Studies in Chronic Granulomatous Disease showed two breakthroughs during this past decade. First, the discovery of 7 Nox/Duox family proteins, Noxo1and Noxa1 (homologues of gp91^phox, p47^phox and p67^phox) may clarify novel physiological mechanisms for superoxide regulation in various organs, such as the regulation of blood pressure, mucosal defense system in respiratory/digestive tract and nephron. Secondly, the success in bone marrow transplantation and gene therapy for CGD should facilitate treatment for other genetic diseases as well.

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  Heme oxygenase (HO) plays a central role in heme metabolism. At the same time, it protects cells from injury evoked by various oxidative stresses. A detailed analysis of the first human case of HO-1 deficiency revealed that HO-1 is involved in the protection of multiple tissues and organs. It is particularly important that in vivo HO-1 production is localized to selected cell types, e.g. renal tubular epithelium, reflecting the fact that HO-1 plays particularly important protective roles in these cells. In addition to renal epithelial cells and tissue macrophages, a minor subpopulation of circulating monocytes produced low, but significant levels of HO-1 and the number of these monocytes increased during episodes of acute inflammatory illnesses, indicating that monocytes play significant roles in controlling inflammation. On the other hand, excessive level of HO-1 induced by HO-1 gene transfection led to paradoxical susceptibility of the cells to oxidative injury. These results indicated that HO-1 expression is carefully controlled in vivo with regard to its location and the magnitude. Furthermore, it has been recently shown that HO-1 is involved in the immune regulation mediated by regulatory T cells. From these findings, it seems feasible to meticulously induce HO-1 protein in vivo as a novel therapeutic intervention to control various forms of inflammatory disorders.

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  The immune and skeletal systems share a number of regulatory molecules including cytokines, signaling molecules, transcription factors and membrane receptors, in common. Consequently, the physiology and pathology of one system may very well affect the other. Research into the cartilage and bone destruction associated with rheumatoid arthritis (RA) has highlighted the importance of the interplay between the immune and skeletal systems. This interdisciplinary field called osteoimmunology has attracted much attention in recent years. Recently, animal models deficient in immunomodulatory molecules have been found frequently to develop an unexpected skeletal phenotype. Receptor activator of NF-κB ligand (RANKL) is an essential factor for the induction of osteoclastogenesis that links the immune and skeletal systems. Thus, osteoimmunology is becoming increasingly important for understanding the pathogenesis of bone destruction in RA and for developing new therapeutic strategies for diseases affecting both systems. Here we summarize recent advances on the study of the regulation of cartilage and bone destruction by the immune system.

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  T-cell telomerase activity was high in the active and inactive stages of systemic lupus erythematosus (SLE). In contrast, B-cell telomerase activity was very high only in the active stage. Compared with normal subjects, SLE patients had a shorter T-cell telomere, but their B-cell telomere length did not differ from that of normal subjects. These findings suggest that T cells are always activated, and that the manifestation of the disease requires the activation of not only T but also B cells. B-cell inhibition alone may be sufficient to suppress the clinical symptoms of SLE, but we consider that the essential treatment of SLE should target T cells as well. In recent years, various biologicals have begun to be used for the treatment of SLE. It is interesting how the use of such biologicals in the future will change T- and B-cell telomerase activity. In formulating a therapeutic strategy using biologicals for SLE, the measurement of telomerase activity in T and B cells seems useful for the preparation of target cells, selection of therapeutic drugs, and evaluation of therapeutic responses.

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  Recent clinical studies of rheumatoid arthritis reveal that therapeutic intervention early in rheumatoid arthritis leads to less joint damage, indicating the importance of early diagnosis of RA for improvement of prognosis. According to the data of our “Early Arthritis Prospective Cohort”, we have found that early arthritis patients, described as undifferentiated arthritis, progress to rheumatoid arthritis at high frequency if the patients positive with anti-cyclic citrullinated peptide antibody (anti-CCP antibody) and bone marrow edema at the entry. In addition, we are going to classify the pathologic status (disease severity) of early arthritis patients by serologic variables, radiographic findings and genetic analysis.

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  Recently, it has become possible to measure the concentration of serum cartilage oligomeric matrix protein (COMP) in various arthritis, and it is expected to be a novel biomarker indicative of cartilage destruction. In this study, we evaluated the diagnostic effectiveness of serum COMP in rheumatic diseases and analyzed the inhibition of cartilage destruction in patients with rheumatoid arthritis who were prescribed with infliximab (IFX) for one year. The changes in the concentration of serum COMP and the joint narrow space of Sharp score (ΔSharp-JNS) were evaluated. The level of serum COMP decreased from 23.04±7.14 U/l to 8.69±2.89 U/l (p<0.005) and improved ΔSharp-JNS (−0.50±6.38 points). We believed that these results were influenced by the effects of methotrexate (MTX) that was prescribed together with IFX, and we analyzed the group that was administered only MTX therapy as a reference. However, the serum COMP concentration and Sharp-JNS in the MTX group did not decrease. The serological and radiological results revealed that IFX inhibited cartilage destruction, and it is possible that serum COMP is one of the novel biomarkers in RA patients treated with anti-tumor necrosis factor-α antibody therapy.

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  A 52-year-old female visited the outpatient department of Sapporo Medical University hospital in 1984 due to a refractory rash on the skin of the trunk. Histological findings of a skin biopsy specimen indicated a diagnosis of lupus erythematosus profundus (LEP). The eruption remained quiescent with moderate doses of prednisolone. In October 2003, she was suddenly admitted to our hospital with abdominal pain, fever and bloody stool. Lupus enteritis was diagnosed based on an elevated level of anti-DNA antibody, low complementemia and diffuse edematous change of the intestinal walls on CT scans. Although high doses of corticosteroids resulted in transient improvement, melena developed again on the 24^th hospital day. Colonoscopy revealed deep ulceration at the rectum and a gastrografin enema indicated perforation. Accordingly, the involved rectum was resected and an artificial anus was constructed on the 50^th hospital day. Examination of the resected specimen by microscopy showed that the ulceration approached at the depth of the subserosal layer with intense infiltration of inflammatory cells around the vessels. The pathogenesis of the rectal lesion might have been due to vasculitis associated with systemic lupus erythematosus (SLE). The disease did not recur under the administration of 10 mg of prednisolone daily until November 2004. Colonic function made a remarkably untroubled recovery after the artificial anus was closed in February 2005. The LEP was generally accompanied by a mild form of SLE. This case seemed to be rare in that SLE was associated with severe lupus enteritis and a refractory rectal ulcer developed from LEP. Patients with SLE and intestinal involvement should be carefully monitored in cooperation with a surgeon.

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  We report a case of systemic lupus erythematosus (SLE) complicated with hypertrophic pachymeningitis. A 34-year old woman who was diagnosed as SLE in 1985 was admitted to our hospital for a high grade fever and a headache. Laboratory findings showed increased titer of anti-double strand DNA antibody and decreased number of platelets. She complained a severe headache and hearing loss which were worsened by head-up position, resembling the symptoms of intracranial hypotension. MRI findings revealed thickened dura and she was diagnosed as hypertrophic pachymeningitis. Both clinical symptoms and laboratory findings were resolved after methyl-prednisolone pulse therapy followed by a high dose of prednisolone. Although hypertrophic pachymeningitis is a rare complication with SLE, it should be considered in SLE patients with severe headache.

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