Profiling Human Leukocyte Antigens in Vogt-Koyanagi-Harada Syndrome

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 formed in 32 consecutive Chinese patients with Vogt-Koyanagi-Harada syndrome and 52 unrelated healthy Chinese individuals. Re­ sults indicated that HLA-DR4 was identified in 24 of the 32 patients with Vogt-KoyanagiHarada syndrome (75.0%), but only in 12 (23.1%) of the 52 control subjects (P = .0003; relative risk, 10.0). Human leukocyte antigenDQw7, also correlated with the disease, was identified in 19 (59.4%) patients, and in 19 control subjects (36.5%; P = .0230). The twohaplotype association detection demonstrated that HLA-DR4 and HLA-DQw7 were related through linkage disequilibrium, suggesting that the disease was primarily associated with only one of the antigens. The comparison between HLA-DR4-positive and HLA-DR4negative patients with Vogt-Koyanagi-Harada syndrome in regard to clinical manifestations has shown that the HLA-DR4-positive group had a lower visual acuity at the first visit than did the HLA-DR4-negative group. However, both groups responded well to corticosteroid treatment. No other significant correlations between HLA-DR4 positivity and ocular fea­ tures, including complications or systemic features, were found. Therefore, we concluded that the presence of HLA-DR4 may represent susceptibility to Vogt-Koyanagi-Harada syn­ drome, but may not represent specific tissue involvement or determine the prognosis. A decreased frequency of HLA-DQwl in the patient group was also noticed. Further stud­ ies showed a higher percentage of HLA-DQwl

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 (Dr. Wang), Beijing, People's Republic of China. Reprint requests to Tian-Sheng Hu, M.D., Department of Ophthalmology, Peking Union Medical College Hos­ pital, Beijing 100730, People's Republic of China.

in HLA-DR4-positive control subjects than in the HLA-DR4-positive patients (P = .0308), which indicated that HLA-DQwl was nega­ tively associated with the disease. This pro­ tective effect from HLA-DQwl was also stud­ ied.

VOGT-KOYANAGI-HARADA SYNDROME, a com­ mon type of uveitis in Japanese individuals, has been reported throughout the world. Most of the patients found in the United States have been of Oriental or American Indian descent. 1,2 In China, the incidence of Vogt-KoyanagiHarada syndrome has been found to be 9.2% to 14.2% at the uveitis service in two medical centers. 34 The immunologic mechanism of this syndrome has been studied since the 1970s when Tagawa and associates 66 found a close association between Vogt-Koyanagi-Harada syndrome and either HLA-Bw22J (Bw54) or HLA-LD-Wa (Dwl5) in Japan and suggested the possibility of a disease susceptibility gene. Ohno 7 later identified HLA-DRw53, HLA-Dwa, and HLA-DR4 as Vogt-Koyanagi-Harada syn­ drome-relevant antigens in Japanese individu­ als. Recently, HLA typing on racially diverse American patients with Vogt-Koyanagi-Harada syndrome showed an increased frequency of HLA-DR4, HLA-DQw3, and HLA-DRw53; and a higher percentage of patients with VogtKoyanagi-Harada syndrome who were positive with these antigens were of American Indian descent. 8 To investigate this association further, we performed HLA-A, -B, -DR, and -DQ region typing in 32 Chinese patients with VogtKoyanagi-Harada syndrome.

Material and Methods Patients and control subjects—Thirty-two consecutive unrelated patients with Vogt-

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Koyanagi-Harada syndrome who had various stages of disease (19 males and 13 females) were examined in the uveitis service in the Department of Ophthalmology, Peking Union Medical College Hospital from 1986 through 1988. The detailed medical histories of uveitis symptoms and systemic changes were obtained from each patient at the first visit. The patients underwent complete ophthalmic examinations. Vogt-Koyanagi-Harada syndrome was diag­ nosed on the basis of criteria proposed by Sugiura. 9 All patients received corticosteroids either systemically or topically depending on the severity of symptoms. The disease onset was between 14 and 61 years of age. Of these 32 patients, 30 (93%) were from northern China and all patients were of Han nationality. The Han Chinese represent almost 94% of the total population in China and constitute the great homogeneous mass of the Chinese people. The Han nationality also outnumbers the minority nationalities in most provinces or autonomous regions. Fifty-two unrelated healthy staff mem­ bers and students from Peking Union Medical College Hospital (24 men and 28 women), who ranged in age from 19 to 62 years, were used as control subjects. Of these 52 subjects, 50 (96%) were of Han nationality and 42 (81%) were from northern China. The individuals with au­ toimmune diseases or inherited diseases were excluded before blood samples were collected. Human leukocyte antigen typing—Human leu­ kocyte antigen typing trays (Terasaki HLA-ABC and DRw tray, One Lambda, Inc., California), including a panel of 57 antisera (15 for HLA-A, 28 for HLA-B, ten for HLA-DR, and four for HLA-DQ), were used. B-lymphocyte lymphokwik (One Lambda, Inc., California) and rabbit complement for both HLA-A, -B, -C (class I), and HLA-DR (class II) typing were from the same source. Lymphocytes were isolated from peripheral venous blood. The B-lympho-kwik method was used for isolating B lymphocytes. Human leukocyte antigen typing was per­ formed by using a standard microlymphocytotoxicity test.10 Statistical analysis—The results were exam­ ined by the Chi-square test. Fisher's exact test with correction was used instead of the chisquare test when the sample number was less than five.11 The relative risk was calculated by using the method of Svejgaard and associates. 12 The relative linkage disequilibrium under both the autosomal recessive model and the rare autosomal dominant model was estimated us­ ing the formulas of Porta and McHugh. 13

TABLE 1 FREQUENCIES OF HLA-A, -B, -DR, AND -DO. ANTIGENS IN PATIENTS WITH VOGT-KOYANAGI-HARADA SYNDROME AND CONTROL SUBJECTS CONTROL PATIENTS (N=32)

SUBJECTS (N=52)

NO. (%)

NO. (%)

A1 A2 A3 A9 A24 A10 A26 Aw34 A11 A19 A29 A30 A31 A32 Aw33 A28 Blank

5(15.6) 14(43.6) 2 (6.3) 5(15.6) 4 (12.5) 4(12.5) 1 (3.1) 0 16(50.0)

1 (1.9) 17(32.7)

—

—

0 3 (9.4) 2 (6.3) 3 (9.4) 1 (3.1) 2 (6.3) 6(18.8)

3 (5.8) 5 (9.6) 4 (7.7) 0 4 (7.7) 3 (5.8) 13(25.0)

B5 B51 B7 B8 B12 B44 B13 B14 B15 Bw62 B16 B17 Bw57 B21 Bw22 Bw54 Bw55 B27 B35 B37 B40 Bw60 Bw41 Bw42 Bw53

4(12.5) 3 (9.4) 1 (3.1) 1 (3.1) 3 (9.4) 3 (9.4) 5(15.6) 0 6(18.8) 4(12.5) 0 3 (9.4) 1 (3.1) 2 (6.3) 3 (9.4) 1 (3.1) 1 (3.1) 4(12.5) 5(15.6) 2 (6.3) 12 (37.5) 8 (25.0) 0 0 0

8(15.4) 1 (2.0) 4 (7.7) 0 0 1 (1.9) 11(21.1) 0 7(13.5) 4 (7.7) 8(15.4) 4 (7.7) 2 (3.9) 2 (3.9) 4 (7.7) 2 (3.9) 1 (1.9) 2 (3.9) 5 (9.6) 2 (3.9) 10(19.2) 9(17.3) 2 (3.9) 0 3 (5.8)

HLA ANTIGEN*

Continued on following page. 'Indented entries are splits of the preceding entry.

1 (1-9) 17(32.7) 15(28.8) 8(15.4) 3 (5.8) 6(11.5) 17(32.7)

Vogt-Koyanagi-Harada Syndrome

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TABLE 1 (Continued) FREQUENCIES OF HLA-A,-B,-DR, AND-DQ ANTIGENS IN PATIENTS WITH VOGT-KOYANAGI-HARADA SYNDROME AND CONTROL SUBJECTS CONTROL PATIENTS (N=32)

SUBJECTS (N=52)

ANTIGEN*

NO. (%)

NO. (%)

Bw59 Bw67 Blank DR1 DR2 DR3 DR4 DR5 DRw6 DR7 DRw8 DRw9 DRw10 Blank

1 (3.1) 0 10(31.3) 0 8 (25.0) 3 (9.4) 24 (75.0) 2 (6.3) 9(28.1) 7(21.9) 1 (3.1) 5(15.6) 1 (3.1) 3 (9.4)

2 (3.9) 3 (5.8) 15(28.8) 2 (3.9) 10(19.2) 3 (5.8) 12(23.1) 11(21.2) 9(17.3) 18(34.6) 6(11.5) 12(23.1) 3 (5.8) 15(28.8)

DQw1 DQw2 DQw3 DQw7 Blank

11 (34.4) 7(21.9) 21 (65.6) 19(59.4) 19(59.4)

29(55.7) 7(13.5) 35(67.3) 19(36.5) 27(51.9)

HLA

♦Indented entry is split of the preceding entry.

Results Human leukocyte antigen typing for HLA-A, -B, -DR, and -DQ was performed (Table 1). The frequency of HLA-DR4 was markedly different between patients with Vogt-Koyanagi-Harada syndrome and control subjects. Human leuko­ cyte antigen-DR4 was identified in 24 (75.0%) of the 32 patients, whereas it was identified in only 12 (23.1%) of the control subjects (P = .0003; relative risk, 10.0). The frequency of HLA-DQw7 was increased in the patients (19 [59.4%] in the patients and 19 [36.5%] in con­ trol subjects [P = .0230]). A decreased frequen­ cy of HLA-DQwl (ten [31.3%] in patients and 27 [51.9%] in control subjects) was also ob­ served, although it was not statistically signifi­ cant. It seemed that HLA-DQwl was negatively associated with the disease. When compared with the test population, our HLA frequencies in the control group were similar to those de­ scribed by the Third Asia-Oceania Histocompatibility Workshop and Conference. 14 The joint

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occurrence of HLA-DR4 and HLA-DQw7 anti­ gens among patients with Vogt-KoyanagiHarada syndrome and control subjects was sta­ tistically analyzed to discriminate primary and secondary disease haplotype association and was shown in the autosomal recessive model, Z = 0.2073; and in the rare autosomal dominant model, Z = 1.4357, which indicated an insignif­ icant difference. Therefore, linkage disequilib­ rium existed between HLA-DR4 and HLADQw7. The ocular and systemic clinical features of HLA-DR4-positive patients and HLA-DR4negative patients were compared. The ocular features during the active stage and the compli­ cations in relation to HLA-DR4 were deter­ mined (Table 2; the ocular features such as exudative retinal detachment and neovascularization were not included in the database be­ cause the clinical records of some patients were unavailable). Although the HLA-DR4-positive group had a higher percentage of vitreous opac­ ity than did the HLA-DR4-negative group, this difference was not statistically significant. No other ocular signs were statistically significant­ ly different between the HLA-DR4-positive and HLA-DR4-negative groups. The positivity of HLA-DR4 also did not appear to be related to specific systemic features (Table 3). Visual acu­ ity improved after corticosteroid treatment (Figure). Human leukocyte antigen-DR4-positive patients had worse visual acuity than HLATABLE 2 COMPARISON OF OCULAR FEATURES BETWEEN HLA-DR4-POSITIVE AND HLA-DR4-NEGATIVE PATIENTS*

FEATURES

Active stage Onset age s 40 years1 Mutton-fat keratic precipitates Iris nodules Vitreous opacity Complications Cataract Glaucoma Posterior synechiae

HLA-DR4-POSITIVE

HLA-DR4-NEGATIVE

PATIENTS (N = 24)

PATIENTS

13 of 23

4 of 7

16 of 24 9 of 23 16 of 22

6 of 8 3 of 7 3 of 6

11 of 24 4 of 24 17 of 24

5 of 8 2 of 8 6 of 8

(N = 8)

♦Because patients with unclear records were not included in the analysis of some features, the number of patients varied. f 40 years was the average age of onset of our patients with Vogt-Koyanagi-Harada syndrome.

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TABLE 3 COMPARISON OF SYSTEMIC FEATURES BETWEEN HLA-DR4-POSITIVE AND HLA-DR4-NEGATIVE PATIENTS* HLA-DR4-P0SITIVE

HLA-DR4-NEGATIVE

FEATURES

PATIENTS (N = 24)

PATIENTS (N = 8)

Meningeal symptoms Vitiligo Hair abnormality Ear symptoms

13 of 20 11 of 20 18 of 22 13 of 20

3 of 7 3 of 7 4 of 7 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-DR4positive 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 coexpression 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 HLADQwl 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 HLADR4-positive patients, only seven (29.2%) were positive for HLA-DQwl (a significant dif­ ference at P = .0308). It seemed that HLADQwl 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 autoreactive T-lymphocyte activation. When nonsusceptible class II molecules could outcompete 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-associated diseases in other types of uveitis have been described. 3136 Our observations of HLADR4-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 positivity 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 antigen-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.

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t

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20/25 20/30

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20/50 "

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DR4+ Patients DR4- Patients

♦

20/100" FC HM NLP NLP

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20/ 50

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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 ­ 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 vitiligo. 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 VogtK 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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24. Kashiwabara, H., Shishido, H., Tomura, S., Tuchida, H., and Miyajima, T.: Strong association between IgA nephropathy and HLA-DR4 antigen. Kidney Int. 22:377, 1982. 25. Holl, G. N., Cornell, P., Park, M., Barbetti, A., Yuge, J., Kreiger, A. E., Kapla, H. J., Pepose, J. S., Heckenlively, J. R., and Culbertson, W. W.: An asso­ ciation between acute retinal necrosis syndrome and HLA-DQw7 and phenotype Bw62, DR4. Am. J. Oph­ thalmol. 108:370, 1989. 26. Zaltas, N. M., Ahmed, R., and Foster, C. S.: Association of HLA-DR4 with ocular cicatricial pemphigoid. Curr. Eye Res. 8:189, 1989. 27. Wakefield, D., Lane, J., and Penny, R.: Retinal vasculitis associated with HLA-DR4. Brief definitive report. Hum. Immunol. 14:11, 1985. 28. Thomson, G., Robinson, W. P., Kuhner, M. K., Joe, S., Macdonald, M. J., Gottschall, J. L., Barbosa, J., Rich, S. S., Bertrams, J., Baur, M. P., Partanen, J., Tait, B. D., Schober, E., Mayr, W. R., Ludvigsson, J., Lindblom, B., Farid, N. R., Thompson, C , and Deschamps, I.: Genetic heterogeneity, modes of in­ heritance, and risk estimates for a joint study of Caucasians with insulin-dependent diabetes mellitus. Am. J. Hum. Genet. 43:799, 1988. 29. MacLaren, N., Riley, W., Skordis, N., Atkin­ son, M., Spillar, R., Silverstein, J., Klein, R., and Rotter, J.: Inherited susceptibility to insulin depen­ dent diabetes is associated with HLA-DR1, while DR5 is protective. Autoimmunity 1:197, 1988. 30. Nepom, G. T.: A unified hypothesis for the complex genetics of HLA associations with IDDM. Diabetes 39:1153, 1990. 31. Rothova, A., Van Veenedaal, W. G., Linssen, A., Glasius, E., Kijlstra, A., and Dejong, P. T. V. M.: Clinical features of acute anterior uveitis. Am. J. Ophthalmol. 103:137, 1987. 32. Rothova, A., Kijlstra, A., Buitenhuis, J., Van Der Gaag, G., and Feltkamp, T. E. W.: HLA-B27 associated uveitis. A distinct clinical entity? In Saari, K. M. (ed.): Uveitis Update. New York, Elsevier Sci­ ence Publishers, 1984, pp. 91-95. 33. Zhang, X. Y., Hu, T. S., and Wang, X. M.: Acute anterior uveitis and HLA. Chin. J. Ophthalmol. 26:2, 1990. 34. Takano, M., Miyajima, T., Kiuchi, M., Ohmori, K., Amemiya, H., Yokoyama, T., Hashizume, H., Iwasaki, Y., Okamoto, S., and Sato, H.: Behcet's disease and the HLA system. Tissue Antigens 8:95, 1976. 35. Lehner, T., and Batchelor, J. R.: Classification and immunogenetic basis of Behcet's syndrome. In Lehner, T., and Barnes, C. G.(eds.): Behcet's Syn­ drome. Clinical and Immunological Features. New York, Academic Press, 1979, pp. 13-32. 36. Dunston, G. M., and Haider, R. M.: Vitiligo is associated with HLA-DR4 in black patients. A pre­ liminary report. Arch. Dermatol. 126:56, 1990. 37. Foley, L. M., Lowe, N. J., Misheloff, E., and Tiwari, J. L.: Association of HLA-DR4 with vitiligo. J. Am. Acad. Dermatol. 81:39, 1983.