Hemophagocytic syndrome (HPS) is a life-threatening disorder characterized by pancytopenia and activation of macrophages. Recently, corticosteroid incorporated in lipid microspheres (liposteroid) has been reported to be taken up by macrophages and to suppress their functions. Here we present a case of systemic lupus erythematosus complicated by HPS that was successfully treated with liposteroid in addition to an oral corticosteroidand intravenoushigh-dose cyclophosphamidetherapy. The serum levels of tumor necrosis factor-a and ferritin that have been reported to be associated with activity of macrophages remarkably reduced after liposteroid administration. This case suggests that liposteroid is useful for the treatment of HPS.

Retinoic acids, a group of natural and synthetic vitamin A derivatives, have potent antiproliferative and anti-inflammatory properties. Recently, retinoic acids were reported to inhibit Th1 cytokine production. We investigated the effects of retinoic acid on lupus nephritis in a model of NZB/NZW F(1) (NZB/W F(1)) mice. Three-month-old NZB/W F(1) mice were separated into two groups: one treated with all-trans-retinoic acid (ATRA; 0.5 mg i.p., three times weekly for 7 mo) and one with saline as a control. Compared with controls, ATRA-treated mice survived longer and exhibited a significant reduction of proteinuria, renal pathological findings including glomerular IgG deposits, and serum anti-DNA Abs. Splenomegaly was less marked in the treated mice than in controls. Transcripts encoding IFN-gamma, IL-2, and IL-10 in splenic CD4(+) T cells were significantly reduced in treated mice compared with controls. We conclude that treatment with ATRA in SLE-prone NZB/W F(1) mice significantly alleviates autoimmune renal disorder and prolongs survival; this may thus represent a novel approach to the treatment of patients with lupus nephritis.

CD80 and CD86, expressed on the antigen-presenting cells (APCs) provide costimulatory signals for T lymphocytes. Recently, defective expression of CD80 has been reported in systemic lupus erythematosus (SLE) although its mechanism is unclear. Here, expression of the B7 antigens induced by interferon-g, interleukin-4 or granulocyte-macrophage stimulating-factor (GM-CSF) along the differentiation process of APCs was investigated. In contrast to CD86, expression of CD80 on the CD14‡ cells induced by GM-CSF was reduced in SLE. GM-CSF receptor (GMCSFR) was down-regulated by GM-CSF or phorbol 12-myristate 13-acetate in both of the normal controls and SLE patients, while this change was more remarkable in the latter. In the presence of 1-(5-isoquinolinsulfonyl)-2-methylpiperazine, an inhibitor of protein kinase C, the PMA-induced down-regulation of GM-CSFR was reversed in the normal controls but not in SLE. These data suggest that dysregulation of the GM-CSFR might be associated with the defective expression of CD80, leading to dysfunction of the APCs in SLE.

It has been reported that apoptotic cells are increased in the peripheral blood from patients with systemic lupus erythematosus (SLE), where dysfunctions of T helper 1 (Th1) cells are known. In order to study whether apoptosis of Th1 cells is associated with the pathogenesis of SLE, early apoptotic cells in various T-cell subsets were detected using fluorescence-labeled annexin V (AnV). AnV binding was most frequently observed in CD4+CCR5+ T cells, and AnV binding rate (%) in this subset was higher in SLE than in normal controls (14.7 +/- 2.6), although that in active SLE (43.6 +/- 7.3) tended to be lower than that in inactive SLE (48.0 +/- 6.8). CD95/Fas expression was also increased in both active and inactive SLE. In some SLE patients, AnV binding rate changed in inverse proportion to titer of the serum anti-DNA antibody and in proportion to serum complement activity. These data suggest that apoptosis in Th1 cells is important in the pathogenesis of SLE and might play a role in regulating over-activation or autoreactive responses by T cells.

CoVee consumption, RF, and the risk of RAStress is one of the factors that can trigger the onset of rheumatoid arthritis (RA).People working under deadline pressure, and people characterised as hard driving, "type A" personalities may be most likely to experience stress.These are the same people who may consume large quantities of coVee in order to stay at peak performance for longer periods of time.Possibly, therefore, the correlation reported by Heliövaara et al 1 between coVee consumption and RA may, in part, be due to the association between stress and RA.

A tumor marker, CA125, is known to increase in the serum or other body fluids in various malignancies such as ovarian cancer. Here we present a case of progressive systemic sclerosis (PSS) with massive pleural effusion, in which CA125 in the serum and pleural fluid were elevated. The serum level of CA125 decreased in accordance with the change of the pleural effusion. CA125 level may be an indicator for the activity of serositis in some cases with collagen vascular diseases.

It has been reported that production of interleukin (IL)-4, a T helper (Th)-2-type cytokine, might play an important role in the pathogenesis of systemic lupus erythematosus (SLE). On the other hand, it is known that NK1.1(+) cells which belong to CD4, CD8 double-negative, or CD4(+) cells are associated with initial IL-4 production and Th2 differentiation in mice although human equivalent cells are unknown. In order to study the profile of IL-4-producing cells in SLE, cytoplasmic IL-4 and various surface antigens on peripheral mononuclear cells were analyzed. Peripheral mononuclear cells were stimulated for 5 h by phorbol ester and ionomycin in the presence of monensin, fixed, and permeabilized with paraformaldehyde and saponin solution. Then cytoplasmic IL-4 and various surface antigens were analyzed by flow cytometry. IL-4-producing cells in SLE were phenotypically the same as those which produce IL-4 normally and frequently bore activated T-cell (CD7, CD25, CD28, CD29) and NK-cell markers (CD56, CD57). Double-negative T cells and CD57(+) T cells were increased in number and were more frequently positive for cytoplasmic IL-4 in SLE compared with normal controls and various infectious diseases. It was suggested that T cells with NK cell markers, CD57(+) T cells, which are known to extrathymically differentiate, might be involved in the pathogenesis of SLE as a counterpart of mouse NK1.1(+) cells.

We analyzed the outcome of 23 patients with hematological diseases who were transplanted with bone marrow cells from unrelated donors in comparison with 46 transplanted from related donors at a single institute during the same time period. Two unrelated donor patients and one related donor patient with CML failed engraftment. The incidence of acute GVHD was higher in unrelated donors than that in related donors(52% vs. 34%). However, there was no difference for the incidence of grade II-IV GVHD between unrelated and related donors (28% vs. 25%). The incidence and severity of acute GVHD decreased after applying HLA DNA typing. Two unrelated donor patients were died of acute GVHD within 100 days, but no one in related donor patient died of acute GVHD. These results show that HLA DNA typing and the management of acute GVHD are important in patients transplanted from unrelated donors.

Regarding the diagnosis of APS, as Kaburaki et al (6) discuss in their letter in this issue ofthejournal, thrombocytopenia is too controversial to be included as one item of criteria and confusion in the definition of APSwill follow.Asherson defined APSpatients without any underlying diseases as cases of primary APS (7), and when patients have some factors ofSLE (less than 4 items of SLE criteria), he termed them as secondary APS to lupus-like disease.Here however, "lupus-like disease" should be clearly defined.Many individuals, including apparently healthy ones, carry one or two factors related to SLE criteria, but we usually do not classify them as patients with lupus-like disease.Wesuggest that use of "APSsecondary to lupus-like disease" be avoided and that a new more appropriate criteria of APSand primary APSbe designed.

We present a 31-year-old female patient with systemic lupus erythematosus (SLE) which was accompanied by prolactinoma. Her SLE flared when the plasma levels of prolactin (PRL) increased, and subsided when these levels decreased following the administration of bromocriptine, irrespective of the glucocorticoid dosage. For the 29 plasma samples obtained during the clinical course, PRL levels were significantly correlated to the serum anti-DNA antibody titers (r = 0.55, p < 0.05) and inversely to the serum complement activity (r = -0.33, p < 0.05). This result suggests that PRL may play a role in the pathogenesis of SLE in some patients.

In this study time for initial assessment of monthly intravenous cyclophosphamide (CP) pulse therapy is discussed for a better outcome with less complications. Eleven patients with lupus nephritis (LN) resistant to conventional therapy (serum creatinine level < or = 2.7 mg/dl) were given 500 mg/m2 of CP 7-9 times with an interval of one month. Urinary protein (Up) decreased in all patients after 3 courses of CP pulse therapy and kept similar levels thereafter. In one group of patients (n = 7), Up decreased to < 2 g/day after 3 courses, while in the other group (n = 4), it did not decrease to < 4 g/day. Creatinine clearance increased by 0-100% in the former group, while it decreased by 5-20% in the latter group after 6-9 courses. Renal function of the patients with insufficient response after 3 courses tended to show no further improvement or worsened thereafter, although Up decreased during CP pulse therapy. A relatively small dose of CP (500 mg/m2) pulse therapy was useful in most LN patients regardless of the renal histology and it was thought important to assess its effects after 3 courses for a prediction of the clinical course. Modification of the protocol at that time might be necessary in regard to dose or interval of CP administration especially for patients with insufficient outcome.

It has been reported that anti-phospholipid antibodies are detected in some patients with idiopathic thrombocytopenic purpura (ITP). To study the significance of determination of anti-phospholipid antibodies in patients with ITP, clinical and laboratory findings were compared between patients whose sera were positive for these antibodies (Group A) and non-positive patients (Group B). Anti-cardiolipin antibody (aCL) was determined by enzyme-linked immunosorbent assay and lupus anticoagulant (LA) was determined by activated partial thromboplastin time (aPTT) and thromboplastin time inhibition test. Seven out of 27 cases of ITP belonged to Group A and 3 of the 7 were confirmed to have anti-phospholipid antibody syndrome (APS). There was a tendency for habitual abortion, and thrombosis, megakaryocytes in the bone marrow and platelet-associated IgG (PAIgG)-positive cells were more frequent in Group A than in Group B. However, it was difficult to discriminate APS from ITP alone, when there were no symptoms or signs of APS. Therefore, measurement of anti-phospholipid antibodies in ITP was thought to be useful for the differential diagnosis of APS and subsequently for the prevention of thrombosis.

Anti-DNA antibody, especially high-affinity anti-DNA antibody (ADNA), is thought to have an important role in the pathogenesis of lupus nephritis. In this study, ADNA which binds to double-stranded DNA under a high concentration of sodium chloride was measured in patients who had received immunoadsorption (IA) therapy with a dextran-sulfate column. Titers of high-affinity ADNA in the cases with renal dysfunction tended to be higher than in those without renal dysfunction. The change in the titer of high-affinity ADNA paralleled the clinical course. These findings suggest that measurement of high-affinity ADNA is useful for follow-up of the clinical course of patients who have undergone IA therapy.

The expression of intercellular adhesion molecule-1 (ICAM-1) on peripheral blood mononuclear cells (PBMC) from patients with systemic lupus erythematosus was observed by flow cytometry. ICAM-1 expression on PBMC was increased in the patients with active disease, and was increased especially on CD5- or CD19+ lymphocytes and monocytes. Furthermore, when B cells were fractionated by Percoll-density gradients, ICAM-1 was more expressed on the low- and the intermediate-density B cells, which are thought to contain activated B cells, than on the high-density B cells, which are thought to contain resting B cells. This might be due to the polyclonal B-cell activation occurring in vivo. Together with the function of B cells and monocytes as antigen presenting cells, this enhanced expression of ICAM-1 on these cells might be associated with the mechanism to maintain the pathophysiology of this disease.

We examined the effects of gamma-interferon (gamma-IFN) and the new immunosuppressant FK506 on resting B cell proliferation of New Zealand black/white F1 hybrid (B/W F1) mice, an animal model of human systemic lupus erythematosus (SLE). gamma-IFN and FK506 inhibited in a dose-dependent manner both B cell proliferation and autoantibody production of resting B cells respectively. There was a synergistic interaction between gamma-IFN and FK506 in their inhibition and they did not exhibit cell cytotoxicity. This in vitro synergism of gamma-IFN and FK506 may have clinical application in that low doses of gamma-IFN and FK506 combinations may be effective to correct polyclonal B cell activation of patients with SLE.

Evans症候群に橋本病と抗リン脂質抗体症候群を合併した1例を経験した.症例は33歳女性で,昭和61年に当科に入院し, Evans症候群と診断された.退院後,近医で通院加療されていたが,平成2年9月に突然構音障害が出現し,さらに高度の甲状腺機能低下症も認められたため,平成3年5月に当科に再入院した.検査の結果, Evans症候群の増悪および橋本病と抗リン脂質抗体症候群の合併と診断された.構音障害については,頭部MRIで多発性脳梗塞が認められ,抗リン脂質抗体症候群によるものと考えられた.本症例においては,抗カルディオライピン抗体の産生が根本的な病態であり,抗カルディオライピン抗体が血小板および赤血球と交差反応している可能性が考えられた.さらに,橋本病の病因として,甲状腺組織との交差反応性も疑われた.

To characterize B cell hyperactivity in autoimmune NZB/NZW (B/W) F1 mice, we studied the effects of murine recombinant interferon gamma (IFN-gamma) on interleukin 4 (IL-4) induced resting B cell growth and differentiation. The number of resting B cells of B/W F1 mice were decreased, with more sensitivity to IL-4 than normal mice. Thus, resting B cell hyperresponsiveness to IL-4 was in a dose-dependent manner suppressed by IFN-gamma. This action was most noticeable when IFN-gamma was added to the culture system simultaneously with IL-4. As well, IFN-gamma did not exhibit cytotoxicity. These results suggest that IFN-gamma may have regulatory effects on IL-4 mediated B cell triggering.