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The suppressive functions of Fc receptor and complement (C4.C3) receptors were studied in the granulocytes from patients with systemic lupus erythematosus (SLE). The inhibition of complement receptors was mainly due to immune complex bearing C4 or C3 fragments and to complement fragments in part, because 1. the inhibitory activity was present mostly in macromolecular fraction of SLE serum on gel filtration, and 2. the inhibitory activity was precipitated by 4% polyethylene glycol. The suppression of the complement receptors correlated with SLE disease activity.

Rheumatoid synovial fluids generated significantly greater amounts of superoxide, lysosomal enzymes, and superoxide dismutase from neutrophils into extracellular fluid than osteoarthritic synovial fluids. Rheumatoid factors isolated from serum suppressed superoxide-generating activity of performed immune complexes, but did not suppress that of intermediate-sized immune complexes isolated from RA serum. Synovial fluid neutrophils has a greater capacity to generate superoxide and lower intracellular superoxide dismutase activity, compared with peripheral neutrophils of the corresponding patients. These results suggest that neutrophil superoxide release may be modulated, both by rheumatoid factor and by intracellular and extracellular superoxide dismutase.

Changes of plasma, hypothalamic and pituitary immunoreactive beta-endorphin (IR-beta-end), methionine-enkephalin (IR-Met-enk) and ACTH (IR-ACTH) were studied under various conditions of feeding and watering in rats. When rats were fed from 17:00 to 09:00 hr and water was given ad lib, plasma IR-beta-end and IR-ACTH had parallel circadian rhythms with a peak before feeding and drinking. In the hypothalamus, IR-beta-end and IR-Met-enk showed parallel circadian rhythms with a decrease before these behaviors. When rats were fed from 09:00 to 17:00 hr, the peaks of plasma IR-beta-end and IR-ACTH shifted to one hour before the onset of feeding and drinking. When feeding and watering were restricted to 17:00-09:00 hr and 09:00-12:00 hr respectively, plasma IR-beta-end and IR-ACTH exhibited parallel circadian rhythms with two separate peaks at one hour before drinking and feeding, respectively. In the hypothalamus, IR-beta-end, IR-Met-enk and IR-ACTH showed parallel circadian rhythms with a decrease before feeding but not before drinking. When rats were fed from 17:00 to 20:00 hr, plasma IR-beta-end increased and neurohypophysial IR-beta-end and IR-Met-enk decreased at 16:00 hr, one hour before feeding. It was observed that locomotor activities increased at the time of transition from light to dark and at one hour before the onset of feeding and drinking. The present results suggest that endogenous opioid peptides may have some physiological roles in feeding and drinking behaviors.

The diagnostic criteria for malignant rheumatoid arthritis (MRA), which was proposed by the Research Group of MRA and periarteritis nodosa supported from the Ministry of Health and Welfare has been widely used since 1973. This diagnostic criteria was established for selecting RA patients with life-threatening extraarticular manifestations caused by vasculitis. However, in practice, RA patients with extraarticular involvements related to vasculitis, as well as, cases which were not related to vasculitis were diagnosed as MRA in this criteria. Because of the aforementioned and after research, we revised the diagnostic criteria for MRA. At first, we defined MRA as RA patients having intractable and severe extraarticular manifestations by various causes including vasculitis. One hundred and sixty-nine patients with MRA and 227 patients with RA from 39 medical facilities were analysed. Sixteen extraarticular clinical manifestations and 9 laboratory findings were compared between MRA and RA patients. Comparison of specificity in each criterion for MRA was made by using the Second quantitative analysis. Thereafter, the combinations of the variables which were most specific to MRA were studied. At the same time, sensitivity and specificity for MRA were also studied. The revised criteria are as follows: A. Clinical and Laboratory Findings--(1) visceral infarction, (2) myocarditis, (3) skin ulcer or skin infarction, (4) episcleritis or iritis, (5) polyneuritis, (6) high titers of rheumatoid factor, (7) immune complexes or low complement levels, (8) subcutaneous nodule, (9) pleuritis or pericarditis, (10) interstitial pneumonitis or lung fibrosis. B. Histopathological Findings from Biopsy Specimens--necrotizing vasculitis and/or granulomatous vasculitis and/or endoarteritis obliterans in small and/or medium size arteries.(ABSTRACT TRUNCATED AT 250 WORDS)

It has been suggested that human neutrophils exposed to performed immune complexes or activated complement fragments generate O2- anions in extracellular medium. In vivo studies have revealed that oxygen intermediates produced by immune complex-activated neutrophils play an important role in subsequent tissue damage. Since it is difficult to obtain direct evidence that O2- is released into plasma in patients with systemic lupus erythematosus (SLE), we studied the capacities of their sera to stimulate O2- release by human neutrophils in vitro. Sera from patients with SLE significantly enhanced O2- generation by neutrophils compared to normal sera. The enhancing activity of serum in the induction of increased O2- generation correlated positively with the presence of serum immune complexes and negatively with serum complement levels. The enhancing factors were analyzed by serum fractionation on Sephadex G-200 gel filtration, and were concluded to be immune complexes of intermediate size containing an activated complement fragment.

Evidence was obtained for the binding of C1q to the membrane of cultured vascular smooth muscle cells derived from human umbilical cord veins. C1q was fixed to the cell membrane at 4 degrees C, whereas it was ingested into the cytoplasm, as a cytoplasmic inclusion, when tested at 37 degrees C. The addition of C1q in advance inhibited the subsequent binding of C1q. Neither fibronectin nor laminin was detected on the cell membrane. Aggregated IgG bound to vascular smooth muscle cells in the case of preincubation with C1q at 4 degrees C, whereas aggregated IgG did not bind to the cells in the absence of C1q. The addition of C1q molecules to the cells in suspension enhanced superoxide generation by vascular smooth muscle cells. There was no effect of C1q on superoxide generation by the cells in monolayer. These results suggest that C1q binds on the membrane of vascular smooth muscle cells via its specific receptor that mediates immune complex binding to the cells and superoxide generation. These properties elucidate the mechanisms by which circulating immune complexes deposit in the vascular wall, and subsequent degradation of tissue components surrounding vascular smooth muscle cells occurs through oxidative burst of the cells.

51Cr release as lytic and cell detachment as nonlytic injury were employed to estimate neutrophil-mediated injury of cultured human vascular smooth muscle cells and endothelial cells. The reagents hydrogen peroxide or hypoxanthine-xanthine oxidase produced dose-dependent killing and nonlytic cell detachment, which were specifically inhibited by catalase but not by superoxide dismutase. The concentration of hydrogen peroxide or xanthine oxidase to induce cell detachment was less than lytic dose, suggesting that cell detachment was a much more sensitive assay of injury. Neutrophil-mediated cell lysis averaged 15% at most and was mostly dependent on hydrogen peroxide, while neutrophil-mediated cell detachment was nearly 100% and its dependency on hydrogen peroxide varied from 46% to 60%. These results suggest that vascular smooth muscle cells and endothelial cells in neutrophil-mediated events are destroyed by a hydrogen peroxide-dependent process, mainly via a nonlytic cell detachment mechanism. There was no striking difference of sensitivity to hydrogen peroxide between vascular smooth muscle cells and endothelial cells. Vascular smooth muscle cells and endothelial cells contained fairly high concentrations of superoxide dismutase, but not catalase, activity. The sensitivity of these cells to hydrogen peroxide but not to superoxide may arise from the fact that these cells lack intracellular catalase activity. The injury of vascular cells, which constitute important components of blood vessels, may lead to vascular injury and subsequent tissue damage.

Serum antibodies to cytoskeletal systems were measured by indirect immunofluorescence using human skin fibroblasts and HEp2 cells as substrate. Healthy adults had IgM antibodies to vimentin and cytokeratin at 60 times serum dilution. IgG concentration did not have a correlation with IgG anti-cytoskeletal system antibodies and IgM concentration correlated with anti-vimentin and anti-cytokeratin antibodies. In patients with adult T-cell leukemia (ATL), IgG antibody titer against actin and vimentin was increased in spite of a decreased IgG concentration. IgM antibodies to vimentin was decreased in its titer together with a decreased IgM concentration. Antibody titer to HTLV-1, leukemic cell counts in peripheral blood and disease type, acute or chronic, did not have correlations with anti-cytoskeletal system antibodies. A third of the patients with ATL showed negative anti-EBNA antibody, suggesting that the functional impairment in EBV-specific killer cells was present. In contrast, the patients with infectious mononucleosis showed increased serum IgM concentration and IgM anti-vimentin antibody titer. It was suggested that the autoantibodies to cytoskeletal systems associated with viral infection were mainly composed of IgG in ATL and of IgM in infectious mononucleosis.

The immunoblot technique was used to detect low molecular weight IgM (LMWIgM) in the serum and synovial fluid (SF) of patients with rheumatoid arthritis (RA). LMWIgM was detected in 64% of 58 RA sera and in 47% of 17 RA SF. The levels of IgM and rheumatoid factor (RF) were significantly higher in the positive sera of LMWIgM. Sequential studies revealed that LMWIgM appeared in the serum while the titer of RF was high. Our analysis also suggested the presence of several other oligomeric LMWIgM with monomeric IgM.

To study the physiological roles of endogenous opioid peptides in drinking and feeding behaviors, the effects of water deprivation and fasting on plasma immunoreactive (IR) beta-endorphin (beta-end), IR-Antidiuretic hormone (ADH) and IR-Prolactin (Prl), pituitary IR-beta-end and IR-methionine-enkephalin (IR-Met-enk) and IR-ADH, and hypothalamic IR-beta-end and IR-Met-enk were observed in rats. The effects of water deprivation on hypothalamic dopaminergic system was also studied. In water deprived rats, plasma IR-beta-end and Prl were decreased significantly. In the neurointermediate lobe, IR-Met-enk, but not IR-beta-end, was decreased, although these peptides did not change in the anterior lobe and hypothalamus. Intraperitoneal injection of haloperidol reversed the decrease in plasma IR-beta-end in water deprived rats but did not change it in control rats. Subcutaneous injection of CB-154, on the other hand, decreased the plasma IR-beta-end in control rats but not in water deprived rats. The dopamine (DA) turnover rate in hypothalamus, in addition, was increased in water deprived rats as compared with controls. In fasted rats, IR-beta-end in plasma, but not in pituitary lobes and hypothalamus, was increased. The present results suggest that the increase of hypothalamic dopaminergic activity, in part, is related to the suppressed secretions of pituitary IR-beta-end and Prl in water deprivation, and plasma IR-beta-end play some roles in feeding behavior in rats.

It would appear to us that the patients with rheumatoid arthritis (RA), in whom articular bone lesions were confined to the wrist and/or carpal joints in X-ray films, may follow a milder disease activity than do the patients with the hand and finger joint lesions. To clarify it, the present study was performed retrospectively. RA patients showing stage II or more lesions in the wrists and/or carpal joints but no lesions over stage II in any hand and finger joint (MCP, IP and PIP) radiologically after 5 years or more duration were regarded as the carpal type (C type). The clinical and laboratory data were compared between 44 patients of the C type RA and 44 patients of other type RA, matched in the sex, age and disease duration. Significant differences were observed in the following parameters between the 2 groups; the functional class, Lansbury's activity index, number of the affected joints, ESR, CRP and hemoglobin values, and ADL scores. That is, Hb values and ADL scores were higher, but the others were lower, in the C type RA group than in other type RA group. The positive percentage and titer of rheumatoid factor were not significantly different between the 2 groups. It was concluded that C type RA patients are milder in the activity and fewer in the number of affected joints than other type RA patients. Furthermore it was suggested that C type RA patients may have milder clinical course and better prognosis than other type RA patients.

The circadian rhythm, suppression with dexamethasone, and stimulation by corticotropin-releasing hormone (CRH) of plasma immunoreactive (IR) proopiomelanocortin N-terminal (NT) and IR-ACTH were studied in nine normal subjects and two patients with Addison's disease. The RIA for human NT (hNT) used was specific for NT except for partial cross-reactivity with gamma 2MSH. In normal subjects, plasma IR-hNT and IR-ACTH had almost parallel circadian rhythms and were suppressed by dexamethasone. The mean plasma levels of IR-hNT and IR-ACTH at 0800 h were 140 +/- 23 (SD) and 23 +/- 5 pg/ml, respectively. Plasma IR-hNT increased in parallel with IR-ACTH 15 to 30 min after iv injection of 100 micrograms ovine CRH. Maximum percent increases in plasma IR-hNT and IR-ACTH were 185 +/- 47 and 235 +/- 10%, respectively. In Addison's disease, on the other hand, plasma levels of IR-hNT and IR-ACTH were markedly elevated and the circadian rhythms were parallel. The mean plasma IR-hNT and IR-ACTH levels at 0900 h were 4363 and 1750 pg/ml, respectively. These results suggest that plasma hNT and ACTH are produced from a common precursor in the pituitary gland and secreted concomitantly under various physiological conditions such as stimulation by CRH and inhibition by glucocorticoid.

We have encountered a patient with rheumatoid arthritis (RA) who developed multiple subcutaneous swellings containing sterile milky fluid. The resected material showed chronic granulomatous changes compatible with rheumatoid inflammation. We suggest that multiple chronic rheumatoid inflammation may occur in the bursae as well as joint synovium as one of the extraarticular manifestations of RA.

Under apparently normal conditions, the smooth muscle cells obtained from veins of human umbilical cord do not possess receptors for C3b or the Fc portion of IgG. These receptors were not expressed even after exposure to neutrophil lysate or a superoxide-generating system. The lack of these receptors argues against the possibility that smooth muscle cells participate in the pathogenesis of immune complex diseases through binding of C3b or Fc fragments.

A differential diagnosis of polymyalgia rheumatica (PMR) and rheumatoid arthritis (RA) can be difficult in elderly patients, especially at the prodromal phase of RA. Furthermore, it was felt that there might be a diagnostic criteria for PMR specific to the Japanese. Accordingly, we have retrospectively studied the PMR patients who had come to our hospital, for making a diagnostic criteria. We especially stressed the distinguishing of PMR from RA in elderly patients. The criteria proposed are as follows: 1. Bilateral muscular pain persisting for 2 weeks at least in more than two of the following areas; neck, shoulders or shoulder girdle, upper arms, hips or pelvic girdle and thighs. 2. Normal serum myogenic enzymes. 3. ESR of more than 40 mm/h. 4. No swelling in the hand joints. PMR is defined by the presence of all of the 4 items. The criteria demonstrated a 93.1% sensitivity and 98.3% specificity for PMR.

Exposure of normal human serum to various concentrations of hydrogen peroxide as low as 68.8 microM resulted in the generation of chemotactic activity for human neutrophils, which was inhibited by adding catalase prior to the exposure. Maximum chemotactic activity was obtained by hydrogen peroxide at a concentration of 1.1 mM, and the concentration greater than 1.1 mM expressed decreased activity. On the contrary, hydrogen peroxide less than 1.1 mM produced dose-dependent chemotactic activity. The generation of chemotactic activity is initiated at an incubation time of 5 minutes, and subsequently increases with up to 90 minutes. The suppression of chemotactic activity was minimum even after 180 minutes. The maximum activity was obtained by 1024-fold dilution of serum treated with 13.8 mM hydrogen peroxide. These results suggest that the disappearance of chemotactic activity at the high-dose range of hydrogen peroxide is due to neutrophil deactivation rather than inactivation of the chemotactic activity after it was generated. Similarly, purified human C5 exposed to hydrogen peroxide generated chemotactic activity. The chemotactic activity was inhibitable by antiserum to human C5. The molecular weight of chemotactically active substance was approximately 15,000. The generation of chemotactic activity was not inhibited by addition of EGTA or EDTA. These results imply that hydrogen peroxide generates C5a-like chemotactic factor through hydrolysis of C5.