(Stroke. 1995;26:415-417.)
© 1995 American Heart Association, Inc.
Articles |
Human Leukocyte Antigen in Patients With Moyamoya Disease
From the Department of Neurosurgery, Tokyo Medical and Dental University, Bunkyo-ku (M.A., Y.M.), and the Department of Cell Biology, Tokyo Metropolitan Institute of Gerontology, Itabashi-ku (M.A., K.O., M.S., M.Y., K.Y.), Tokyo, Japan.
Correspondence to Masaru Aoyagi, MD, Department of Neurosurgery, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113, Japan.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Background and Purpose Progressive stenosis or occlusion of bilateral internal carotid arteries by fibrocellular intimal thickening results in cerebral ischemia in moyamoya disease. In an attempt to elucidate the still-unknown etiologic factors in moyamoya disease, we assessed human leukocyte antigens in patients with this disease.
Methods We investigated 32 unrelated Japanese patients with moyamoya disease for typing of human leukocyte antigen A, B, C, and DR/DQ and compared the results with those from 178 unrelated control subjects.
Results We found a significant association of human leukocyte
antigen B51 with moyamoya disease (corrected P<.05,
2 test). Although no significant associations
were observed in DR/DQ typing, the frequency of the B51-DR4 combination
was significantly higher in moyamoya patients than in control subjects
(P<.002, Fisher's exact test).
Conclusions These findings suggest that there may be a genetic predisposition for moyamoya disease and that host factors may play a role in the development of intimal thickening in early childhood.
Key Words: cerebrovascular disease • leukocytes • moyamoya disease
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Moyamoya disease is an unusual form of chronic cerebrovascular occlusive disease characterized by progressive stenosis or occlusion at the distal ends of the bilateral internal carotid arteries.1 2 An unusual vascular network at the base of the brain (moyamoya vessels) is considered to represent the secondary collateral system formed as a result of progressive ischemic changes in the brain.3 The incidence of the disease is highest during the first decade of life, and the second and lower peak occurs in the third decade.4 Histopathologic investigations5 6 have shown that the main vascular lesions are stenosis or occlusion with fibrocellular thickening of the intima. Arteries outside the brain occasionally show similar stenosis with thickened intima.7
The etiology of moyamoya disease is still unknown. The findings that the incidence of the disease is highest in but not confined to Japanese persons8 and that the condition is frequently familial9 have suggested the possibility of a genetic factor in its pathogenesis.
It has been shown that the genetic inheritance and expression of certain major histocompatibility class I or II antigens place an individual at increased risk of various diseases.10 Kitahara et al11 investigated the human leukocyte antigens (HLA) A, B, and C in 18 patients with moyamoya disease and showed significant associations between the disease and Aw24, Bw46, and Bw54 antigens. In the present study, we further investigated HLA class I and class II in 32 unrelated Japanese patients with moyamoya disease.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Thirty-two unrelated Japanese patients with moyamoya disease were selected for HLA-A, HLA-B, HLA-C, and HLA-DR typing; 29 of these patients underwent HLA-DQ typing. Moyamoya disease was confirmed by cerebral angiography, which showed bilateral stenosis or occlusion of the distal portions of the internal carotid arteries and moyamoya vessels near the circle of Willis. Patients comprised 26 females and 6 males. The mean age of the patients was 20.7±9.7 (mean±SD) years, ranging from 1 to 49 years. Indirect arterial bypass surgery (encephalo-duro-arteriosynangiosis12 ) was performed in all patients. The control group comprised 178 unrelated Japanese subjects who underwent HLA-A, HLA-B, HLA-C, and HLA-DR typing and 54 who underwent HLA-DQ typing. None of the subjects had a history of cerebrovascular diseases. Informed consent was obtained from the patients or their relatives, and the study was approved by the ethical committee of the Tokyo Metropolitan Institute of Gerontology.
Lymphocytes were isolated from heparinized peripheral blood by Ficoll-Hypaque centrifugation. B and T cells were further separated by passage over nylon-wool columns. HLA typing was performed by a standard microlymphocytotoxicity assay using the HLA-ABC plate (HS 72, Hoechst) and Terasaki DR tray (DR 60 II, One Lamda).
Fisher's exact and 2 tests were used to compare
HLA frequencies between patients and control subjects. The
probabilities were further corrected by multiplying the numbers of
types tested (10 for HLA-A, 18 for HLA-B, 6 for HLA-C, 14 for HLA-DR,
and 4 for HLA-DQ). Relative risks were calculated by the method of
Woolf.13
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Clinical information, including age at onset and clinical symptoms, is shown in Table 1
. The mean age of patients
at onset of moyamoya disease was 10.5±10.4 (mean±SD) years. In 27
(84%) patients the onset of disease occurred before the age of 20
years (childhood moyamoya) and in 5 patients after the age of 20 (adult
moyamoya). Twenty-four of the childhood moyamoya patients showed
symptoms due to cerebral ischemia, and the other 3 patients showed
convulsions. Two adult moyamoya patients showed cerebral hemorrhage,
and the other 3 showed cerebral ischemia.
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The frequency distributions of the different HLA antigens are listed in
Tables 2 and 3. The frequencies of
HLA-B51, HLA-B67, and HLA-DR1 were significantly higher in patients
with moyamoya disease than in control subjects (P<.002,
P<.01, and P<.05, respectively), and that of
Cw1 was significantly lower in moyamoya patients than in control
subjects (P<.05). The association of HLA with moyamoya
disease was significant only in HLA-B51 by using corrected probability
values (P<.05). The relative risk of HLA-B51 was 3.7. The
frequencies of Aw24, Bw46, and Bw54, which previously had been shown to
be significantly higher in moyamoya patients than in control
subjects,12 did not differ between moyamoya patients and
control subjects. Further analysis among different subgroups of
moyamoya patients showed that the variables of sex, age at onset, and
clinical features (seizures, cerebral ischemia, or intracranial
hemorrhage) were not significantly associated with HLA-B51.
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No significant associations were observed between HLA-DR and HLA-DQ.
However, 85% of moyamoya patients who had the B51 antigen were
heterozygous for HLA-DR4. The frequency of DR4 in B51-positive subjects
was significantly higher in moyamoya patients than in control subjects
(P<.002), suggesting linkage disequilibrium between the two
loci in the patients (Table 4).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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It is of interest that we observed a significant association between moyamoya disease and the phenotype HLA-B51. HLA-B51 is believed to be an immunogenetic marker for a subgroup of Behçet's disease14 15 and has also been associated with Kawasaki disease in certain populations.16 17 Recently, idiopathic childhood stroke has also been shown to be associated with HLA-B51.18 Behçet's disease is known to cause systemic inflammatory vasculitis primarily involving the skin and eyes, but it may include other organs including the brain, leading to strokelike symptoms.14 15 Kawasaki disease can manifest itself as severe vasculitis, especially involving the coronary arteries.17 Idiopathic childhood stroke has been suggested to occur because of isolated central nervous system vasculitis19 that is possibly of a transient nature.
The frequent involvement of arteries outside the brain in moyamoya disease has suggested systemic etiologic factors in its pathogenesis.7 Frequent incidence of preceding infections has been shown in moyamoya disease,4 although no apparent evidence of vasculitis has been observed in histological examinations.5 The phenotype HLA-B5 (B51 and B52) has been found to be associated with a high response of streptococcal nucleases.20 A recent investigation18 showed that activation of neutrophil functions in Behçet's patients was associated with HLA-B51. Masuda et al21 recently have shown that macrophages and T lymphocytes colocalize in the superficial layer of the intimal thickening in moyamoya disease, suggesting a role of chronic inflammatory stimuli in the smooth muscle cell proliferation of the intima. It is possible that patients who have B51 antigens are susceptible to a certain form of vasculitis, which may lead to the development of intimal thickening in moyamoya disease.
The reason for the discrepancy between our results and those of the previous study11 is not clear. However, the association was not significant when the results of the previous study were evaluated using corrected probability values.
The correlation of the high frequency of the B51-DR4 combination with the development of intimal thickening in moyamoya disease is not known at present. Studies of larger populations are necessary to confirm the association of the B51-DR4 combination with moyamoya disease.
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Acknowledgments |
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This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, and Culture, Japan.
Received November 8, 1994; revision received December 19, 1994; accepted December 19, 1994.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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1. Kudo T. Spontaneous occlusion of the circle of Willis: a disease apparently confined to Japanese. Neurology. 1968;20:485-496.
2. Nishimoto A, Takeuchi S. Abnormal cerebrovascular network related to the internal carotid arteries. J Neurosurg. 1968;29: 255-260.
3.
Suzuki J, Takaku A. Cerebrovascular "moyamoya"
disease:
disease showing abnormal net-like vessels in base of brain. Arch
Neurol. 1969;20:288-299.
4.
Suzuki J, Kodama N. Moyamoya disease: a review.
Stroke. 1983;14:104-109.
5. Hosoda Y. Pathology of so-called "spontaneous occlusion of the circle of Willis." Pathol Annu. 1984;19:221-244.
6.
Yamashita M, Oka K, Tanaka K. Histopathology of the brain
vascular network in moyamoya disease. Stroke. 1983;14:50-58.
7.
Ikeda E. Systemic vascular changes in spontaneous occlusion
of the circle of Willis. Stroke. 1991;22:1358-1362.
8. Goto Y, Yonekawa Y. Worldwide distribution of moyamoya disease. Neurol Med Chir. 1992;32:883-886.
9.
Kitahara T, Ariga N, Yamaura A, Makino H, Maki Y. Familial
occurrence of moyamoya disease: report of three Japanese families.
J Neurol Neurosurg Psychiatry. 1979;42:208-214.
10. Tiwari JL, Terasaki PI. Overview. In: Tiwari JL, Terasaki PI, eds. HLA and Disease Association. New York, NY: Springer-Verlag; 1985:33-48.
11.
Kitahara T, Okumura K, Semba A, Yamaura A, Makino H. Genetic
and immunologic analysis on moya-moya. J Neurol Neurosurg
Psychiatry. 1982;45:1048-1052.
12. Matsushima Y, Fukai N, Tanaka K, Tsuruoka S, Inaba Y, Aoyagi M, Ohno K. A new surgical treatment of moyamoya disease in children: a preliminary report. Surg Neurol. 1981;15:313-320. [Medline] [Order article via Infotrieve]
13. Woolf B. On estimating the relation between blood group and disease. Ann Hum Genet. 1955;19:251-253. [Medline] [Order article via Infotrieve]
14. Ohno S, Asanuma T, Sugiura S, Wakisaka A, Aizawa M. HLA-BW51 and Behçet's disease. JAMA. 1978;240:529. Letter.
15. Chajek-Shaul T, Pisantry S, Knobler H, Matzner Y, Glick M, Ron N, Rosenman E, Brautbar C. HLA-B51 may serve as an immunogenetic marker for a subgroup of patients with Behçet's syndrome. Am J Med. 1987;83:666-672. [Medline] [Order article via Infotrieve]
16. Krensky AM, Grady S, Shanley KM, Berenberg W, Yunis EJ. Epidemic and endemic HLA-B and DR associations in mucocutaneous lymph node syndrome. Hum Immunol. 1983;6:75-77. [Medline] [Order article via Infotrieve]
17.
Krensky AM, Berenberg W, Shanley K, Yunis EJ. HLA antigens in
mucocutaneous lymph node syndrome in New England.
Pediatrics. 1981;67:741-743.
18. Mintz M, Epstein LG, Koenigsberger RM. Idiopathic childhood stroke is associated with human leukocyte antigen (HLA)-B51. Ann Neurol. 1992;31:675-677. [Medline] [Order article via Infotrieve]
19.
Dusser A, Goutieres F, Aicardi J. Ischemic strokes in
children. J Child Neurol. 1986;1:131-136.
20.
Greenberg LJ, Gray ED, Yunis EJ. Association of HLA-5 and
immune responsiveness in vitro to streptococcal antigens. J Exp
Med. 1975;141:935-943.
21.
Masuda J, Ogata J, Yutani C. Smooth muscle cell proliferation
and localization of macrophages and T cells in the occlusive
intracranial major arteries in moyamoya disease. Stroke. 1993;24:1960-1967.
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