Brain, Vol. 122, No. 9, 1689-1696,
September 1999
© 1999 Oxford University Press
HLA-DPB1*0501-associated opticospinal multiple sclerosis
Clinical, neuroimaging and immunogenetic studies
1 Department of Neurology, Neurological Institute and 2 Department of Radiology, Graduate School of Medical Sciences, Kyushu University and 3 Division of Immunogenetics, Department of Neuroscience and Immunology, Kumamoto University Graduate School of Medical Sciences, Japan
Correspondence to:
Dr J. Kira, Department of Neurology, Neurological Institute, Faculty of Medicine, Kyushu University, Fukuoka 812–8582, Japan E-mail: kira{at}neuro.med.kyushu-u.ac.jp
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Abstract |
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In order to clarify the relationship between the clinical phenotype and the human leucocyte antigen (HLA) in multiple sclerosis in Asians, 93 Japanese patients with clinically definite multiple sclerosis underwent clinical MRI and HLA-DPB1 gene typing studies. According to a neurological examination, 29 patients were classified as opticospinal multiple sclerosis, 17 as spinal multiple sclerosis and 47 as Western type multiple sclerosis showing the involvement of multiple sites in the CNS including either the cerebrum, cerebellum or brainstem. The opticospinal multiple sclerosis showed a significantly higher age of onset, higher expanded disability status scale scores and higher CSF cell counts and protein content than the Western type multiple sclerosis. On brain and spinal cord MRI, the opticospinal multiple sclerosis showed a significantly lower number of brain lesions, but a higher frequency of gadolinium-enhancement of the optic nerve and a higher frequency of spinal cord atrophy than in Western type multiple sclerosis. The frequency of the HLA-DPB1*0501 allele was found to be significantly greater in opticospinal multiple sclerosis (93%) than in healthy controls (63%, corrected P value = 0.0091 and relative risk = 7.9), but not in Western type multiple sclerosis (66%) or spinal multiple sclerosis (82%). The marked differences in the clinical and MRI findings as well as in the immunogenetic backgrounds between the opticospinal multiple sclerosis and Western-type multiple sclerosis together suggest that HLA-DPB1*0501-associated opticospinal multiple sclerosis is a distinct subtype of multiple sclerosis.
multiple sclerosis; human leucocyte antigen; MRI; Asians
EDSS = expanded disability status scale; HLA = human leucocyte antigen; OB = oligoclonal bands; RR = relative risk
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Introduction |
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Multiple sclerosis is considered to be heterogeneous aetiologically as well as clinically. Susceptibility to multiple sclerosis in Caucasians has repeatedly been shown to be associated with HLA-DRB1*1501-DQA1*0102-DQB1* 0602 (Olerup and Hillert, 1991
; Spurkland et al., 1991), whereas multiple sclerosis in Asians showed no such association with any HLA class II molecules as a whole group. Multiple sclerosis in Asians is well known to show a selective and severe involvement of the optic nerves and spinal cord (Shibasaki et al., 1981). In Japanese, we previously reported the existence of two subtypes of multiple sclerosis, namely, Asian type multiple sclerosis, in which the clinically estimated main lesions are confined to the optic nerves and spinal cord, and Western type multiple sclerosis showing disseminated lesions in the CNS including the cerebrum, cerebellum and brainstem (Kira et al., 1996). We found a significant association of the HLA-DRB1*1501 allele only in Western type multiple sclerosis and a lack of any such association with the allele in Asian type multiple sclerosis (Kira et al., 1996; Ono et al., 1999). We preliminarily reported a significant association of susceptibility to Asian-type multiple sclerosis only with the HLA-DPB1*0501 allele among the HLA-A, B, C, DR, DQ and DP antigens and genes examined (Ito et al., 1998). In this study, we grouped together both the opticospinal form and spinal form as Asian type multiple sclerosis and performed HLA studies. Also, in order to clarify precisely the relationship between the clinical phenotype and the HLA association in Japanese patients with multiple sclerosis, we separately analysed opticospinal multiple sclerosis, spinal multiple sclerosis and Western type multiple sclerosis by means of neurological, MRI and immunogenetical examinations. Since the prevalence rate of multiple sclerosis in Asians is extremely low (Kuroiwa et al., 1975), it is hard to collect a sufficient number of well-characterized multiple sclerosis patients for such studies. Therefore, our present study represents the largest combined clinical, neuroimaging and immunogenetic study on multiple sclerosis in Asians. We found distinctive clinical features and HLA genotypes in each multiple sclerosis subtype. |
Material and method |
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Patients
According to the criteria of Poser and colleagues (Poser et al., 1983
), 93 consecutive and unrelated patients, 31 males and 62 females, were diagnosed as having clinically definite multiple sclerosis and subjected to brain MRI at the multiple sclerosis clinic in Kyushu University Hospital between 1987 and 1998. All patients showed a relapsing–remitting or relapsing–progressive course. All patients were subjected to a thorough neurological examination and routine laboratory tests. All of them were followed and evaluated clinically by one of the authors (J.K.) between 1987 and 1998 in our clinic. All available medical records were analysed retrospectively for the present study. All patients were residents of Kyushu island, the southernmost part of mainland Japan. None of the patients enrolled in the present study were seropositive for human T-cell leukaemia virus type I. All patients with neuromyelitis optica without any subsequent relapses were excluded to avoid any contamination of those with acute disseminated encephalomyelitis. The patients whose clinically estimated main lesions were both in the optic nerve and spinal cord (opticospinal form), and those who showed spinal cord involvement at different levels and different time (spinal form) were classified as having Asian type multiple sclerosis. All patients with spinal form had cervical and thoracic cord involvement at different times. Such patients had no clinical evidence of disease in either the cerebrum or cerebellum, although those with minor brainstem signs in addition to moderate to severe opticospinal or spinal involvement [brainstem function score 1 in Kurtzke's Functional Systems (Kurtzke, 1983)], such as mild gaze-evoked nystagmus or transient double vision on lateral gaze, were included. The rest of the multiple sclerosis patients, who showed an involvement of multiple sites in the CNS including either the cerebrum, cerebellum or brainstem, were classified as having Western type multiple sclerosis. The diagnosis of the different forms of multiple sclerosis was made before the HLA study, and thereafter the diagnosis remained unchanged throughout the study. In the present study, 47 were classified clinically as having Western type multiple sclerosis, while 46 patients were classified as having Asian type multiple sclerosis. The disability status of the patients was scored by one of the authors (J.K.) throughout the study according to Kurtzke's Expanded Disability Status Scale (EDSS) (Kurtzke, 1983).
MRI
All MRI studies were performed on a high-field-strength (1.5 T) superconducting General Electric Signa MRI system, as described previously (Kira et al., 1996). For the brain MRI, both the T2-weighted spin-echo (SE) images [2000-ms repetition time and 80-ms echo time (SE 2000/80)] and intermediate-weighted images (SE 2000/20 or 30) were obtained simultaneously in the axial plane. T1-weighted images (SE 400/20 or 600/25) were also obtained for most subjects. For the contrast-enhanced study, MRI was initiated 2–3 min after the intravenous administration of gadolinium–pentetic acid (0.1 mmol/kg), using the T1-weighted sequences on the sagittal and axial plane. Lesions larger than 1 mm in diameter on a 7.5 x 7.5 cm photocopy were considered abnormal, and the abnormal lesions larger than 5 x 3 mm were considered to be large confluent lesions and the rest to be small lesions. For spinal cord MRI, T2-weighted (SE 2000 or 3000/80 or 102) as well as T1-weighted (SE 400 or 500/16 or 20) images were obtained in the sagittal and axial planes. A contrast-enhanced study was also done using the T1-weighted sequences. Spinal cord MRIs were evaluated independently by two examiners (one of the two was an experienced neuroradiologist who was not informed of the diagnoses) and only definite changes were counted. The length of abnormal segments was expressed as a percentage of vertebral length.
HLA-DPB1 typing
Since we recently found a significant association between the HLA-DPB1*0501 allele and susceptibility to the Asian type multiple sclerosis (Ito et al., 1998), we compared the frequency of each HLA-DPB1 allele in patients with opticospinal multiple sclerosis, spinal multiple sclerosis and Western type multiple sclerosis as well as in 92 healthy controls. The HLA-DPB1 alleles were determined at the DNA level by hybridization between the HLA-DPB1 gene amplified by a polymerase chain reaction and sequence-specific oligonucleotide probes, as described elsewhere (Kimura and Sasazuki, 1991). The nomenclature of the HLA alleles followed the World Health Organization Nomenclature Committee for factors regarding the HLA system (Bodmer et al., 1994).
Statistical analysis
The frequencies of the HLA-DPB1 alleles were compared using either the 
2 test or Fisher's exact probability test when the criteria for the 2 test were not fulfilled. The P values (Puncorr) were corrected (Pcorr) by multiplying them by the number of alleles tested (13). The relative risks (RRs) were calculated according to the method of Woolf (Woolf, 1955). The Mann–Whitney U test, the 2 test and Fisher's exact probability test were all used to compare the clinical and MRI data between the multiple sclerosis subtypes. Neurological (J.K.), neuroimaging (I.H. and F.M.), immunogenetical (H.I. and Y.N.) and statistical (K.Y. and others) studies were done independently in the present study.
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Results |
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Clinical findings
The frequency of female patients tended to be higher in opticospinal multiple sclerosis than in Western type multiple sclerosis (P = 0.0697), although the spinal form of multiple sclerosis also showed a similar male to female ratio to that of Western type multiple sclerosis (Table 1
). The age at onset was significantly higher in opticospinal multiple sclerosis and spinal multiple sclerosis than in Western type multiple sclerosis (P = 0.0410 and P = 0.0415, respectively). Although the duration of disease did not differ significantly between Western type multiple sclerosis and opticospinal multiple sclerosis, opticospinal multiple sclerosis had a significantly greater number of exacerbations than Western type multiple sclerosis (P = 0.0494). Spinal multiple sclerosis had a shorter duration of disease and a smaller number of exacerbations than Western type multiple sclerosis (P = 0.0257 and P = 0.0193, respectively). The relapse rate per year was higher in opticospinal and spinal multiple sclerosis than in Western type multiple sclerosis, although the difference did not reach statistical significance. The EDSS score was significantly higher in opticospinal multiple sclerosis than in Western type multiple sclerosis (P = 0.039), whereas it did not differ significantly between spinal multiple sclerosis and Western type multiple sclerosis.
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The cell counts and the total protein content in the CSF were significantly higher in opticospinal multiple sclerosis than in Western type multiple sclerosis (P = 0.0432 and P = 0.0483, respectively). The spinal multiple sclerosis showed a slight but insignificant increase in the cell number in comparison with Western-type multiple sclerosis while the protein amounts were similar for both types. The frequency of an increased IgG index was significantly lower in spinal multiple sclerosis than in Western type multiple sclerosis (P = 0.0008), and the frequency of IgG oligoclonal bands (OB) also tended to be lower in the former than in the latter (P = 0.0841). There was no significant difference in the frequency of either an increased IgG index or OB between opticospinal and Western type multiple sclerosis.
MRI findings
On brain MRIs, both opticospinal multiple sclerosis and spinal multiple sclerosis showed a significantly lower number of large and small lesions on the T2-weighted images than the Western type multiple sclerosis (P = 0.0001 and P = 0.0001 in opticospinal multiple sclerosis, and P = 0.0006 and P = 0.0005, respectively, in spinal multiple sclerosis) (Table 2). Moreover, the frequency of gadolinium-enhancement of the brain lesions was also significantly lower in opticospinal and spinal multiple sclerosis than in Western type multiple sclerosis (P = 0.0008 and P = 0.0012, respectively). In contrast, gadolinium-enhancement of the optic nerves was only seen in opticospinal multiple sclerosis, but not in either Western type or in spinal multiple sclerosis (P = 0.0025, opticospinal multiple sclerosis versus Western type).
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Regarding the spinal cord MRI findings, the frequency of high-signal-intensity lesions on the T2-weighted images was higher in spinal and opticospinal multiple sclerosis than in Western type multiple sclerosis, although the difference did not reach statistical significance. The length of abnormal intensity segments was longer in opticospinal multiple sclerosis than in Western type and spinal multiple sclerosis, although the difference was again not statistically significant. In opticospinal multiple sclerosis, the frequency of spinal cord atrophy was significantly higher (P = 0.0446) and the frequency of gadolinium-enhancement of spinal cord lesions as well as spinal cord swelling tended to be higher than in Western type (P = 0.0564 and P = 0.0808, respectively). Spinal multiple sclerosis showed a twofold to threefold higher frequency of spinal cord swelling, atrophy and cavity formation than Western type multiple sclerosis, although the difference was not statistically significant because of the small number of subjects.
HLA-DPB1 typing
The frequency of subjects with the DPB1*0501 allele was significantly higher in both the opticospinal multiple sclerosis patients and all Asian type multiple sclerosis patients in comparison with the healthy control subjects (Pcorr = 0.0091 and Pcorr = 0.0091; RR = 7.9 and RR = 4.8, respectively), but not in Western type multiple sclerosis and spinal multiple sclerosis (Table 3). The frequency of DPB1*0301 was greater in Western type multiple sclerosis than in the healthy controls (Puncorr = 0.0047), but this difference lost significance after the P value was corrected (Pcorr = 0.0611). None of the other alleles showed any significant differences in either of the multiple sclerosis subtypes in comparison with the healthy controls. When opticospinal and Western type multiple sclerosis were compared, the frequency of DPB1*0501 was significantly higher in opticospinal multiple sclerosis than in Western type multiple sclerosis (Pcorr = 0.0494) while the frequency of DPB1*0301 was significantly lower in the former than in the latter (Pcorr= 0.0312).
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Comparison of clinical and MRI findings between Western type multiple sclerosis and HLA-DPB1*0501-positive opticospinal multiple sclerosis (Table 4
)The DPB1*0501-positive opticospinal multiple sclerosis showed a significantly higher frequency of females, a higher number of exacerbations and higher EDSS scores than did the Western type multiple sclerosis (P = 0.0467, P = 0.0479 and P = 0.0363, respectively). The age of onset and relapse rate per year were also higher in the DPB1*0501-positive opticospinal multiple sclerosis than in Western type multiple sclerosis, although the difference did not reach statistical significance (P = 0.0806 and P = 0.1344, respectively). The DPB1*0501-positive opticospinal multiple sclerosis had a significantly lower number of brain lesions (P = 0.0003 in the case of large lesions and P = 0.0002 in the small lesions) as well as a lower frequency of gadolinium-enhancement of the brain lesions (P = 0.0012) and a higher frequency of optic nerve enhancement (P = 0.0020) than Western type multiple sclerosis. The frequency of spinal cord atrophy was significantly higher in the DPB1*0501-positive opticospinal multiple sclerosis than in Western type multiple sclerosis (P = 0.0426). Moreover, the frequency of spinal cord lesions on MRI was higher and the length of abnormal segments was longer in the DPB1*0501-positive opticospinal multiple sclerosis than in Western type, but the difference was not statistically significant. The CSF cell counts and total protein content were significantly greater in the DPB1*0501-positive opticospinal multiple sclerosis than in the Western type (P = 0.0465 and P = 0.0470, respectively).
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Discussion |
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In the present study we revealed for the first time that a susceptibility to opticospinal multiple sclerosis, but not to either spinal multiple sclerosis or Western type multiple sclerosis, was strongly associated with the HLA-DPB1*0501 allele. In addition, regarding the selective involvement of the optic nerve and spinal cord, HLA-DPB1*0501-associated opticospinal multiple sclerosis showed the following characteristic features in comparison with Western type multiple sclerosis: (i) a higher frequency of female patients; (ii) an older age of onset; (iii) higher number of exacerbations; (iv) higher EDSS scores; (v) a lower number of brain MRI lesions; (vi) a higher frequency of gadolinium-enhancement of the optic nerves; (vii) a higher frequency of abnormal findings on the spinal cord MRI; and (viii) higher cell counts and total protein content in the CSF. The MRI findings corresponded closely to the neurological findings in this subtype of multiple sclerosis. Marked intrathecal inflammatory reactions may well have caused the severe destruction of the optic nerves and spinal cord, thereby contributing to the higher EDSS scores in the DPB1*0501-associated opticospinal multiple sclerosis.
The positive frequency of the HLA-DRB1*1501 allele in the present series was higher in Western type multiple sclerosis than in the controls (33% versus 14%, Puncorr = 0.0106 and RR = 3.0), but not in the other multiple sclerosis subtypes (8% in the DPB1*0501-associated opticospinal multiple sclerosis and 20% in the spinal multiple sclerosis). An association of the HLA-DRB1*1501 allele with Western type multiple sclerosis has recently been confirmed by other groups in Japan (Ma et al., 1998). Since the immunogenetic background as well as the clinical and MRI findings were markedly different between Western type multiple sclerosis and DPB1*0501-associated opticospinal multiple sclerosis, both are likely to be distinct multiple sclerosis subtypes. The strong association of opticospinal multiple sclerosis with the HLA class II allele suggests that this subtype of multiple sclerosis is also an autoimmune disease in which certain CNS antigens are presented by the disease-associated HLA class II molecule.
Regarding HLA-DPB1 alleles, no association with multiple sclerosis has been reported in several studies on Caucasians (Roth et al., 1991; Middleton et al., 1992; Ciusani et al., 1995). However, the reanalysis of five earlier reports on HLA-DPB1 in Caucasian patients with multiple sclerosis by Dekker and colleagues revealed a highly significant increase of HLA-DPw3 (DPB1*0301) in multiple sclerosis, and they also showed that the HLA-DPB1*0301 allele was significantly more frequent in their own Caucasian and Cantonese patients with multiple sclerosis lacking the DQB1*0602 allele compared with the controls (Dekker et al., 1993). The frequency of the HLA-DPB1*0301 allele was also greater in Western type multiple sclerosis compared with the healthy controls in the present study, yet it lost its significance after correction was made. However, since the same association of the allele with multiple sclerosis has been reported in Caucasian and Cantonese multiple sclerosis patients (Dekker et al., 1993), this association in the present series may be significant. In contrast, none of the opticospinal multiple sclerosis patients had the HLA-DPB1*0301 allele in the present study, and therefore, the difference in its frequency was significant between opticospinal and Western type multiple sclerosis even after the correction. The recognition of myelin proteins by T cells during the early stages of epitope spreading in the development of multiple sclerosis has recently been shown to involve HLA-DPB1*0301 restricted responses in Caucasian patients with multiple sclerosis (Yu et al., 1998). Therefore, concerning the HLA-DPB1 molecules, it is possible that a restriction molecule involved in the development of multiple sclerosis is DPB1*0501 in opticospinal multiple sclerosis while it is DPB1*0301 in some patients with Western type multiple sclerosis.
The HLA-DPB1*0501 allele is the most frequent DPB1 allele found in Asians (44.9–73.1% in phenotype frequency), whereas it is rare in Caucasians (2.6–5.3% in phenotype frequency) (Imanishi et al., 1992). This large difference in the phenotype frequency of the allele among ethnic groups may explain the reason why opticospinal multiple sclerosis is common in Asians but not in Caucasians (Kuroiwa et al., 1975; Shibasaki et al., 1981). It is interesting to note that multiphasic Devic's neuromyelitis optica in Western literature also shows similar features to those seen in the present cases of DPB1*0501 associated opticospinal multiple sclerosis, such as marked CSF pleocytosis, few brain MRI lesions but extensive spinal cord lesions on MRI, yet it is extremely rare (Mandler et al., 1993; O'Riordan et al., 1996). We therefore consider that the primary role of HLA-DPB1*0501 in opticospinal multiple sclerosis will be clarified by studying whether or not opticospinal form of multiple sclerosis, including multiphasic Devic's neuromyelitis optica in Caucasians, also shows an association with the HLA-DPB1*0501 allele. The association of disease susceptibility with the distinct HLA class II molecules in opticospinal multiple sclerosis and Western type multiple sclerosis suggests that different CNS antigens may be presented to T cells, thereby producing a marked difference in the distribution of CNS lesions.
The spinal multiple sclerosis in our series showed a very low frequency of either OB or an increased IgG index. OB-negative multiple sclerosis has been reported to have a benign clinical course (Zeman et al., 1996). As a result, spinal multiple sclerosis in our series may represent OB-negative benign multiple sclerosis. Spinal multiple sclerosis in the present study, however, was different from that in Western multiple sclerosis series, since our patients with spinal multiple sclerosis showed a relapsing–remitting course while the spinal form in Western multiple sclerosis series has been reported frequently to show a chronic progressive course from the onset (Poser et al., 1978; Paty et al., 1979), although both showed a higher age at onset (Poser et al., 1978) and few brain MRI lesions (Thompson et al., 1991). It has also been reported that primary progressive multiple sclerosis is different from relapsing–remitting multiple sclerosis in its HLA profiles (Olerup et al., 1991). As primary progressive multiple sclerosis is extremely rare in Asians (Shibasaki et al., 1981), we could not recruit a large enough number of such patients to carry out immunogenetic studies at this time. On the other hand, spinal multiple sclerosis may also be a mixture of `premature' opticospinal multiple sclerosis or Western type multiple sclerosis, because spinal multiple sclerosis showed an intermediate value between Western type multiple sclerosis and opticospinal multiple sclerosis in the frequency of either DPB1*0501 or DRB1*1501 allele, and also because spinal multiple sclerosis in the present series showed a significantly shorter duration of disease than other subtypes of multiple sclerosis. Some patients in the spinal multiple sclerosis group may therefore later show an involvement of either the optic nerve (opticospinal multiple sclerosis) or other CNS sites (Western type multiple sclerosis). A longer observation period as well as the recruitment of patients with primary progressive form of multiple sclerosis are required to clarify whether spinal multiple sclerosis in Asians may be either a distinct subtype or a heterogenous mixture.
In summary, the results of our study strongly suggest that multiple sclerosis in Asians is in most parts an admixture of the HLA-DPB1*0501-associated opticospinal multiple sclerosis and the DRB1*1501-associated Western type multiple sclerosis. Since the frequency of this disease-associated HLA allele is much higher in opticospinal multiple sclerosis (93%) than in Western type multiple sclerosis (33%), and DPB1*0501-associated opticospinal multiple sclerosis showed a restricted distribution of lesions, a search for the responsible autoantigens may therefore be valuable in elucidating the mechanism of opticospinal multiple sclerosis.
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Acknowledgments |
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This work was supported in part by Grants Nos. 10470154, 10557062 and 10877099 from the Ministry of Education, Science, Sports and Culture of Japan, and grants from the Neuroimmunological Disease Research Committee, the Ministry of Health and Welfare of Japan, and from the Japan Multiple Sclerosis Society.
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Received March 19, 1999. Accepted April 15, 1999.
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