Superantigens are classified into 3 groups, bacterial, viral and plant. The first are products mainly of virulent pathogenic bacteria, such as Staphylococcus aureus, Streptococcus pyogenes and Yersinia pseudotuberculosis. The second are products mainly of endogenous or exogenous mouse mammary tumor viruses. A lectin from stinging nettle rhizome (Urtica dioica) was reported as a plant superantigen. Superantigens activate T cells in a TCR Vβ selective way in association with MHC class II molecules expressed on accessory cells, such as macrophages or dendritic cells. Most of the bacterial superantigens have been implicated in the pathogenesis of certain infectious diseases, such as toxic shock syndrome, scarlet fever, and Yersinia pseudotuberculosis infection. We consider that overactivation of T cells by bacterial superantigens is primarily involved in the pathogenesis of the infectious diseases caused by these bacteria.
In addition, it was reported that superantigenic factors are involved in the pathogenesis of Kawasaki disease, psoriasis, insulin-dependent diabetes melitus and rheumatoid arthritis. So far concrete evidences have not been obtained on the involvement of superantigenic pathogens in these autoimmune diseases. The concept of superantigen would increase its importance on the investigation of pathogenic mechanisms of infectious, inflammatory and autoimmune diseases.

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Rheumatoid arthritis (RA) is a deforming, destructive arthritis of unknown etiology. Although the true cause of RA is unknown, pathophysiology of joint destruction has been extensively studied for the past few years. The most pertinent pathological features of affected joint are neo-vascularization, cell infiltration, and thickening of synovial membrane, which all lead to joint destruction by eliciting abnormal immune reactions.
The abnormal immune reactions include production of various cytokines from cells in synovial membrane, and upregulated expression of adhesions molecules. CD 44 is ubiquitously expressed on cells in synovial membrane and is considered to be adhesion molecule, since it binds to hyaluronic acid which is present abundantly in articular matrix. Thus adhesion molecules act not only for transmigration of lymphocytes into synovial membrane but also for perpetuation of rheumatoid inflammation by holding inflammatory cells in articular matrix.
Hyaluronic acid has been used for treatment in patients with osteoarthritis. Recently, the double bind multi-center clinical trial clearly showed that the significant efficacy of hyaluronic acid in patients with RA. The basic and clinical profile of hyaluronic acid as an alternative therapeutic adjunct in patients with RA is briefly reviewed.

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Kawasaki disease, an acute febrile illness which affects infants and young children, is characterized by diffuse mucosal inflammation, indurative edema, polymorphous rash, and nonsuppurative cervical lymphadenopathy. About 15-20% of patients suffer coronary arterial damage, and they may develop myocardial infarction, chronic coronary insufficiency, and sudden death. Since Kawasaki originally described this disease entity in 1967, the number of such patients in Japan has reached 100, 000.
While the etiology is still unknown, the epidemiological features of this disease indicate that it is related to an infectious agent. Immunologically, both a highly increased level of several cytokines and the activation of immunocompetent cells have been demonstrated. Pathology have revealed that the vascular lesion begins with endothelial cell damage, the initial step of which may be activation of the endothelial cell to express ICAM-1 and ELAM-1 by cytokines. Thus, the etiologic factor (s) would predispose to an activation of both the immune system and the endothelial cells.
Some mitogenic materials including superantigen, stress protein, and so forth, would be the candidates. According to the clinical findings, inflammatory changes at the site of a previous BCG inoculation seems to be an early and specific manifestation of Kawasaki diseasse. We postulated that molecule (s) that are cross-reactive between the suspected infectious agent and the mycobacterial BCG antigen may contribute to this inflammatory process. Using BCG lysates or recombinant stress protein, HSP65, as antigen for Western blotting, convalescent, but not acute, phase sera of Kawasaki disease did react with HSP65 antigen, suggesting bacterial stress protein may be the causative agent which abnormally activate immune system. Moreover, epitope mapping of human mitochondrial protein, P1 antigen, indicated that convalescent phase sera of Kawasaki disease contained autoantibody to this human HSP65 cognate antigen.
Thus, Kawasaki disease may be induced by the exposure of bacterial HSP65, and recognition of autologous HSP65 cognate antigen by activated immune system may exaggerate the autoimmune response.

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We attempted to investigate the effect of air pollution on functions of neutrophils collected from Fisher rats exposed to diesel engine exhaust. Rats were exposed either to a high concentration of diesel exhaust (H-group) or to the diesel exhaust from which particles deprived through filters (non-dust; ND-group) for six months. The concentration of NO₂ gas and diesel exhaust particles was 2.6 ppm and 7.8 mg/m³ in H-group, and 2.1 ppm and 0.02 mg/m³ in ND-group, respectively. Phagocytic activity of the neutrophils from H-group was depressed. In addition, phagocytic activity of the neutrophils was further depressed in the ND-group. Neutrophil chemotaxis under agarose toward FMLP was decreased in either H-group or in ND-group, as compared with that of the control group.
These findings suggest that the inhalation of NO₂ may impair the peripheral blood neutrophil functions such as phagocytosis and chemotaxis. The preservation of the neutrophil phagocytic activity in H-group as compared with ND-group seems to be partly due to the modulation of the stimulated alveolar macrophage function by diesel particles ingestion, which may finally potentiate the neutrophil function. And the toxic gas elements of the inhaled exhaust may be easily absorbed into blood by reaching the higher concentration of gas to pulmonary alveolar regions, which leads to the deterioration of neutrophil phagocytic activity in ND-group.

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Chronic exposure to industrial dust is known to cause diffuse lung diseases such as silicosis. We hypothesized that other common and inactive small particles may cause activation of alveolar macrophages and provide the trigger for lung injury or pulmonary fibrosis, via synthesis of chemoattractant for neutrophils such as leukotriene (LT) B₄. SiO₂ (1 to 5 μmφ) was used as positive control, latex beads (0.1, 0.5, 1.0, 3.0 μmφ) were used as inactive particles. Those particles were incubated with rat alveolar macrophages at 37°C for 90 min. The amount of generated LTB₄, quantitated by reverse-phase HPLC, was 8.8±1.6 (control), 24±1.9 (SiO₂) (p<0.05), 17±1.7 (0.1μmφ latex beads), 31±2.2 (0.5 pm4 latex beads) (p<0.05), 37±3.8 (1 μmφ latex beads) (p<0.05), 20±2.1 (3μmφ latex beads) (p<0.05) ng/2×10⁶ cells. The concentration of LDH was also elevated in SiO₂ and latex beads (1 and 3 μmφ) (p<0.05) .
These results may suggest that inhaled inactive particles induce diffuse lung disease via generation of LTB₄.

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Myeloperoxidase (MPO) activity of peripheral polymorphonuclear leukocytes was examined in 5 patients with psoriasis and 5 patients with pustulosis palmaris et plantaris using a highly sensitive chemiluminescence method. Three patients with psoriasis (two pustular psoriasis and one psoriasis vulgaris) showed high MPO activities on per cell basis compared with the normal value, whereas there was no case exhibiting a high MPO activity among patients with pustulosis palmaris et plantaris. In these three patients with psoriasis, the oral administration of roxithromycin, 600 mg daily for 4 to 28 weeks, reduced the MPO activity of polymorphonuclear cells up to the normal value.
Our results indicate that roxithromycin has an in vivo ability to decrease the MPO activity of neutrophils and eosinophils.

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The purpose of this study was to investigate the changes in matrix accumulation, matrix metalloproteinase (MMP) activities and tissue inhibitor of metalloproteinase (TIMP) expression in glomeruli of anti-GBM and anti-Thy-1 nephritic rats. In glomeruli of anti-GBM nephritic rats, an increase in fibrous crescent was observed from day 20 to day 35. The activities of MMP 1, 2 and 9 significantly decreased in glomeruli of anti-GBM nephritic rats from day 1 to day 35. TIMP expression in mesangial area of anti-GBM nephritic rats increased rapidly from the 1st day with a peak of day 10. In addition, TIMP expression in crescent also increased by day 15 and more sustained increase until day 35. Mesangial matrix increased in glomeruli of anti-Thy-1 nephritic rats with a peak of day 8 and rapidly decreased to the normal level by day 30. The activities of MMPs in glomeruli of anti-Thy-1 nephritic rats showed little change during the experimental periods. Although TIMP expression in anti-Thy-1 nephritic rats increased from day 1 to day 8, then this expression decreased rapidly to the normal level by day 16. Trypsin-treated glomeruli of anti-GBM nephritic rats had a 12 fold increase in MMPs activities at day 5.
These results suggest that the maintained decline of MMPs activities in nephritic rats may be associated with the process of glomerulosclerosis.

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In order to clarify the antinephritic mechanisms of TJC-160, we investigated the effect on the increased expression of TIMP in glomeruli of crescentic-type anti-GBM nephritic rats. We administered TJC-160 (30mg/kg/day, p.o.) to the rats from the 20th day to the 35th day after anti-GBM nephritis induction. TJC-160 suppressed proteinuria and total/fibrous crescent formation in glomeruli. TJC-160 suppressed the increased expression of TIMP in crescent, compared to vehicle injected control nephritic rats. In addition, TJC-160 inhibited the decreased activities of metalloproteinase (MMP) -1 and 2, 9 in glomeruli. Despite the inhibition of the decreased MMP activities, TJC-160 did not enhance the MMP activities in normal glomeruli in the in vitro study. TJC-160 had no effect on the activity of MMP in trypsin treated glomeruli of nephritic rats at the 25th and the 35th days.
These data show that the effect of TJC-160 to inhibit the process of fibrous crescent formation in anti-GBM nephritic rats may be partly due to the ability of TJC-160 to prevent TIMP expression in nephritic glomeruli.

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