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The HLA—B8 antigen is one of the characteristic antigens associated with organ specific autoimmune diseases among Caucasians. Among the Japanese, HLA—B8 positives have been assumed to be extremely rare. By using some HLA-B8 typing sera, a new HLA-B antigen, HLA-Bw4 positive, was found in the Japanese. This new HLA-B antigen, tentatively called HOK-1, showed a phenotype frequency of 3.7% and a gene frequency of 1.9 ± 0.6%. This antigen has a strong linkage disequilibrium with HLA-Cw1 among the Japanese.

To elucidate the immunogenetic background of idiopathic inflammatory myopathies (IIM) such as polymyositis (PM), dermatomyositis (DM) and any overlapping subsets, with other collagen vascular diseases, HLA class I antigens and class II alleles were determined and compared from individuals with various clinical and serological features of IIM, including pulmonary interstitial lesions (PI). Seventy-three Japanese patients with myositis (32PM, 18DM, 23 overlapped subsets) and 62 healthy unrelated controls were enrolled onto the study. Statistical differences between groups were determined by the Fisher's exact probability test. Serum fluorescent antinuclear antibody, rheumatoid factor (RF), anti-SS-A/Ro antibody, anti-Jol antibody and anti-Ul RNP antibody were examined using routine methods. PI was detected by chest X-ray and/or computed tomography. In patients with DM, the frequency of the HLA-DRB1 * 1302-DQA1 * 0102-DQB1 * 0604 haplotype was significantly higher than in the healthy controls (42.1% vs 17.7%), and in the patients with PM (42.1% vs 9.4%). Furthermore, the frequency of the HLA-DRB1 * 0405-DQA1 * 03-DQB1 * 0401 haplotype was higher in the PM patients with PI than in the controls (50.0% vs 17.7%), and PM without PI (50.0% vs 5.5%). These results suggest that in terms of HLA class II association, Japanese DM and PM, and PM with and without PI, belong to different clinical groups.

A 29-year-old female with systemic lupus erythematosus who developed accerelated hypertension, motor paralytic bladder and various other neurological abnormalities is described. Cystometry demonstrated flaccid atonic neuropathic bladder. Elevated protein level and albuminocytologic dissociation were recognized in her cerebral spinal fluid. Magnetic resonance imaging study detected high signal intensities in themedulla oblongata andcauda equina. Her clinical symptoms and laboratory abnormalities were resolved after two courses of methyl-prednisolone pulse therapy. Possible roles of antiphospholipid antibodies were considered in the pathogenesis of her neurologic abnormalities.

To elucidate the clinical characteristics and pathogenesis of scleroderma-rheumatoid arthritis (SSc-RA) overlap syndrome, we analyzed the clinical features of 5 patients with SSc-RA overlap. Their HLA phenotypes and genotypes were also determined. Generalized skin sclerosis, severe seropositive polyarthritis, pulmonary fibrosis, anti-topoisomerase I antibodies, and HLA-DR4,53;DQA1*0301;DBQ1*04 haplotype were observed in all of the patients. Similar clinical features were recognized in most of the 10 cases reported previously. Our case studies indicate that SSc-RA overlap may be a distinct entity.

近年,治療抵抗性の特発性血小板減少性紫斑病(ITP)に対し,メチルプレドニゾロン(M-PSL)パルス療法の成績が散発的に報告されている.本療法は小児例では有効とされているが,成人例での有用性は確立していない. 今回,われわれは標準的な副腎皮質ホルモン療法が無効であった成人ITP 4例に対し, M-PSLパルス療法を施行した.その結果, 2例はパルス療法後も長期に寛解あるいは部分寛解を維持し,他の1例では一過性の効果を認めた.残りの1例は, M-PSLパルス療法は無効で,摘脾や免疫抑制剤の投与にも抵抗性を示した.今回の成績は, M-PSLパルス療法が治療抵抗性の成人ITPに対しても有用な治療法の1つになりうることを示唆している.

HLA class II alleles in the DQA1, DQB1, DRB1, and DPB1 genes were investigated in Japanese patients with myasthenia gravis (MG) by digestion of polymerase chain reaction amplified DNAs with allele specific restriction endonucleases (PCR-RFLP). A significantly higher frequency of DQB1*03, which includes *0301, *0302, *0303 and determines the serological DQ3 specificity, was observed in female patients less than 30 years in age at onset of disease compared with healthy controls (90.5 vs. 53.2%). This study also confirms the high incidence of DPB1*0201 in early-onset female patients compared to the controls (85.7 vs. 40.3%). Moreover, 81.0% of the early onset female patients were found to carry both DQB1*03 and DPB1*0201, compared to 17.7% of the controls. Since DQB1*03 and DPB1*0201 are not in linkage disequilibrium, both these alleles are supposed to be synergistically involved in disease development in early-onset female MG. In contrast, no obvious association of HLA-DQA1, DQB1, DRB1 and DPB1 alleles with either late-onset patients or patients with thymoma was observed. Clearly, the genetic background of Japanese females with early onset MG is different from that of other patients with MG.

Genetic polymorphism of the epidermal growth factor (EGF) receptor gene following Taq I digestion was compared between samples of genomic DNA from glioma-derived cell lines and Caucasoid and Japanese subjects. The same three allelic forms of the EGF receptor gene, marked by variant fragments of approximately f 2.8, f 1.6 and f 0.8 kb in size were common to both ethnic groups and the 12.8- and 11.6-kb fragments were found in the glioma-derived cell line DNA. A further variant fragment of approximately 13.8 kb in size has been shown to be thus far restricted to the Japanese. These data suggest that most allelic forms of the EGF receptor gene recognized by Taq I restriction fragment length polymorphism have a long evolutionary history and probably do not predispose to development of malignant glioma.

Frequencies of HLA class I and II antigen speificities were determined in Japanese patients with Behcet's disease (BD), and their association with various clinical features or immunogenetic predisposition to this disease were studied. Compared to controls, a significantly high frequency of B 51 and a low frequency of DQw 1 were observed in patients with ocular involvement, especially in those who did not have genital ulcer. In patients without ocular lesions, however, no significant difference of HLA antigen frequency was observed compared to the control group. The positive association of B 51 and the negative one of DQw1 were also observed in male patients but not in female patients. When patients were further subdivided into 2 groups according to the age of onset, Dr1 was found to be significantly Frequent in patients with early-onset compared to those with late-onset or controls.These results suggest that BD is genetically complicated disease and the susceptibility genes in the HLA region are different among male and female patients, among patients with or without ocular lesions, or those with early or late-onset.

Sulphasalazine (SASP)による慢性関節リウマチの長期的治療成績をauranofin (AF)と比較検討した.短期的(3～6カ月)にはSASP群41例中8例が副作用のため脱落し,残る33例では79%が有効, 21%が無効と判定された. AF群39例では6例が副作用のため脱落し,残る33例のうち58%が有効, 42%が無効であったが両群間の有効率には差を認めなかった.しかし, SASPはAFと比べて疾患活動性,リウマトイド因子などを早期に改善した.さらに,両薬剤の治療継続率をKaplan-Meier法で検討した. AF群よりSASP群では治療開始9～18カ月の区間で有意に継続率は高値であったが,その後は両群とも約20%の継続率を示した. AFでは数カ月以後に蛋白尿の出現する症例を認めたのに対し, SASPの副作用は軽症のものが多く,しかも早期に出現した.これらの成績はSASPを遅効性抗リウマチ剤の第1選択薬として用いうる可能性を支持している.

Anticardiolipin antibodies (aCL) were recently discovered to recognize a complex consisting of phospholipids and apolipoprotein H (apo H). In this study, we determined the serum apo H levels in 36 systemic lupus erythematosus (SLE) patients with or without antiphospholipid antibodies (aPL), including aCL and lupus anticoagulants, to clarify the possible effects of aPL on apo H levels in vivo.The apo H levels were low in SLE patients as compared with 22 healthy controls. However, no associations were found between apo H levels and circulating aPL or clinical features of the antiphospholipid antibody syndrome. A secondary hyperlipidemic state, which probably related to lupus nephritis (proteinuria) and/or prednisolone treatment, increased apo H levels in SLE patients.

Human leukocyte phenotypes and genes in the HLA class II regions were studied in 46 Japanese patients with myasthenia gravis. When the HLA phenotypes of the patients with myasthenia gravis were compared with the controls, an increased frequency of HLA-DRw53 was observed in females less than 30 years of age. The genomic DNAs of the HLA-DRw53-positive patients and DRw53-positive controls were analyzed by using four complementary DNA probes for HLA class II genes. With DQB complementary DNA as the probe, a higher incidence of the 6.5-kb or 8.2-kb BamHI fragment was observed in the patients (76.0%) compared with the controls (19.0%). In contrast, no significant difference was observed between patients and controls when complementary DNAs for DRB, DQA, and DPB were used as probes. These results indicate that the genetic background of Japanese females with early-onset myasthenia gravis is different from other patients with myasthenia gravis, and that DQB genes can greatly influence the onset of myasthenia gravis.

We studied allotypes of the fourth component of complement (C4) and factor B in 76 patients with Sjogren's syndrome (SS) and in 63 normal subjects. C4A-null (C4AQ0) was found in 10 of 28 patients who had primary SS, compared with 1 of 63 control subjects (P less than 0.005). In contrast, no significant difference in the frequency of any C4 allotype was observed between patients with secondary SS and control subjects. An association of HLA-DRw53 with primary SS in Japanese patients has been reported. Since there is no linkage disequilibrium between DRw53 and C4AQ0, it is possible that at least 2 genes in the major histocompatibility complex may determine susceptibility to the development of primary SS in the Japanese population.

We investigated the HLA-DPB1 allele in 43 unrelated Japanese patients with myasthenia gravis (MG) using digestion of polymerase chain reaction (PCR)-amplified DNA with allele-specific restriction endonucleases (PCR-RFLP method). We found a higher frequency of the DPB1*0201 allele in female patients whose ages at onset were less than 30 years (83.3%) than in controls (35.6%). The study also included serologic typing of HLA-A, -B, -C, and -DR antigens in 72 patients with MG, and confirmed previous results demonstrating a strong association of HLA-DR53 with early onset of MG in females. These results indicate that both the DPB1*0201 allele and DR53 play key roles in the disease process of MG in early-onset females, and that the genetic background of Japanese females with early-onset MG is different from that of other patients with MG.

Possible association between HLA antigens and antibody response to rubella vaccine was examined in 71 seronegative adult females, aged from 18 to 23, immunized with QEF vaccine. High responders (HAI antibody titer greater than or equal to 1:32) with HLA-B15 were significantly higher in frequency than those without HLA-B15 (p < 0.05). On the other hand, subjects with HLA-A9 had a tendency toward low immune responsiveness, including all the three non-responders. These results suggest that the antibody response to rubella vaccine may be influenced by the host-genetic factors relating to HLA antigens.

The etiologic role of the thymus and thymoma in myasthenia gravis (MG) is still obscure. In this report, we presented a MG patient affected with thymoma whose myasthenic symptoms had disappeared after the surgical removal of thymoma together with non-thymomatous thymus. The patient had been continuously in remission when the thymoma recurred 6 years after.We have speculated that there is a possibility that either the thymomatous or non-thymomatous thymus can have an effect positively or negatively on the development of myasthenic symptoms.

The HLA-A, B, DR and MB antigens were investigated in patients suffering from Takayasu disease (Aortitis syndrome). Out of twenty-one HLA-A and B antigens tested, only HLA-Bw92 was significantly deviated (30/47, PF = 63.8%, RR = 7.8) from the controls (14/76, PF = 18.4%). Since in the Japanese, HLA-Bw52 is in positive linkase disequilibria with HLA-DR2 and MB1, the association of the DR2 and MB1 antigens with Takayasu disease was studied. The HLA-DR2 antigen was significantly increased (23/30, PF = 76.7%, RR = 6.0) in patients compared with the controls (18/51, PF = 35.3%). Moreover, an almost perfect association of MB1 (29/30, PF = 96.7%, RR = 12.6) with Takayasu disease was demonstrated. This finding supports the hypothesis that the genes in the HLA-D region play a major role in determining the susceptibility to Takayasu disease.

Antigenic determinants recognizable by human antisera (Hon 7 and 2075abs sera) were found in a partially purified antigen preparation obtained from an HLA-D and -DR homozygous cell line (EBV-Wa). Sequential coprecipition tests showed that two determinants detectable with Hon 7 and 2075abs sera (Hon 7 and 2075abs determinants) were present on different molecules. These two antigenic determinants were shown to be allotypic and were expressed predominantly in the B-cell-rich fraction. Family studies showed that both antigenic determinants segregated concordantly with respectiveHLA haplotypes. In the population study, the 2075abs and Hon 7 determinants were shown to be in strong linkage disequilibrium and the 2075abs determinant perfectly correlated with the HLA-DRw4 specificity. The results indicate that the Hon 7 determinant is coded for by a gene distinct from alleles at theHLA-DR locus. Furthermore, the locus (Hon 7) coding for the Hon 7 determinant is suggested to be very closely linked with theHLA-DR locus.

The authors report an autopsied case of systemic lupus erythematosus (SLE) with pulmonary hypertension. The patient was a forty-five-year-old female who had been troubled by obstinate Raynaud's phenomenon for ten years before the definite diagnosis of pulmonary hypertension was made. Microscopic examina tion of the pulmonary vasculature yielded findings consistent with plexogenic pulmonary arteriopathy. However, the deposition of immune complexes in the pulmonary vascular endothelium was not detected by enzyme antibody study. This case suggests, therefore, that "pulmonary Raynaud's phenomenon" is a possible pathogenesis of pulmonary hypertension in patients with SLE.

Twenty-three unrelated Japanese patients with asthma who showed a high total serum IgE level, a strong skin test response to Dermatophagoides farinae, and a high score on a radioallergosorbent test (RAST) using Dermatophagoides farinae were typed for HLA-A locus, -B locus, and -D region antigens. No significant difference in the frequencies of HLA-A, -B, and -DR antigens were observed between the asthma patients and the healthy controls. A significant difference in the frequency of MB3', however, was found between the asthma patients and the healthy controls (corrected p = 0.04, relative risk = 18.5).

慢性関節リウマチ(RA)では人種を越えてHLA-DR4, DRw 53が有意に相関する.近年, HLAクラスIII領域中の遺伝子が全身性エリテマトーデスをはじめとする種々の自己免疫疾患の発症に関与する可能性が示唆されている.今回私たちは, RA患者のクラスIII領域でコードされているC4A, BおよびProperdin factor B蛋白のアロタイプの頻度を検討した.健常人と比較して, RAとくに男性RA患者では高率にC4B5を有していた.しかし日本人ではC4B5, DR4, DRw53の遺伝子間に強い連鎖不平衡が存在すること,他人種ではRA患者のC4B5陽性頻度が増加していないことなどから考えて,今回認められたC4B5とRAの相関は2次的なものと考えられた.さらに, C4と21-hydroxylase遺伝子をプローブとし, BamHI, TaqI, HindIII, KpnIを用いたrestriction fragment polymorphismによりクラスIII領域の遺伝子構築を検討した. C4遺伝子をプローブとしHindIIIを用いたときには, C4B5陽性者のみにHindIIIの6.0kbと10kbのバンドが認められた.しかもRA患者ではTaqIでは6.0kbを欠く症例が多かった.しかしながら, RA患者のみに特異的なバンドは見いだせなかった.

To study the gene products of the HLA complex, we produced two monoclonal antibodies, termed HU-18 and HU-23. They were active in complement-dependent cytotoxicity and detected B-cell alloantigens encoded by a locus (or loci) linked to HLA. When three types of HLA-DR4 homozygous B-cell lines with different HLA-D specificities were tested for reactivity with HU-18 and HU-23, they displayed distinct reaction patterns depending on the HLA-D specificities they possessed: EBV-Wa (HLA-DYT homozygous), negative for both HU-18 and HU-23; KT2 and KOB (HLA-DKT2 homozygous), positive only for HU-18; and ER (HLA-Dw4 homozygous), positive for both. These differential reaction patterns were further confirmed by testing against a panel of 17 HLA-DR4-positive peripheral blood lymphocytes with known HLA-D specificities. Thus, these monoclonal antibodies allow us to identify HLA-DYT, HLA-DKT2, and HLA-Dw4 solely by serologic methods. This is the first clearcut serologic identification of these three HLA-DR4-associated HLA-D specificities, which have been indistinguishable by conventional serology and identified only by cellular techniques. It is hoped that immunochemical investigations using HU-18 and HU-23 will advance our understanding of the HLA-D region on a molecular level.

We have isolated and sequenced cDNA clones corresponding to the DR beta 1 and DR beta 2 loci from two homozygous B-cell lines typed as DR7 (Burkhart) and DR9 (ISK). These nucleotide sequences were compared to beta 1 and beta 2 chains of other DR haplotypes. The first-domain sequences of beta 2 chains are identical in DR4 and DR7 haplotypes. In addition, there is strong sequence homology within the 3' untranslated regions of beta 1 genes from DR4, -7, and -9 haplotypes, thus confirming the close evolutionary relationship among these three haplotypes. In contrast, the first-domain sequences of beta 1 molecules from these haplotypes are very different from each other and do not reflect the DR4, -7, -9 family relationship. Two explanations for the differences in degree of diversity between beta 1 and beta 2 chains are suggested. The differences may be a consequence of selection pressures; this implies functional differences for products of the beta 1 and beta 2 loci. Alternatively, closely linked segments of the human class II region may differ in their underlying rates of variation, independent of selection pressures, and this may in part account for the extraordinary diversity found in the beta 1 first domain.

Three families of human Ia molecules, DP, DQ, and DR, have previously been defined. A cDNA clone, pDSH-9.1, encoding the alpha chain of a DQ molecule derived from an HLA-DRw9 homozygous cell line has been isolated and sequenced. Comparison of the nucleotide and predicted protein sequence to those of other DQ alpha subunits reveals that DQ alpha subunits derived from DR4, -7, and -9 cells are very similar to each other but quite different from a DQ alpha subunit derived from a DRw6 cell line. These studies suggest that certain Ia haplotypes have a common evolutionary history. Furthermore, in the context of current serologic and biochemical knowledge, they suggest that the gene encoding the DQ alpha subunit is in strong linkage disequilibrium with the DR locus.

We have analyzed the structures of HLA-DS molecules from DR1, 2, 3, 4, 5, and 7 cell lines by two-dimensional gel electrophoresis and examined the relationship of HLA-DS molecules to those expressing the supertypic specificities MT1, MB3, and MT3. These studies have allowed us to conclude that the HLA-DS locus is as polymorphic as HLA-DR and that the MT1 and MB3 supertypic specificities reside on DS molecules. Furthermore, MT1 molecules from DR1, DR2, and DRw6 cell lines are structurally different as are MB3 molecules from DR4 and DR5 cell lines. In addition, studies using two MT3 specific reagents, a monoclonal antibody, 109d6, and an alloantiserum, Hon, suggest that MT3 is a cross-reactive determinant present on products of two different loci: a DS4 molecule and a DR7-like molecule.

To examine the role of host-dependent factors to natural rubella infection, the positive rates of HAI antibody according to HLA-A and -B antigens were studied in 93 children, aged 9 to 10, who were exposed only to a recent epidemic (single-exposure group), and in 199 adult females, aged 18 to 23, who were exposed also to a former epidemic (dual-exposure group). Furthermore, the phenotype frequencies of HLA antigens were investigated in seronegative subjects in both groups, as well as in 58 adult female vac-cinees, in comparison with those of the Japanese population. The seropositive rates by the HLA antigens, 38.7% and 73.4%, respectively, in each exposure group were found in subjects having some HLA antigens. Several of these candidate HLA antigens varied in phenotype frequencies in seronegative subjects of all three groups from those of the average Japanese. Although a few types were statistically significant, no contradictory findings in susceptibility were obtained among the groups during the study, which suggested strongly that subjects with HLA-Bw51 and -Bw16 are susceptible to rubella infection, and subjects with HLA-Aw33 are less susceptible. In addition, when the seropositive rates were compared in all combinations of HLA-A and -B antigens classified according to expected susceptibility, the positive rates were arranged in order of susceptibility with significant statistical differences in several groups.

Japanese patients with primary Sjogren's syndrome (SS), patients with SS and rheumatoid arthritis (SS-RA), and patients with SS and connective tissue disease without RA (nonrheumatoid connective tissue disease [SS-CTD]) were typed for HLA antigens. Patients with primary SS and those with SS-RA had higher frequencies of DRw53 than did those who had SS-CTD; however, the group with SS-CTD showed a negative correlation with DRw52. These data indicate that Japanese and white patients with SS have different HLA specificities, and that genetic factors involved in the development of SS-CTD might be different from those in primary SS and SS-RA.

Sixty-four Japanese insulin dependent juvenile onset diabetes mellitus (JOD) were studied in relation to HLA-A, B, and DR. Significant deviations were observed. HLA-Bw54 was increased ( PF = 49.2%, RR = 6.4) and HLA-B5 was decreased ( PF = 7.9%, RR = 0.19). Using radioimmunoassay, two HLA-DR antigens were investigated. Hon 7 antigen, so-called MT3 (W1A4x7), which has linkage disequilibrium between HLA-Bw54, is highly associated ( PF = 96.9%, RR = 27.8) with JOD found in the Japanese.