Rheumatoid arthritis (RA) and collagen-induced arthritis (CIA) are characterized by hyperplasia of the synovium and progressive joint destruction. The transcription factor-κB (NFκB) plays apivotal role in the coordinated transactivation of cytokine and adhesion molecule genes, whose activation has been postulated to be involved in destructive changes of articular cartilage and bone in arthritic joints. In particular, interleukin-1 (IL-1) and tumor necrosis factory α (TNFα) are important cytokines which perpetuate arthritis and induce joint destruction in both rheumatoid arthritis and collagen-induced arthritis. We hypothesized that synthetic double-stranded DNA high affinity for NFκB could be introduced in vivo as“decoy” cis elements to bind the transcription factor and to block the activation of proinflammatory cytokine genes such as IL-1 and TNFα. We reported here that in vivo transfection of NFκB decoy ODN by intraarticular injection into collagen-induced arthritis in rats improved paw swelling. Histologic and radiographic studies showed a marked suppression of joint destruction in ankles treated by NFκB decoy ODN transfection. NFκB decoy ODN also suppressed the production of IL-1 and TNFα by synovium in the arthritic joints. Results demonstrated that administration of NFκB decoy ODN in arthritic joints of collagen-induced arthritis in rats led to amelioration of arthritis. These findings suggest that intraarticular transfection of NFκB decoy ODN may provide a useful therapeutic strategy for inflammatory arthritis.

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Antimicrobial peptides, defensins (human β-defensins, hBDs-1/-2) and LL-37 (a peptide of human cathelicidin CAP 18) are expressed at epithelial tissues, where they participate in the innate host defense by killing invaded microorganisms. We have evaluated the effects of hBD-1/-2 and LL-37 on mast cell functions (histamine release and PGD₂ production) using rat peritoneal mast cells. The results revealed that hBD-2 and LL-37 but not hBD-1 induced histamine release and intracellular Ca²⁺ mobilization, and that hBD-2 was more potent than LL-37. Interestingly, histamine release and intracellular Ca²⁺ mobilization elicited by hBD-2 and LL-37 were markedly suppressed by both pertussis toxin (PTx) and U-73122, a phospholipase C (PLC) inhibitor. In addition, among the peptides examined, only hBD-2 induced PGD₂ production that was completely abolished by indomethacin (COX-1/-2 inhibitor) but not NS-398 (COX-2 inhibitor), suggesting that hBD-2-induced PGD₂ production is mediated by COX-1 but not COX-2. Likewise, the PGD₂ production was completely suppressed by PTx and U-73122. We suggest that hBD-2 and LL-37 activate mast cells to mobilize intracellular Ca²⁺ and release histamine or generate PGD₂ in a G protein-PLC-dependent manner. Thus, hBD-2 and LL-37 may have modulatory effects on inflammatory and allergic reactions by releasing histamine and/or prostanoids from mast cells.

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Systemic lupus erythematosus (SLE) involves multiple genes. Major genes that predispose to SLE are related to key events in pathogenesis, and may involve a variety of genes in immune system. Because of complex polygenic control and of heterogeneity of human genome, several hundred affected sibpairs are assumed to be necessary to show linkages for many of the contributing loci. In this respect, SLE-prone mouse strains are useful for the genome-wide search of SLE-susceptibility candidate genes. In the present studies, we analyzed genetic contribution to the aberrant activation of B cells using SLE-prone (NZB×NZW) F1 mouse model. Results showed that NZB type regulatory region polymorphism in FcγR IIB gene on chromosome 1 was significantly linked to hyper-IgG and high level of IgG anti-DNA antibodies. Extensive studies on murine models are expected to form the basis for identification of target genes and for clarification of the genetic mechanisms underlying SLE.

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The gastrointestinal tract is colonized with more than 10¹⁴ micro-organisms that weigh more than 1 kg. Such microflora are in close contact with the largest mass of lymphoid tissue in the body, the gut-associated lymphoid tissue, and thereby provides the principal driving force in postnatal maturation of the mammalian immune system. Our studies of germ-free animals showed that if such stimuli are not available to the developing immune system during infancy, the maturation of Th 1-dependent immune-deviation mechanisms is inhibited, resulting in a possible lifelong dysregulation of Th 2 response. Recently, several studies showed that psychological stress disrupts the integrity of the intestinal microflora and thereby contributes to the symptomatology of functional gastrointestinal disorders. Furthermore, our recent work demonstrated that such microflora modulate the regulation of hypoth-alamic-pituitary-adrenal axis function in response to stress exposure, which indicates bidirectional communication between the brain and intestinal microflora. Taken together, these results suggest that intestinal microflora and/or their bacterial products, such as lipopolysaccharide and peptidoglycan, stimulate phagocytic cells within the o gut-associated lymphoid tissue, the brain, or elsewhere, and thus influence the function not only of immune system but also of central nervous system.

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We have searched the human genome for genes that predispose to rheumatoid arthritis using microsatellite marker analysis and affected sib-pair linkage studies. Three principal chromosome regions of linkage, D1S253/214, D8S556 and DXS 1232/984, have been assigned for rheumatoid arthritis disease loci. We are now assigning the truncated form of Dbl proto-oncogene, which does not contain the 23^rd and 24^th exons, as a candidate gene for DXS 1232/984. Dbl proto-oncogene is one of the GDP/GTP exchange factors and activates Rho family GTPase. In this minireview, We describe our results and Rho family dependent signal transduction correlated with congenital diseases. Genetic linkage mapping and progress of genomic sequence-project will make it possible to identify new genes correlated with many diseases.

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Host responses against mycobacterial infection result in protection and granulomatous inflammation. Mycobacterial and host factors participate in the process. Mycobacteria are rich in lipids that may be involved in the pathogenesis. Host responses against the infection include both cell-mediated immune responses (host defense) and delayed-type hypersensitivity (expression of lesions) . A surface glycolipid of tubercle bacilli acts as both nonspecific inflammatory stimulus and specific T cell-dependent immunogen. Hosts produce chemokines, proinflammatory and immunoregulatory cytokines in response to glycolipids. The event leads to the recruitment of mononuclear cells, angiogenesis, and apoptosis. Mycobacterial glycolipid is a pleiotropic molecule, which induces pathogenesis and protective responses in the host. The pathogenesis of mycobacterial disease is a multistep process, involving a complex interaction between a range of bacterial and host factors.

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The purpose of the present study was to examine whether bacterial biofilm concerned with bacterial colonization and growth of subgingival plaque. We observed subgingival plaque of 95 severe adult periodontitis-affected teeth by scanning electron microscope. In the coronal one-third zone of subgingival plaque, cocci, rods and others established biofilm by glycocalyx-like structure. In the middle one-third zone, several kinds of bacterial species were coaggregated. Film-like microcolonies were also observed in this zone. We detected filamentous microorganisms appeared to come out from the film-like colonies, and observed holes which microorganisms had been passed through the colonies. In the apical one-third zone, several kinds of bacterial species aggregated by glycocalyx-like structures, which comprised netlike and mucoidal structure. In the “plaque-free zone”, two types of bacterial colonization were observed : bacterial cell wall directly contacted with the root surface, and microorganisms adhered to the root surface mediated by glycocalyx netlike materials. In this zone, five periodontal disease-associated bacteria, including Porphyromonas gingivalis, were detected using back-scattered electron imaging modes. The results of the present study suggested that bacterial biofilms were partially related to colonization and growth of subgingival plaque.

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Conventional NSAIDs therapy include the risk of developing significant injury to upper gastrointestinal (GI) tract and annualized incidence rate of symptomatic ulcer and ulcer complication in NSAIDs users ranged from 2% to 4%. In a Japanese survey of 1, 068 patients with GI mucosal damages in 1989, high figures were obtained for gastric lesion, i. e., over 60% for gastric mucosal damage, about 40% for gastritis, and about 15% for gastric ulcers duo to use of NSAIDs, while the figure was under 2% for duodenal ulcers, unlike in other countries. To determine whether the frequency of NSAIDs GI lesion in recent 10 years has a lower incidence of GI lesion compared with before and we evaluated the prophylactics efficacy of teprenone against NSAIDs induced lesions.
Material and methods ; We investigated in a large scale survey of prevalence of upper GI ulcers in total patients with rheumatoid arthritis (RA) (5, 915 cases) and osteoarthritis (OA) (3, 377 cases) who were required NSAIDs therapy and also evaluated NSAIDs ulcer prevention by co-administration of teprenone. Evaluated period was ranged from 1991 to 1999.
Results and conclusions ; The GI ulcer complications were seen more than 2 from 1991 to 1993. However, incidence of lesions was gradually deceasing from 1994 and at 1998 and 1999, occurrence rate of GI ulcers was less than 0.5%. A comparison of incidence of GI ulcers between teprenone co-administered group (T group) and none defensive drug users group (none T group) revealed that the incidence was significantly lower for the T group than none T group.
These results indicated that the incidence NSAIDs induced GI ulcers in Japan was obviously decreasing and teprenone extras a strong prophylactic effect against NSAIDs induced lesions.

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