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SUMMARY Fas antigen (CD95) is a membrane-associated molecule that mediates apoptotic cell death and may play a role in the induction and maintenance of T cell tolerance. To elucidate the involvement of Fas antigen in human autoimmune diseases, we analysed Fas antigen expression by peripheral T cells from patients with SLE and rheumatoid arthritis (RA), using three-colour flow cytometry. Both CD4+ and CD8+ T cell from SLE patients expressed Fas antigen in a higher density than did these cell from healthy donors and from RA patients. Enhancement of Fas antigen density was noted in Fas+CD45RO+ memory T cell from SLE patients. More remarkably, a significant expression of Fas antigen was observed in CD45RO− naive T cells from SLE patients CD4+CD45RO− T cells from SLE patients co-expressed Fas antigen and early to intermediate activation antigens such as CD25 and CD71, and late activation antigen HLA-DR in only FashiCD4+ naive T tells. Such up-regulation of Fas antigen expression in SLE patients seems to be clinically meaningful, because mean fluorescence intensity (MFI) of Fas antigen on CD4+ T cell subsets inversely correlates with the absolute size of CD4+ T tell subsets in peripheral blood of SLE patients. These results suggest that T cells with increased Fas antigen expression may be highly susceptible to apoptotic cell death, in vivo. A putative mechanism for lymphopenia in SLE patients is discussed.

症例は, 61歳男性.昭和60年11月,関節痛,紫斑,視力障害が出現し,当科第1回目の入院となった.患者血清は, 4°C静置で白色沈降物を形成し,この沈降物は顕微鏡下に結晶構造を呈していた.患者血清のアセテート膜電気泳動では, γ位にM-peakを認め,免疫電気泳動でmonoclonal IgG λ typeであることが明らかになった.さらに,種々の検索により,沈降物はこのM-peakより形成されていると思われた.基礎疾患を認めないため,本症例を本態性結晶性クリオグロブリン血症と診断し,血漿交換療法後,ステロイド治療を行ったところ臨床所見は改善し退院した.本例は,ステロイド剤の減量に伴い,その後2回にわたり再燃しており,それぞれ血漿交換療法,大量ステロイドおよび免疫抑制剤の投与で寛解した.

膠原病に伴うレイノー症状は単なるvasospasmではなく,基盤に器質的変化による末梢循環障害が存在していることが考えられている.したがって難治性の手指潰瘍や指切断をきたすこともあり,これまでにも抗血小板剤や血管拡張剤が使用されてきた.今回,強力な抗血小板作用および末梢血管拡張作用を併せもつ経口プロスタサイクリン製剤であるberaprost sodium (BPS)を,レイノー症状を呈する膠原病患者15例に投与し,サーモグラフィーを用いた冷水負荷試験で手指表面温度の変化を詳細に検討した.方法は15°Cの冷水に30秒間手指を浸し,その後15分間の手指表面温度をサーモグラフィーで観察した. BPSは60～120μg/日を6～12週投与し,再度冷水負荷試験を施行して投与前と比較した.その結果, BPS投与後は手指表面温度,冷水負荷による手指温度の回復,手指末端と基節部との温度差のいずれも投与前に比べ有意に改善しており,膠原病のレイノー現象の基盤に存在している末梢循環障害に対するBPSの効果が確かめられた.

症例は18歳,女性.昭和63年発症の全身性エリテマトーデス(以下SLE).平成2年1月,発熱,精神症状が出現し,某院でステロイドの増量を受けたが解熱せず,頭痛,項部硬直,髄液異常が出現し,当科に転院した.臨床,検査所見より中枢神経ループス(以下CNS-lupus)と診断し,ステロイドーパルス療法を施行した.第8病日,当科入院時の髄液培養よりEnterococcus faecium (以下E. faecium)が同定され,同菌による髄膜炎の合併に対して抗生物質の静注,髄腔内投与を施行し治癒した. E. faeciumによる髄膜炎は非常にまれな日和見感染症で,その発症にステロイド治療中の免疫能低下状態に加え,本症例ではCNS-lupusによる血液脳関門の障害などが関与したと思われた.

慢性関節リウマチ(以下RA)は,関節周囲以外の全身性の骨粗鬆症も報告されている.われわれはdual energy X-ray absorptiometry (DEXA法)を用い53例の女性RA患者の骨塩量を測定した.第2-4腰椎,橈骨幹部,全身の骨塩量を計測し,また腰椎,橈骨は正常女性対照の年齢による補正値,全身骨塩量は総脂肪量での補正値にて検討した.腰椎ではstageや活動性,検査所見との差を認めなかった.しかし橈骨骨幹部や全身骨塩量はstage IV群がstage I-III群より低下し,また握力の低下に有意に相関して低下した.検査所見では,血清学的検査との関係を認めなかったが,リンパ球サブセットのCD4細胞の減少例, CD4+CD45RA細胞の減少例, CD8+HLA・DR細胞の増加例で有意に低下することが示され, RAのosteoporosisにRAの自己免疫機転が関与することが示唆された.

By flow cytometric method with dichlorofluorescin diacetate, we analysed oxidative products of neutrophils in patients with Behcet disease, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and progressive systemic sclerosis (PSS) .The rate of “primed” cells that produced oxidative products in unstimulated neutrophils was higher in patients than in normal control, but in PMA-stimulated neutrophils, there was no differences in patients and normal control. And there were statistical correlations of the primed cells in unstimulated neutrophils and some markers of disease acitivities. This flow cytometric method could clarify the influence of time and temperature from sampling to assay, and was useful to study the functions of cells.

We evaluated the effects of Z-100, extracted from human type Mycobacterium tuberculosis strain Aoyama B, on collagen-induced arthritis (CIA) in mice. One hundred thirty-five DBA/1J mice, 8 weeks of age, were assigned to 9 groups and immunized with bovine type II collagen (CII) or CFA. From the next day, Z-100 at doses of 0.004, 0.04, or 0.4 mg/kg B.W./d for 48 d was intradermally injected into the tail base. Methotrexate (MTX) at daily doses of 0.1, 0.3, or 1.0 mg/kg B.W. and cyclophosphamide (CY) at a daily dose of 5 mg/kg B.W. were used as reference drugs. The effects of these drugs on CIA mice were evaluated in terms of the incidence of CIA, the arthritis index (AI), and hind paw edema, after which the animals were sacrificed at 49 d, and both anti-CII antibody titer and delayed-type hypersensitivity (DTH) reaction were measured. In the arthritic control groups, the AI and hind paw edema were significantly increased after the second immunization on day 28. The anti-CII antibody titer and DTH reaction were significantly increased compared to normal mice on day 49. Z-100 significantly inhibited the AI at a dose of 0.4 mg/kg/d on day 49, and suppressed the incidence of both CIA and hind paw edema. Increases in both anti-CII antibody titer and DTH reaction in CIA mice were prevented by treatment with Z-100 at 0.4 mg/kg/d. MTX, in a dose-dependent manner, and CY, at a dose of 5 mg/kg/d, inhibited the incidence of CIA, AI, hind paw edema, anti-CII antibody titer and DTH reaction in CIA mice. Z-100 at a dose of 0.4 mg/kg was as effective as MTX was at a dose of 0.3 mg/kg against the DTH reaction, and it had no side effects. These results suggest the usefulness of Z-100 in patients with chronic rheumatoid arthritis.

There are two major forms of the Fas molecule, membranous Fas and soluble Fas (sFas). To clarify the clinical significance of sFas in autoimmune diseases, we designed a sandwich ELISA to determine serum concentrations of sFas and its molecular structure, and we then analysed the correlation between levels of sFas and laboratory findings in patients with SLE and other autoimmune diseases. The levels of serum sFas were significantly higher in SLE patients than in subjects with other autoimmune diseases and in healthy donors, and the frequency of a positive serum sFas was much greater in SLE patients with high SLE disease activity index scores than in those with low scores. In addition, sFas-positive SLE patients showed a significant difference in various laboratory parameters from sFas-negative SLE patients. Serial measurements of serum sFas levels in SLE patients with active disease revealed that the elevated level of sFas dramatically decreased with improvement in clinical and laboratory findings, following corticosteroid therapy. We propose that the serum level of sFas can serve as an appropriate marker for evaluating SLE disease activity. Serum sFas is heterogeneous with respect to molecular structure, thus several mechanisms are involved in the generation of sFas.

OBJECTIVE To investigate whether anticardiolipin antibodies (aCL) in patients with systemic lupus erythematosus (SLE) bind to beta 2-glycoprotein I (beta 2GPI), and to search for a relationship between the presence of IgG and/or IgM anti-beta 2GPI antibody and clinical manifestations in SLE patients. METHODS IgG and IgM anti-beta 2GPI in 308 Japanese SLE patients were measured using phospholipid-independent enzyme immunoassays. Relationships to clinical histories and to various laboratory data were examined. RESULTS The values of anti-beta 2GPI and aCL, as measured by conventional enzyme immunoassay, showed a strong correlation, but the anti-beta 2GPI assay was more useful in distinguishing beta 2GPI-dependent aCL from beta 2GPI-independent aCL. The presence of IgG anti-beta 2GPI was associated with an increased frequency of a history of thrombosis. Comparisons of various laboratory data suggested that the titer of anti-beta 2GPI may fluctuate with disease activity. CONCLUSION The results suggest that pathogenic aCL is directed against structurally altered beta 2GPI and that enzyme immunoassay for anti-beta 2GPI may prove useful in evaluating the risk of thrombosis and monitoring the clinical course in patients with SLE.

Rheumatoid factor (RF), an autoantibody against the Fc portion of denatured IgG, has long been recognized as an important biologic marker not only for rheumatoid arthritis but also for other auto-immune diseases. In this study, we measured the level of serum RF in four patients with RF positive systemic vasculitis using laser nephelometry. Three patients were diagnosed as polyarteritis nodosa and the other patient was diagnosed as systemic vasculitis without the finding of typical necrotizing vasculitis from biopsies. In the result, we found that the level of RF paralleled the disease activity in these cases. When active phase of the disease, the level of RF showed very high, and after the treatment combined with plasmapheresis, corticosteroid and immunosuppressive agent, the level of RF decreased in accordance with CRP, ESR and clinical features. These suggested that RF was the disease specific marker for RF positive vasculitis and beneficial informations for proper diagnosis and better treatment could be provided by measurement of the level of RF in patients with RF positive systemic vasculitis.

A 43-years-old woman was admitted to the Hokkaido University Hospital because of high fever, muscle weakness and dyspnea in May 1993. She had has muscle weakness of upper extremities since December 1992. She had developed swollen hand, polyarthralgia and Raynaud's phenomenon. High fever and severe dyspnea developed in May 1993. Chest roentogenogram was normal in April 1993. Physical examination showed Velcro rales in both lower lung fields. Her laboratory data showed increased muscle enzymes, high titers of anti-nuclear-antibody (1: 1280) and anti-RNP-antibody (index 199.4 (normal7)). Anti-DNA, anti-Sm and anti-Jo-1-antibodies were all negative. Blood gas analysis showed severe hypoxemia. Chest roentogenogram revealed diffuse bilateral interstitial infiltrates prominent in the bases. Diagnosis of mixed connective tissue disease with acute interstitial pneumonitis was made. She was treated with steroid pulse therapy (methylprednisolone 1 g x 3 days) followed by high dose oral prednisolone (60 mg/day), and diffuse interstitial infiltrates disappeared within one week. Prednisolone could be tapered to 17.5 mg/day without relapse. Acute interstitial pneumonitis is a rare complication of mixed connective tissue disease, but may be life threatening. In such cases, high dose steroid therapy should be started without delay.

The antigenicity of the 60-kd human Ro (SS-A) synthesized in vitro from its complementary DNA as a beta-galactosidase fusion protein (beta-gal-Ro) was evaluated by Western blotting. In this analysis, almost all the anti-Ro (SS-A)-positive sera that bound beta-gal-Ro also bound affinity-purified 60-kd human Ro (SS-A) (P less than 0.005). Three of the 27 anti-Ro (SS-A) precipitin-positive sera, however, did not show reactivity on Western blot analysis, which suggests that in some sera, antigenicity to Ro (SS-A) is destroyed by denaturation. Of the 22 sera that were reactive with beta-gal-Ro, 2 were not reactive with affinity-purified human Ro (SS-A). Two serum samples that did not react with beta-gal-Ro were also reactive with affinity-purified human Ro (SS-A). Nevertheless, except for a small percentage of Ro (SS-A) precipitin-positive sera, the frequency of antibody binding to the fusion protein was similar to the frequency of binding to the purified antigen in Western blots. Recombinant Ro (SS-A) antigen may therefore be valuable in the serologic evaluation of anti-Ro (SS-A) autoantibodies.

Juvenile dermatomyositis (JDMS) is a relatively rare disease characterised by vasculopathy.1-4 Involvement of the gastrointestinal tract may occur in some subjects and is often life threatening. We describe here a case of fatal JDMS with gastrointestinal perforation. Immunohistochemical examination by antibody against factor VIII seems to be useful for evaluating the pathological basis of vasculopathy in JDMS. A 13 year old Japanese girl was admitted in April 1994 with high fever, muscle pain, and muscle weakness. She noticed a facial rash for two months before admission. Physical examinations were; blood pressure 135/90 mm Hg, temperature 38°C, and weight 50 kg. She presented with an erythematous rash on her face, neck and arms, heliotropic eruption, Gottron’s sign, and nail fold telangiectasia. Proximal muscular weakness and pain were prominent. Laboratory findings were as follows; stool occult blood negative, leucocyte count 5800/mm3, erythrocyte count 4800 × 103/mm3, thrombocyte count …

症例は30才,男子で,発熱,皮疹,関節痛,腹痛,粘血便を主訴として入院した.その後,回腸壊死によるイレウス症状を呈し,開腹手術を施行.切除した回腸組織は典型的な多発性動脈炎の組織像であつた.手術後,パルス療法に引き続いてステロイド大量投与を行ない,腹部症状,皮疹,その他の臨床症状も急速に改善した.また,本症例は入院時HBs抗原が陽性であり,その後, GPT上昇, HBs抗原陰性化, HBc抗体, HBs抗体陽性となり, HBウイルス初感染後のB型肝炎の像を示した.多発性動脈炎の死亡率は高く,特に消化管症状を呈するものの予後は不良であるとされている.本症例は早期手術と,ステロイドホルモンの大量投与により救命し得た例であり,特にパルス療法の効果が著しく,多発性動脈炎に対するパルス療法の有効性を示した1例である.さらに,最近多発性動脈炎の病因として, HBs抗原抗体複合物の関与が注目されており, HBs抗原陽性例の報告が欧米では多い.本邦ではこの様な例はきわめて少ないが,本症例は, HBウイルス初感染時に多発性動脈炎を発症した例で, HBウイルスの多発性動脈炎発症への関与を示唆する貴重な1例と考えられた.

A seventy-two-year old female had chest pain since October 1981. In July 1982, she was admitted for congestive heart failure. In October 1982, compression fractures of vertebrae on Th12 and L1, and Bence Jones protein in the urine were found. She was transferred to our hospital for further examination about multiple myeloma in November 1982. Her laboratory data included mild normocytic normochromic anemia, leukocytes 9, 600/cmm, plasma cells 34% in peripheral blood, total protein 4.5g/dl, decreased all classes of immunoglobulins, BUN 99mg/dl, and creatinine 6.9mg/dl. Her serum and urine showed M-bow only against anti-λ antiserum in immunoelectrophoresis. She was diagnosed as Bence Jones λ type plasma cell leukemia associated with renal failure. Her renal function was gradually improved after chemotherapy and plasmapheresis were started. After a month her renal function became worse, but the response to further treatments including chemotherapy and plasmapheresis could not be obtained. She was died of renal failure on 19th December 1982. In autopsy specimen, many tubular casts and Bence Jones λ type proteins in tubular epithelial cells were found. Bence Jones proteins were purified from patient's urine by ammonium sulfate precipitation method followed by DEAE column chromatography. This purified λ type Bence Jones proteins were used as a standard marker in the measurement of λ type free light chains in the patient's serum. Patient's serum free light chains were serially measured during her clinical course, and were markedly decreased after initial treatment. We discussed about the negative role of Bence Jones proteins on renal function in multiple myeloma. Plasmapheresis treatment along with chemotherapy shows beneficial effect on renal function mainly by removing free light chains from the serum in the patient with Bence Jones type multiple myeloma.

自己免疫性溶血性貧血(AIHA)とBasedow病との合併例を経験したので報告する.患者は28才の女性で,高熱,動悸,全身倦怠感,軽度の黄痩のため入院した.クームス試験陽性.ハプトグロビン消失,赤血球形態正常であるためAIHAと診断した.また,甲状腺機能亢進症状があり.123I摂取率高値, TRHテストにてTSHが無反応, T3抑制試験にて1231摂取率抑制されず,さらにTSH受容体抗体(TBII)を認め, Basedow病と診断した.赤血球自己抗体は,温式の血液型特異性をもたないIgGκ型の抗体が検出されたほか,冷式抗体の存在も疑われた. AIHAとBasedow病の確実な合併例は文献上本例が3例目で,両疾患の免疫学的な関係について考察を加えた。

SLEの発症をみた二組の一卵性双生児例を経験した.一組は20才の姉妹例で,両者ともSLEを発症している.両者の間では発症時期の違いの他,免疫学的検査等の一部に不一致を認めたが,両者の間の環境因子に特に違いはなく,日光曝露が発症時期に影響を与えたと考えられた.もう一組は22才の兄弟例で,兄はSLEであつたが,弟はBFP以外は特記すべきものがなかつた.この両者も環境因子は同等であつた.以上の二組の血縁者調査では,姉妹例では,他に免疫学的異常を認める者はなかつたが,兄弟例では,他に抗核抗体弱陽性者を認め,父方のHLAハプロタイプが一致していた.この両組について, MLC,免疫グロブリン産生能, ALAについて検討した.

当科126例のSLE群と, 70例の非SLEリウマチ疾患群においてARA新旧両基準について検討した. SLE群の臨床症状では関節炎90%,蝶形紅斑62%が多く, Tanらの報告と比較すると新基準では漿膜炎が低頻度である以外に有意差はなかつた. ARA新基準に加えられた項目では,抗核抗体99%,抗DNA抗体83%と高かつた. Sm抗体は陽性率26%であるがLE細胞やBFPと同様に特異度はきわめて高かつた. ARA基準の平均陽性項目数はSLE群では旧基準5.40項目,新基準5.61項目であり, 4項目以上陽性症例の割合はそれぞれ88.1%, 96.8%と有意に増加が認められた.対照群の特異度は98.6%から95.7%と減少したが有意差はなく,新基準は感度に勝ることが示された.

目的:超音波パルスドプラー法(以下PDE)を用い,当科全身性エリテマトーデス(以下SLE)患者を対象に肺高血圧症(PH)の検索を行い,臨床検査所見について比較検討した.方法:超音波断層法とPDEの複合システムを用い,右室流出路又は肺動脈弁口部での血流速度パターンを表示しPH patternを検討した.結果: SLE 42例中7例にPH patternが認められ,この群ではRaynaud現象,抗RNP抗体,血小板減少が高頻度に認められた.

症例は35才女性.昭和57年3月顔面,三叉,嗅神経麻痺にて発症,約1カ月後にレイノー現象,関節痛が出現した.検査所見では白血球減少,抗核抗体640×陽性(斑紋型),抗RNP抗体16×陽性を認め,唾液腺造影所見および小唾液腺生検所見より,乾燥症状を欠くsubclinical Sjogren症候群(SJS)と診断した. SJSの末梢性脳神経障害の報告は少なく,多発性脳神経障害を初発症状とするSJS例は極めてまれと考えられたので報告する.