6) 35(67.3) and HLA-DR4-negative groups. The positivity
DQw7 19(59.4) 19(36.5) of HLA-DR4 also did not appear to be related to
Blank 19(59.4) 27(51.9) specific systemic features (Table 3). Visual acu­
ity improved after corticosteroid treatment
♦Indented entry is split of the preceding entry. (Figure). Human leukocyte antigen-DR4-posi-
tive patients had worse visual acuity than HLA-
Results
TABLE 2
COMPARISON OF OCULAR FEATURES BETWEEN
Human leukocyte antigen typing for HLA-A, HLA-DR4-POSITIVE AND HLA-DR4-NEGATIVE
-B, -DR, and -DQ was performed (Table 1). The PATIENTS*
frequency of HLA-DR4 was markedly different
between patients with Vogt-Koyanagi-Harada HLA-DR4-POSITIVE HLA-DR4-NEGATIVE
syndrome and control subjects. Human leuko­ PATIENTS PATIENTS
cyte antigen-DR4 was identified in 24 (75.0%) FEATURES (N = 24) (N = 8)
of the 32 patients, whereas it was identified in Active stage
only 12 (23.1%) of the control subjects (P = Onset age s 40 years1 13 of 23 4 of 7
.0003; relative risk, 10.0). The frequency of Mutton-fat
HLA-DQw7 was increased in the patients (19 keratic precipitates 16 of 24 6 of 8
[59.4%] in the patients and 19 [36.5%] in con­ Iris nodules 9 of 23 3 of 7
trol subjects [P = .0230]). A decreased frequen­ Vitreous opacity 16 of 22 3 of 6
cy of HLA-DQwl (ten [31.3%] in patients and
Complications
27 [51.9%] in control subjects) was also ob­
Cataract 11 of 24 5 of 8
served, although it was not statistically signifi­
Glaucoma 4 of 24 2 of 8
cant. It seemed that HLA-DQwl was negatively
Posterior synechiae 17 of 24 6 of 8
associated with the disease. When compared
with the test population, our HLA frequencies ♦Because patients with unclear records were not included in
in the control group were similar to those de­ the analysis of some features, the number of patients varied.
scribed by the Third Asia-Oceania Histocom- f
40 years was the average age of onset of our patients with
patibility Workshop and Conference. 14 The joint Vogt-Koyanagi-Harada syndrome.
570 AMERICAN JOURNAL OF OPHTHALMOLOGY
TABLE 3
COMPARISON OF SYSTEMIC FEATURES BETWEEN
HLA-DR4-POSITIVE AND HLA-DR4-NEGATIVE
PATIENTS*
HLA-DR4-P0SITIVE HLA-DR4-NEGATIVE
PATIENTS PATIENTS
FEATURES (N = 24) (N = 8)
Meningeal symptoms 13 of 20 3 of 7
Vitiligo 11 of 20 3 of 7
Hair abnormality 18 of 22 4 of 7
Ear symptoms 13 of 20 5 of 7
•Because patients with unclear records were not included in
the analysis of some features, the number of patients varied.
DR4-negative patients at the first visit. Howev­
er, treatment with corticosteroids had a similar
effect on both groups. Of these 32 patients (64
eyes), 25 of 48 eyes (52.1%) in the HLA-DR4-
positive group and eight of 16 eyes (50%) in the
HLA-DR4-negative group had a marked im­
provement in visual acuity ( s 20/20) after
corticosteroid treatment.
Discussion
Our findings of HLA-DR4 in relation to
Vogt-Koyanagi-Harada syndrome in Chinese
individuals are consistent with findings in
Japanese 7 and American Indian individuals. 8
Human leukocyte antigen-DR4 has been associ­
ated with many other autoimmune diseases,
including rheumatoid arthritis,15"17 insulin-de­
pendent diabetes mellitus, 1518 thyroiditis, 1821
Addison's disease, 22 myasthenia gravis, 23 IgA
nephropathy, 24 as well as acute retinal necro­
sis,25 ocular cicatricial pemphigoid, 26 and retinal
vasculitis in different ethnic groups. 27 Such as­
sociations strongly suggest that the HLA-DR4
gene has an important role in autoimmune
disorders. The two-haplotype association de­
tection for HLA-DR4 and HLA-DQw7 demon­
strated that the increased frequency of either
antigen was caused by the linkage disequilibri­
um between the two antigens in the general
population. This suggested that only one of the
two antigens was primarily associated with the
disease. This HLA-DR4-HLA-DQw7 coexpres-
sion has also been observed in acute retinal
necrosis syndrome. 25 It seemed in our study that
HLA-DR4 was the major haplotype because of
its much higher frequency in patients with
Vogt-Koyanagi-Harada syndrome.
Because of the negative association of HLA-
May, 1992
DQwl with Vogt-Koyanagi-Harada syndrome,
we compared the relationship between HLA-
DQwl and HLA-DR4 in both patients and con­
trol subjects. In HLA-DR4-positive control
subjects, eight of 12 (66.7%) subjects were
positive for HLA-DQwl, whereas in 24 HLA-
DR4-positive patients, only seven (29.2%)
were positive for HLA-DQwl (a significant dif­
ference at P = .0308). It seemed that HLA-
DQwl inhibited HLA-DR4 disease permissive­
ness. A similar negative association has been
observed in insulin-dependent diabetes melli­
tus28,29 and a model has been proposed to inter­
pret this phenomenon. 30 In this model, a hierar­
chy of affinities was presented to determine the
interaction between a diabetogenic peptide and
different class II molecules; binding the peptide
to susceptible class II molecules leads to auto-
reactive T-lymphocyte activation. When non-
susceptible class II molecules could outcom-
pete the binding, the autoimmune activation
would not occur. The mechanism of the de­
crease of HLA-DQwl observed in our study
was unclear. The previously described model
might explain the phenomenon if HLA-DQwl
is a nonsusceptible high-affinity competitor for
HLA-DR4. However, this HLA-DQwl protec­
tive effect requires further study.
Clinically distinct characteristics of HLA-as-
sociated diseases in other types of uveitis have
been described. 3136 Our observations of HLA-
DR4-positive and HLA-DR4-negative patients
with Vogt-Koyanagi-Harada syndrome in re­
gard to some clinical manifestations showed
that the HLA-DR4-positive group had a lower
visual acuity at the first visit than did the
HLA-DR4-negative group. We were unable to
determine the reasons for the lower visual acu­
ity because of inadequate clinical records in
some patients. However, both groups respond­
ed well to corticosteroid treatment. No other
significant correlations between antigen posi-
tivity and ocular or systemic features were
found. The similar complications, such as com­
plicated cataract and secondary glaucoma, in
the two groups suggested a similar visual prog­
nosis. The previously described assay would
suggest that the positivity of the HLA-DR4
allele in Vogt-Koyanagi-Harada syndrome did
not represent specific tissue involvement or
determine the prognosis. Human leukocyte an-
tigen-DR4-positive patients may have lower
initial visual acuity than HLA-DR4-negative
patients, but the treatment outcome was still
favorable. We also could not predict a course of
Vogt-Koyanagi-Harada syndrome by correla­
tion with HLA-DR4 positivity or negativity.
Vol. 113, No. 5 Vogt-Koyanagi-Harada Syndrome 571

20/15+ "
G
a 20/20 "
+->
«
t 20/25
E—
U
<D 20/30 -
+->

H
20/50 " DR4+ Patients
3 ♦ DR4- Patients
o 20/100"
<
FC
00
>
HM

NLP ■—r ■ l l • I
NLP HM C 20/ 20/ 20/ 20/ 20/ 20/
100 50 30 25 20 15+
Visual Acuity Before Treatment
Figure (Zhang, Wang, and Hu). The improvement of visual acuities after corticosteroid treatment. A higher
percentage of HLA-DR4-positive patients had worse visual acuity than HLA-DR4-negative patients at the first
visit. HM indicates hand motion; FC indicates finger counting; NLP indicates no light perception; DR4+ patients
indicates HLA-DR4-positive patients; and DR4— patients indicates HLA-DR4-negative patients.

Because vitiligo, o n e of t h e i m p o r t a n t s y m p ­ 2. Ohno, S., Char, D. H., Kimura, S. T., and

t o m s of V o g t - K o y a n a g i - H a r a d a s y n d r o m e , w a s
f o u n d to b e strongly a s s o c i a t e d w i t h HLA-DR4
in blacks 8 6 a n d whites 3 7 w h e n t e s t e d as a single
d i s e a s e , the association w i t h HLA-DR4 in our
s t u d y could p o s s i b l y h a v e b e e n c a u s e d by vitili-
go. Eleven of 20 of our H L A - D R 4 - p o s i t i v e p a ­
t i e n t s a n d t h r e e of seven of o u r H L A - D R 4 -
negative p a t i e n t s h a d vitiligo. T h e r e w a s n o
significant difference b e t w e e n t h e t w o g r o u p s ,
w h i c h i n d i c a t e d t h a t the a s s o c i a t i o n of Vogt-
K o y a n a g i - H a r a d a s y n d r o m e w i t h H L A - D R 4 in
o u r study was i n d e p e n d e n t .
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