Interleukin-1β is widely known as an inflammatory cytokine, and is an important and indispensable factor to understand inflammation. Therefore many researchers have investigated function and property of interleukin-1β. However some questions still remain to be fully elucidated. To approach these questions, bioimaging technology has been exploited recently. As interleukin-1β is regulated by unique mechanism via transcriptional activation and protein processing, several imaging tools have been developed for analyzing interleukin-1β by applying the regulatory mechanism. In this review I introduce representative interleukin-1β-related imaging technologies including basic principle of them and findings obtained with them. Additionally I referred briefly to other imaging technologies for monitoring inflammation in the last section.

  Skin is an outermost organ that serves as an interface between the host and the environment. The skin provides not only mechanical barrier functions, but also an active immunological barrier that provides the first line of defense against infections. For the effective clearance of pathogens or antigens in the skin, immune cells, especially effector T cells, must quickly exert their effector functions while avoiding the host damage by their excess activation. Therefore, the quality, magnitude, and the duration of the effector T cell activity must be carefully regulated. Here, we will review our recent findings on the effector T cell dynamics, dendritic cell dynamics, and the regulatory mechanisms for effector T cells activation in the skin, as revealed by the live imaging techniques using multi-photon microscopy.

  Osteoclasts are bone-resorbing giant polykaryons that differentiate from mononuclear macrophage/monocyte-lineage hematopoietic precursors. We have originally established an advanced imaging system for visualizing in vivo behavior of osteoclasts and their precursors with intravital two-photon microscopy. By means of the system, we found that sphingosine-1-phosphate, a lipid mediator enriched in blood, controlled the migratory behavior of osteoclast precursors. We also developed pH-sensing chemical fluorescent probes to detect localized acidification by bone-resorbing osteoclasts on the bone surface in vivo, and identified two distinct functional states of differentiated osteoclasts, ‘bone-resorptive’ and ‘non-resorptive’. In this review, we summarize our recent studies on the dynamics and functions of osteoclasts. Our intravital imaging techniques would be beneficial for studying the cellular dynamics in arthritic inflammation and bone destruction in vivo and would thus be useful for evaluating novel therapies targeting aspects of osteoclast dynamics in patients with bone-destructive diseases.

  The nervous system and the immune system are two major systems in human body. Although it was revealed these two systems correlated, the control of immune cell dynamics by the nervous system has come to draw a lot of attention at the present time. Recent advances in basic and preclinical science reveal that reflex neural circuits inhibit the production of cytokines and inflammation in several animal models. One well-characterized cytokine-inhibiting mechanism, termed the “inflammatory reflex”, is dependent upon vagus nerve stimulation that inhibits cytokine production and attenuates the inflammation. And the mechanism for controlling lymphocyte trafficking becomes clear, and molecular basis of immune regulation by the nervous system was reported. On the other hand, the nervous system is protected from the invasion of harmful agents by the barrier. However, there are neuroimmunological disorders, which is associated with autoimmunity, tumor immunity, and infection immunity. Autoimmune autonomic ganglionopathy (AAG) is an acquired immune-mediated disorder that leads to widespread autonomic manifestations, in which autoantibodies to ganglionic nicotinic acetylcholine receptors play a central role. Previously, we elucidated the prevalence of extra-autonomic manifestations in patients with AAG. It is necessary to establish the new systems for the detection of autoantibodies to other subunits of acetylcholine receptor.

  Bone is a component of the skeletal-locomotor system but also functions as an immunological organ that harbors hematopoietic stem and progenitor cells. Since the immune and skeletal systems are closely related through a number of shared regulatory molecules including cytokines and receptors, bone can be affected in various immune disorders. Rheumatoid arthritis is a typical disease in which the immune system affects the bone metabolism. The enhanced activity of osteoclasts by the activation of Th17 cells causes the joint destruction in rheumatoid arthritis. Studies on bone destruction associated rheumatoid arthritis have highlighted the importance of the interplay between the immune and bone systems, and promoted the new interdisciplinary field of “osteoimmunology”. Furthermore, recent studies have suggested that regulation of bone tissues by IL-17 is more complicated than we had expected. IL-17-prodcuing cells contribute to new bone formation at the enthesis in ankylosing spondylitis, and IL-17-producing γδ T cells promote bone regeneration by acting on the mesenchymal stem cells in bone fracture healing. It would be necessary to comprehensively understand the interplay between the immune and bone systems for elucidation of the molecular mechanisms underlying the pathogenesis of various diseases that involves the two systems.

  Osteoclasts are differentiated from precursors of the monocyte/macrophage lineage originated from bone marrow hematopoietic stem cells and are the sole bone-resorbing cells in the body. Osteoclast differentiation is thought to require M-CSF (macrophage colony-stimulating factor) and RANKL (receptor activator of nuclear factor kappa-B ligand) signaling. However, it has recently been proposed that under chronic inflammatory conditions, such as systemic autoimmune diseases (e.g., rheumatoid arthritis), an increase in inflammatory cytokine levels within joints induces pathological osteoclast differentiation, causing excessive bone resorption. In addition, the authors have reported that stimulating mouse bone marrow monocytes and human CD14⁺ monocytes with combination of TNFα and IL-6 can induce differentiation of osteoclast-like cells, which are cells with bone resorption activity. In the present article, we discuss the mechanism of osteoclast differentiation of RANKL-independent bone-resorbing cells, using both data from the aforementioned report as well as the latest findings. Understanding the mechanisms underlying RANKL-independent, cytokine-mediated osteoclast differentiation could facilitate the development of novel therapies for inflammatory joint diseases.

  Kawasaki disease (KD), an acute childhood panvasculitis, presents a variety of ocular complications as well as conjunctival injection among the principal symptoms. However, most pediatricians are unfamiliar with the ophthalmological complications of KD. A 2-year-old girl was referred to us from the ophthalmology department due to injected bulbar conjunctivae and optic disc swelling. She had familial exudative vitreoretinopathy as an underlying disease and the ocular findings had been made by chance while the patient was receiving an eye examination. Although she was afebrile at the time of her first medical interview, KD was diagnosed based on the presence of four of the principal symptoms including fever and dilatation of the coronary arteries. Intravenous immunoglobulin (IVIG) therapy was administered on Day 15 from the onset of fever. After IVIG administration, her laboratory test results showed rapid improvement but her optic disc swelling continued for six months. Eye complications in KD generally occur in the anterior segment, and recovery occurs within two months. Past reports have shown that in three of seven KD cases with optic disc involvement, optic disc swelling lasted over two months. This is the second case in which the condition lasted six months.

  A 51-year-old man was detected nasal bleeding, multiple pulmonary nodule and mass, urinalysis abnormality, renal involvement and high titer of proteinase 3-anti-neutrophil cytoplasmic antibody (PR3-ANCA), and was suspected of granulomatosis with polyangiitis and initiated with steroid pulse therapy. On the day after the start of steroid pulse therapy, generalized peritonitis due to ileal perforation occurred, and emergency ileectomy and peritonitis surgery were performed. Induction therapy with steroid pulse therapy, plasma exchange and intravenous cyclophosphamide therapy (IVCY) and maintenance therapy with glucocorticoid and azathioprine led to good therapeutic outcomes. Gastrointestinal perforation in GPA is a rare complication, and we examined the clinical features, treatment contents, and prognosis of GPA with gastrointestinal perforation from this case and previous reports. Lung involvements were complicated in all reported cases. Gastrointestinal perforations in GPA were frequent in the small intestine, occurred just before and immediately after the start of treatment, and were severe involvement with poor prognosis because of the high mortality rate (46.7%). The frequency of ear, nose and upper respiratory tract lesions in the surviving group was significantly higher than in the dead group (survival 87.5%, death 28.3%, P = 0.041). IVCY were more frequently used in the surviving group (62.5%) than the death group (16.7%), but it was not significantly. GPA complicated with gastrointestinal perforation is a severe condition with poor prognosis, but there is a possibility to improve prognosis by early diagnosis and early initiation of strong treatment.

  A woman in her thirties was diagnosed as Takayasu's arteritis (TAK) by dilatation, wall thickness of her abdominal aorta in contrast-enhanced computed tomography. Although she didn't have any subjective bowel symptoms, fluorodeoxyglucose (FDG)-positron emission tomography (PET) also revealed uptake of FDG in descending colon, and colonoscopy revealed aphthous colitis. After the start of steroid therapy, both arteritis and colitis were improved. FDG-PET can detect TAK and inflammatory bowel diseases at an early stage. FDG-PET is a less invasive module with a high sensitivity for detecting colitis, therefore should be considered for TAK even without physical colon symptoms.