Synovial tissues from patients with rheumatoid arthritis (RA) are characterized by tumor-like proliferation (diffuse and nodular mononuclear cell infiltration and hyperplasia of the stromal connective tissues), which induces the destruction of bone and cartilage. In the previous study, we demonstrated that fibroblast growth factor (FGF)-1, platelet-derived growth factor (PDGF) and PDGF receptors (α, β) were intensely immunolocalized in the synovium of patients with RA higher than osteoarthritis (OA). The receptors for FGF and PDGF are tyrosine kinases. In this study, we examined the expression of tyrosine phosphorylated proteins (PT) in arthritic joints of patients with RA and rats with streptococcal cell wall (SCW)-and adjuvant-induced arthritis. PT was intensely immunostained in synovial lining cell layer, fibroblast-like cells, vascular endothelium and inflammatory mononuclear cells from RA patients in contrast to synovia from OA or normal subjects. Moreover, PT was expressed in synovium, cartilage and skin epidermis of SCW-induced arthritis in Lewis rats (LEW/N). PT expression was detected at day 4 after adjuvantinjection in Lewis rats without clinical apparent arthritis. PT expression was not sustained in athymic Lewis rats (LEW. rnu/rnu) after injection of SCW or adjuvant. This observation demonstrates that persistent expression of PT, as well as chronic arthritis, requires an intact T lymphocyte-dependent immune system. Staining with anti-PT antibody was absent in relatively arthritis-resistant Fisher rats (F 344/N) after injection of SCW or adjuvant. These results suggested that FGF-1 and PDGF-A and B-like factors were active in vivo in inflammatory joints and promoted the tumor-like behavior of rheumatoid synovium throughtyrosine phosphorylation.

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Normal values of IgG subclasses in the serum were measured by the specific monoclonal antibody-based ELISA technique with a Japanese healthy adult population (840 individuals comprising 306 male and 534 female) in their 2nd to 8th decade. The mean IgG 1 concentration in this population gradually increased linearily with increasing age although the mean levels of IgG 2, IgG 3 and IgG 4 showed no age-related significant variations.
The percentages of individual IgG subclasses in the total IgG amount (as the sum of the four subclasses) revealed that the IgG 3 alone increased slightly with age. Possible differences in the percent composition of the IgG subclasses were sought between this population and a non-Japanese US healthy adult population. The percentages of IgG 1 and IgG 3 were approximately 8% and 2% lower but the IgG 2 was approximately 10% higher in the Japanese population than in the US population, with no significant difference in the IgG 4 between these populations.

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Our previous studies showed that serum anti-DNA topoisomerase I (topo I) antibody is associated with pulmonary interstitial fibrosis and restrictive pulmonary function abnormality in patients with systemic sclerosis (SSc). We also demonstrated that at least four epitopes exist on the topo I molecule, and a region from amino acid residues 658700 of the topo I molecule is referred to as epitope region 4 (ER 4). In this study, we examined the reactivity against ER 4 in sera from 28 anti-topo I antibody positive patients with SSc by immunoblotting. We then clarified the clinical significance of this reactivity against ER 4 in terms of the progressive restrictive pulmonary function abnormality.
The reactivity against ER 4 was found to be positive in 15 patients (ER 4+) and negative in 13 patients (ER 4-). Differences in gender, mean age at onset, and mean observation period were not significant among these groups. Restrictive pulmonary function abnormality defined as results of percent vital capacity (%VC) less than 80% was found in 12 ER 4+patients and 8 ER 4-patients, although this difference was not significant. However, when progressive restrictive pulmonary function abnormality is defined as both %VC less than 80% and 10% reduction during their observation period, this abnormality was found exclusively in 9 ER 4+ patients. This difference was significant (p<0.01). Moreover, this progressive abnormality was found in spite of therapy such as prednisolone and D-penicillamine. These results indicated that the reactivity against ER 4 is a useful predictor for the progressive restrictive pulmonary function abnormality in patients with SSc.

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Renal lesions in polymyositis/dermatomyositis are rare and have not been clarified. In order to reveal the renal involvement in dermatomyositis/polymyositis, we performed clinicopathological study of the kidney lesion from 8 cases with dermatomyositis/polymyositis. Proteinuria was noted in two cases; one was membranous nephropathy and the other was amyloidosis. Deterioration in renal function was noted in two cases; one was renal amyloidosis and the other was acute tubular necrosis due to rhabdomyolysis. Mucoid material was positive in the intima by Alcian blue staining and elastic fiber of the intima of the arteriole was multilayered by elastica van Gieson staining in three cases. Similar lesion was noted in small artery of the liver and the spleen from these cases. Furthermore mucoid intimal change was recognized in some of the control cases from the elder without dermatomyositis/polymyositis. These intimal changes seem to be atherosclerotic change rather than due to vasculitis of dermatomyositis/polymyositis. Various lesions should be taken into consideration in cases with proteinuria or deterioration in renal function with polymyositis/dermatomyositis.

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In the generation of lymphokine activated killer (LAK) cells from peripheral blood lymphocytes (PBL), large numbers of LAK cells are obtained by culturing in the anti-CD 3 immobilized flasks. However, the killer activity of the LAK cells which were cultured in these flasks (PBL·anti CD 3-LAK) is low. In this study, CD 4-positive and -negative PBL were cultured. CD 4⁺-LAK cells which were generated from CD 4⁺ PBL exhibited very low killer activity, although the cell proliferation was explosive. Whereas, CD 4^--LAK cells generated from CD 4^- PBL showed high killer activity. CD 4^--LAK cells demonstrated high adhesiveness against the cancer cell line T 98 G, CD 4⁺-LAK cells having no any adhesive tendency. These results may show that the low killer activity of PBL·anti CD 3-LAK is due to the explosive proliferation of CD 4⁺-LAK cells. CD 4^--LAK cells include CD 4^- CD 8^--and CD 4^- CD 8⁺-LAK cells. CD4^-CD8^--LAK cells showed very high killer activity, and CD 4^- CD 8⁺-LAK cells relatively high activity. The culturing of CD 4^- PBL in the anti-CD 3 immobilized flasks is useful to obtain a lot of LAK cells by accompanied high killer activity.

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A 63-years-old woman with polyarthralgia and high fever was admitted to Hokkaido University Hospital in October 1992. Two month before admission, she noticed mild fever. One month later, she developed polyarthralgia and high fever. Antibiotics and intravenous γ globulin therapy were ineffective.
Laboratory findings showed: ESR 38mm/h, WBC 32, 600/μl with 81% neutrophils, LDH 1, 138IU/l, ferritin 19, 900ng/ml. Tumor markers, RF, ANA and other autoantibodies were within normal limits. X-ray film of the hands showed no abnormal sign.
On the 6th day of admission, she developed acute dyspnea and surface lymph node swelling. Her chest X-ray film revealed infiltration of the right upper lung, both hilar lymph node swelling and pleural effusion. Laboratory findings showed increased transaminase (GOT 503IU/l, GPT 182IU/l) and manifestations of DIC. Ultrasonography showed hepatosplenomegaly. Despite anticoagulative with corticosteroid including pulse therapy, she further developed massive melena and hemoptytis. She died on the 17th day of admission.
Findings at her autopsy included multiple infarction of the spleen, necrosis of the transverse and sigmoid colon which was compatible with feeding area of the inferior mesenteric artery. Vasculitis and malignancies were not revealed.
The diagnosis of adult Still's disease was mostly suspected because of the progress of her disease, laboratory findings, and autopsy. Although adult Still's disease is generally considered to have a favorable course, our patient died of acute DIC as a complication of adult Still's disease.

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A 61-year-old man was admitted because of polyarthralgia, purpura and visual disturbance. Precipitate was observed in his serum after being placed at 4°C storage and it could not be resolved completely by warming at 37°C. Light microscopic examination of this precipitate demonstrated the formation of crystals. The immunoelectrophoresis of his serum revealed M-component in the gamma range identified as IgG with lamda light chain. Because the M-component disappeared after formation of the cryoprecipitate, this cryoprecipitate was thought to be consisting of monoclonal IgG with lamda light chain.
Because no underlying disease was found, he was diagnosed as essential crystallizing cryoglobulinemia. Combined therapy with plasmapheresis and administration of corticosteroid and cyclophosphamide is successful in controlling his clinical signs and symptoms.

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We describe here a 25-year-old male patient with systemic lupus erythematosus (SLE), who presented with pulmonary hypertention and renovascular hypertention, which were diagnosed by electrocardiography (ECG) and cardiac catheterization and by elevated plasma renin activity and decreased renal blood flows on renogram, respectively. Serum anticardiolipin (CL) antibody and anti-CL/β₂-glycoprotein I (β₂GPI) antibody were also positive on admission. After treatment with prednisolone (30mg/day), aspirin, ticlopidine, a calcium blocker and an angiotensin converting enzyme inhibitor, he recovered from the manifestations with improvement of ECG findings. Of note, serum anti-CL antibody and anti-CL/β₂GPI antibody also disappeared along with his recovery from the manifestations. The course of our patient therefore suggest that serum anti-CL (anti-CL/β₂GPI) antibody might be involved in the development of pulmonary hypertension and renovascular hypertension.

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We herein report a case of primary Sjögren's syndrome in a young girl whose initial manifestation was high fever. A 16-year-old girl had previously experienced two episodes of short-term hospitalization at a nearby hospital due to a high fever in 1990. Since her serum anti-nuclear antibody was strongly positive, she was suspected of having unclassified connective tissue disease (UCTD) and thus was observed without medication at our outpatient clinic for two years. During this period, she only demonstrated several episodes of low grade fever when under stress such as during examinations at her school. In February 1992, she was admitted to a nearby hospital complaining of high fever, chills and polyarthralgia. Although these symptoms improved soon after the administration of oral prednisolone (30mg/day), she was transferred to our hospital for further examination. Although she did not show any past history of either salivary gland swelling or sicca symptoms, both sialography and a labial gland biopsy were performed because the antibody to SS-A/SS-B proved positive in her serum. These examinations resulted in a definite diagnosis of primary Sjögren's syndrome. Antibodies to SS-A/SS-B were retrospectively identified to be positive in her serum during the first episode of high fever in 1990. This indicates that she was already affected by Sjögren's syndrome in back 1992 when she was 16 years old. Few cases of primary Sjögren s syndrome have been reported in patients younger than 16 years old whose initial manifestation was only a high fever. It is thus considered likely that more cases of primary Sjögren's syndrome could potentially exist in young patients with a fever of unknown origin or UCTD based on an evaluation of serum SS-A/SS-B antibodies, sialography and a labial gland biopsy.

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We report a rare case of Sjögren's syndrome associated with asymptomatic primary biliary cirrhosis, three M-components and orthopathy. A 69-year-old woman visited our hospital for the examination of the swelling of ankle and wrist joints which lasted for 20 years. She was admitted for further examination in September 1990. She complained xerostomia and opthalmological examination revealed superficial keratoconjunctival erosion. She didn't complain of skin itching. Heberden's nodules were also noted on the finger joints. Laboratory data on admission showed elevation of serum transaminase and alkaline phosphatase, and leucine aminopeptidase. Rheumatoid factors and antinuclear antibody were both positive. Positive antimitochondrial antibody test was×80. Anti-smooth muscle antibody was negative. Serum IgG, A and M were 1, 755mg/dl, 2, 134mg/dl and 200mg/dl, respectively. Cellulose acetate electrophoresis of the serum demonstrated M components in the γ-region. Immunoelectrophoresis of the serum showed the presence of IgAκ and IgAλ. High-sensitivity immunofixation electrophoresis showed the presence of IgAκ, IgAλ and Igλ monoclonal proteins in the serum. Bence-Jones protein was negative. In the sternal bone marrow, there was 9.6% plasma cells. Sialography demonstrated globular findings, or stage II according to Rubin-and Holt's criteria. Lip biopsy demonstrated mild lymphoplasmocytic infiltration, or grade I according to Greenspan's focus score criteria. Liver biopsy demonstrated stage II according to Sheuer's criteria. These diseases were supposed to be originated from the same immunological backgroud.

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In this report, we described a case of mixed connective tissue disease (MCTD) associated with Graves' disease and primary biliary cirrhosis (PBC). A 52 year-old woman started to have episodes of Raynaud's phenomenon since 1985. In February, 1992, she suffered from arthralgia of bilateral PIP joints, and then, liver dysfunction was found. In July, 1992, she was admitted to our hospital with low grade fever and polyarthralgia. On admittion, polyarthritis, exophthalmos, diffuse goiter, sausage-like fingers, Raynaud's phenomenon and fine tremor of hands were found. Laboratory data revealed elevated cholangial enzymes, hypergammaglobulinemia, increased level of T 3 and T 4, decreased TSH, positive fluorescent antinuclear antibodies, positive anti-RNP antibody, positive antimitochondrial antibody, and positive thyroid gland stimulatory antibody. Scintigram of thyroid gland showed remarkably elevated uptake, and pathological findings of liver biopsy specimen were compatible with primary biliary cirrhosis.
MCTD is rarely associated with Graves' disease and PBC. We discussed here possible relationship between these diseases.

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Microscopic polyarteritis (MPA) is a systemic necrotizing vasculitis affecting small blood vessels. Most of the cases initially respond to treatment with corticosteroids or cytotoxic agents, but relapse occurs frequently. Recently, we have experienced two cases of MPA accompanying pulmonary manifestations, one is pulmonary hemorrhage, the other is interstitial pneumonitis. Anti-neutrophil cytoplasmic antibody (ANCA) decreased in both cases following the intensive immunosuppressive therapy, however, they died of aggravation of the disease. Titer of plasma thrombomodulin and serum 7 S collagen remained high even after the intensive treatments suggesting that the endothelial damage and the destruction of the tissue basement membrane continued to be present. In addition, the association of interstitial pneumonitis is thought to be a rare but important pulmonary complication of MPA and also discussed with the literature.

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Here we report a case of Sjögren's syndrome (SjS) preceding systemic lupus erythematosus (SLE). A 37-year-old woman was admitted to our hospital in October 1993 because of xerophthalmia, xerostomia, fever and facial erythema.
She had been pointed out hypergammaglobulinemia and leukopenia since 1973 (17-year-old) in the absence of clinical manifestations. She noticed easy fatigability and hypersen-sitivity to common cold in 1985, and then lymph node swellings in both neck and axilla were recognized. Diagnosis of primary SjS was based clinically on Raynaud's phenomenon, dry eyes and dry mouth, and serologically on positive autoantibodies to nuclear antigen, SS-A (Ro) and SS-B (La) antigens. The presence of anti-dsDNA antibody was occurred in August 1992. Five months later, she had suffered from high fever, joint pain, facial erythema. Laboratory data showed albuminuria and high titer of anti-Sm antibody.
On admission, Shirmer's, rose-bengal and gum tests were also positive. The load test of NH₄Cl was also positive. Mouth lip biopsy exhibiting mononuclear cell infiltration around ducts diagnosed SjS. Furthermore, renal biopsy showed focal segmental glomerulonephritis. Immunoglobulins and complements were deposited on the mesangeal cells in glomeruli. Mononuclear cell infiltration and fibrosis was found moderately in interstitium. The data depicted category IIIa in WHO morphological classification of lupus nephritis.
In our present case, SjS precedes SLE by 4 years, and both diseases occurs after a long latent period. This case is very interest in pathogenesis in both diseases and the relationship between them.

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To investigate the role of anti-neutrophil cytoplasmic antibodies (ANCA) from patients with rheumatoid arthritis (RA) in neutrophil activation, we examined the effects of serum and synovial fluid (SF) from 10 RA and 9 osteoarthritis (OA) patients and serum from 10 healthy controls on H₂O₂ production by normal peripheral blood neutrophils (Nt). H₂O₂ was measured by the flow cytometry method described by Bass et al., 1983. The mean intensity fluorescence (MIF) of Nt with RA serum (mean=13.953, n=10) or SF (18.501, 10) and OA SF (14.017, 8) was significantly higher than that with control serum (9.749, 10). MIF was not correlated with the presence of ANCA. Thus, ANCA in RA had no pivotal role in the stimulation of H₂O₂ production by Nt.

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