Bone marrow abnormalities have been found to play a role in the pathogenesis of rheumatoid arthritis (RA). Recent studies have also confirmed the presence of undifferentiated hematopoietic progenitor cells as well as the expression of stem cell factor in the synovial membranes in RA. The present study investigates whether RA synovial fluids contain factors that can induce differentiation of CD 14 positive/HLA-DR positive cells from undifferentiated hematopoietic cells. Synovial fluid specimens from 18 patients with RA and from 10 control patients, including patients with osteoarthritis and Behcet's disease, were studied. Human promyelocytic leukemia cell line HL 60 (5×10⁴/well) were cultured in the presence or absence of the synovial fluids for 5 days, after which the expression of CD 14 and HLA-DR was examined by flow cytometry.
The induction of differentiation of CD 14 positive/HLA-DR positive cells or HLA-DR positive cells from HL 60 cells was significantly enhanced more in the presence of synovial fluids from RA patients than in the presence of those of control patients. However, the sera from the RA patients could not induce the differentiation of CD 14 positive/HLA-DR positive cells or HLA-DR positive cells from HL 60 cells. Most cytokines found in RA synovial fluid could not induce the differentiation of HL 60 cells. Of note, treatment of synovial fluids with hyaluronidase significantly decreased or abrogated their capacity to induce the differentiation of HLA-DR positive cells from HL 60. There was no significant difference in the concentration of hyaluronic acid in the synovial fluid between the RA patients and the control patients. These results indicate that there are factors that can induce differentiation of HLA-DR positive cells from undifferentiated hematopoietic cells in the synovial fluid of RA. The data also suggest that such differentiation factors might be related with qualitative abnormality of hyaluronic acid.

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Provided by the evidences that, in cancer patients, the production of Th 1 cytokines including IL-12, IFN-γ, and TNF-α, is impaired, we asked whether these cytokines can be useful parameters for cancer detection. To the aim 174 patients diagnosed cancer of various organs, and 100 control individuals without cancer were enrolled to the study. We evaluated mitogen-stimulated production of cytokines and induction of Th 1 subset using peripheral blood mononuclear cells in vitro. Th 2 population was measured as the counterpart of Th 1 subset. NK cell activity was also measured. As acquired values did not show the normal distribution we employed a non-parametric test to compare the values between cancer and control.
PHA-induced production of IL-12, IFN-γ and TNF-α, in cancer was lower than that in control. Th 1 subset induced in cancer was lower than that in control. We found no difference in Th 2 subset induction between cancer and control. On the other hand, NK cell activity was augmented in cancer patients. When patients were grouped to early stage and advanced stage, both groups showed suppressed production of all three cytokines and sup-pressed induction of Th 1 cells. Interestingly, none of cytokines nor Th 1 subset differed between the two stages, suggesting that the impaired cytokine production may be a common feature of cancer condition and participate in the etiology of cancer. In contrast, enhanced induction of Th 2 subset was seen in advanced stage compared to early stage, indicating that Th cells might be biased to differentiate to Th 2 cells in advanced stage.
From the results IL-12, IFN-γ, TNF-α and Th 1 subset as well as NK activity appear to be promising parameters for cancer detection. Above all, IL-12 and IFN-γ seem to be the best parameters due to high sensitivity and specificity, and independence from the stage of cancer.

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Sjogren's syndrome (SS) is an autoimmune disease characterized by a chronic inflammatory response mainly localized to the lacrimal and salivary glands. However, it sometimes involves extraglandular organs culminating in systemic disorders. Hematological abnormalities are not uncommon, although they rarely have clinical significance. In this study we examined 99 patients with primary SS who visited our hospital during 1989 to 1999. Patient's mean age was 54.1 years and 95 out of 99 were female. Lymphopenia and leukopenia was noted in 35 patients (35.3%) and 26 patients (26.2%) respectively, and 7 patients (7.1%) had thrombocytopenia. 43 patients (43.4%) had either of these hematological abnormalities.
Patients with lymphopenia showed significantly low frequency of arthralgia and anti-SS-A/B antibody was more common in this group. Only one patient in this group requiredc predonisolone therapy because of polyarthritis and general fatigue while others needed no specific therapy.
Patients with thrombocytopenia were significantly younger and a male/female ratio was higher than those without this abnormality. They had higher tendency to accompany with skin eruption, positive anti-SS-B antibody, anti-nuclear antibody and rheumatoid factor. Three out of 8 patients with thrombocytopenia were treated with predonisolone according to the protocol for idiopathic thrombocytopenic purpura. All of 3 patients had positive PA-IgG and normocellular bone marrow. Autoimmune mechanism such as polyclonal B cell activation may play a role in the pathogenesis of thrombocytopenia.

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A 24-year-old woman was followed for about ten months with oral administration of prednisolone (22.535mg/d) for autoimmune hepatitis. In June 1995, she noticed fatigue and appetite loss and blood chemistry revealed markedly deteriorated liver function. She was admitted to our hospital. The daily dose of prednisolone was increased to 60mg. Her elevated levels of transaminases decreased gradually. Administration of azathioprine (100mg/d) was started with tapering of prednisolone on August 18th. Ten days later, tender cervical lymphadenopathy and high fever occurred. Azathioprine administration was stopped immediately and intravenous antibiotics were given. On September 5th, 50mg of azathioprine was administered again. Two hours later, the patient complained of intolerable pain from the lumbar region to the knee joints, which subsided following two injections of analgesics within a few hours. However, chills, high fever and hypotension (86/30mmHg) subsequently developed. No bacterial growth was detected in blood culture. She was discharged on September 12th. On October 4th, she visited our out-patient clinic. The next day, she took one tablet (50mg) of azathioprine at 10 o'clock. She noted intense pain from the thighs to the knees and calves around noon again. Her home doctor found that she exhibited shock (BP 67/?). She was immediately taken to our department. The same symptoms and signs as the avove-mentioned occurred. Azathioprine was considered responsible for these two adverse reactions (shock) as an allergen. Later, systemic lupus eythematosus was diagnosed in 1996. And she died of pulmonary hypertension in May 1999. Physicians should be aware of the potential adverse effect of azathioprine administered in order to manage the patients with autoimmune disorders.

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A 13-years-old girl was admitted to our hospital with high levels of serum IgM, thrombocytopenia and splenomegaly. Not only IgG but also IgM were found on the surface of platelets by flow-cytometry. Direct Coombs' test was positive, and IgG was also found on the surface of red blood cells. After splenectomy, platelet count was increased and serum IgM was decreased. The biopsy of salivary glands showed infiltration of lymphocytes around the ducts, and Shirmer test revealed slightly decreased secretion of tears, suggesting subclinical Sjögren syndrome.

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We describe a case of a Japanese patient initially presenting with Sjögren's syndrome who later developed polymyositis and sarcoidosis. A 67-year-old woman with a 4 month history of myalgia was admitted in April 1998 for examination. The patient had a 10 year history of symptoms consistent with Sjögren's syndrome. A diagnosis of polymyositis was made based on a biopsy of the muscle and an electromyogram. Positive Shirmer and Rose Bengal tests and results of a minor salivary gland biopsy were all consistent with Sjögren's syndrome. Chest computed tomography detected a bilateral hilar lymphadenopathy. Microscopic examination of a mediastinal lymph node demonstrated multiple noncaseating granulomas with multiple epithelioid cells and Langhans-like giant cells. A diagnosis of sarcoidosis was made based on these findings. Hepatitis C infection was also detected by elevated antibody levels. The patient was given 40 mg/day of oral prednisolone and a remission of her myositis and lymphadenopathy was obtained. The patient exhibited HLA-B 7 and HLA-DR 8. HLA-DR 8 is commonly associated with these three disorders, and HLA-B 7 is also associated with overlap syndrome in Japanese patients. The present case suggested the possiblity of a common etiological background for these three disorders. Furthermore, the importance of genetic background, including HLA phenotype, in determining susceptibility to these disorders was demonstrated.

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We reported 2 children with suspected primary vasculitis of mesenteric vessels. Both children were admitted to our hospital with the complaints of abdominal pain, bloody stool or diarrhea. Laboratory examination simultaneously revealed leukocytosis with dominant neutrophils, positive CRP, and hypoalbuminemia. Although prothrombin time and activated partial thromboplastin time were within normal limits, the increased levels of FDP-E, D-dimer, and von Willebrand factor activity were observed, which suggested the endothelial cell activation and the coagulation/fibrinolysis system activation. Abdominal echography and CT scanning demonstrated the edematous thickening of intestinal or colon walls probably due to the vasculitic permeability changes of mesenteric artery. During the disease courses, skin rash, bleeding tendency, arthritis and proteinuria were not observed, and no autoantibodies including anti-nuclear antibody, anti-DNA antibody, and myeloperoxidase-antineutrophil cytoplasmic antibody, were detected. Taken together, we suspected these children as restricted vasculitis of mesenteric vessels. Intravenous prednisolon was administrated, and the clinical and laboratory abnormalities recovered completely within 2 weeks.
Thus, we suggested that the leukocyte counts, CRP, and the determination of von Willebrand factor and coagulation/fibrinolysis study accompanied with X-ray, echography, and CT scanning will be useful for the early diagnosis of vasculitis before the pathologic and irreversible vascular damage are demonstrated.

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We report three female patients with systemic lupus erythematosus complicated by massive intestinal hemorrhage during the recovery from lupus nephritis (cases 1, 2) or central nervous system lupus (case 3) on high dose corticosteroid therapy. Large number of cytomegalovirus (CMV) antigen-positive leukocytes and cessation of bleeding with concurrent disappearance of the viral antigens after ganciclovir therapy indicated CMV colitis in all of the three patients. No recurrence of the symptom and a favorable response to ganciclovir without reduction in steroid regimen was common to these patients.

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We report a case of a 31-year-old woman with common variable immunodeficiency (CVID) complicated with intractable diarrhea and the functional disorder of renal tubules. The patient became hypogammaglobulinemic after she suffered from measles at 6 years of age. She also suffered from lupus-like syndrome at 7 years of age. The complete remission was obtained by glucocorticosteroid treatment. An intravenous immunoglobulin replacement therapy was introduced at 11 years of age, since then her general condition was stable for more than 20 years. When she was 29 years old, she suffered from generalized malaise, anorexia with body weight loss, and numbness of face. The intractable diarrhea as protein loosing syndrome, and the severe abnormality of electrolyte balance with metabolic acidosis as the functional disorder of renal tubules were found. Her condition was not improved by the electrolytes or alkali replacement therapy. She was admitted for further evaluation and treatment. The intractable diarrhea and the functional disorder of renal tubules were dramatically improved after absolute restriction of food intake under hyperalimentation. When she began to take food, the symptom and sign became worse again. The interstitial nephritis and nonspecific inflammation of intestine were found by the tissue biopsy. The most characteristic finding was the infiltration of lymphocytes (predominantly CD 8+T lymphocytes) in both intestinal mucosa and renal interstitium. The introduction of glucocorticosteroids improved her general condition and biochemical findings. This CVID case is complicated with intractable diarrhea and the functional disorder of renal tubules which is associated with the infiltration of CD 8+lymphocytes in intestine and kidney. We consider that such case is very rare and valuable to report.

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