Objectives-To investigate whether apoptosis occurs in the synovium of rheumatoid arthritis (RA), and the intermediate molecules operating in this process. Methods-DNA fragmentation was detected by in situ nick end labelling (ISNEL) in the synovium ofpatients with RA (n = 11) and control patients with femoral neck fracture (n = 5). The expression of proteins p53, p21WAF1/CIP1, c-myc, proliferating cell nuclear antigen (PCNA), and Bcl-2 was also examined by immunohistochemistry. Results-ISNEL positive synovial cells with apoptosis specific morphology were detected in extremely limited areas in only two RA synovial tissue specimens. Proteins p53, p2lWAFl'cPl, and c-myc, known inducers ofapoptosis or cell cycle arrest or both, were expressed in the sublining cells independent of ISNEL positive cells. PCNA, a marker for cell proliferation, was observed in the synovial lining cells. Bcl-2, an inhibitor of apoptosis, was expressed mainly in infiltrated lymphocytes and in parts of the sublining layer cells of RA; it also did not correspond with ISNEL staining. Conclusions-Our findings indicate that RA synovial cells undergo apoptosis in addition to cell proliferation, but the frequency of apoptosis was very low. We suspect that the apoptotic process in the RA synovium may be suppressed by overexpression of Bcl-2. Although expressed proteins p53, p21WAFl'CIP1, and c-myc were present in the RA synovium, these protooncogenes are probably not implicated in the apoptotic process. (Ann Rheum Dis 1996; 55: 442-449) Apoptosis, or programmed cell death, is a fundamental process that occurs during morphogenesis and development of the immune system.' 2 Although the mechanism of apoptosis is still unclear, the process proceeds through the activation of an intrinsic cell suicide programme and exhibits specific morphology distinct from that associated with accidental cell death. However, synovial cell death does seem to occur during the natural history of RA, counteracting cell proliferation: the synovial fluid often contains rice bodies, which are thought to be derived from the synovial tissue as a result of cell death." 12 Moreover, during the late stage of the disease, the proliferated synovial tissue is replaced by connective tissue.'3 This suggests that apoptosis may also be involved in synovial cell death and in preventing the development of malignancy despite the neoplastic behaviour of synovial cells.To investigate whether apoptosis occurs in the synovium of RA, we studied DNA fragmentation by the in situ nick end labelling (ISNEL) method. We also used immunohistochemical techniques to examine proteins related to apoptosis or cell cycle arrest to investigate the state of synovial cells with respect to apoptosis. Patients and methods PATIENTS AND TISSUESInformed consent was obtained from each patient. Synovial tissue samples were obtained from 11 patients with RA at the time of joint replacement surgery of the hip or knee, or synovectomy of the wrist ( The overall degree of lymphocyte infiltration was assessed as ...

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The PI3K family is thought to participate in TLR signaling, and it has been reported to be a negative regulator of TLR-mediated production of IL-12, a key inducer of Th1 responses. However, the role of individual PI3K subtypes in IL-12 production remains obscure. We defined the distinct regulation of LPS-mediated IL-12 production by p110α and p110β catalytic subunits of PI3K in human APCs. We observed that knockdown of PI3K p110β by small interfering RNA (siRNA) suppressed both LPS-induced IL-12 protein production and mRNA expression in monocyte-derived macrophages and dendritic cells (DCs). Knockdown of PI3K p110α by siRNA reduced LPS-induced IL-12 protein production in both cell types. Conversely, knockdown of PI3K p110α suppressed LPS-induced IL-12 mRNA expression in monocyte-derived macrophages but minimally affected monocyte-derived DCs. PI3K p110β siRNA inhibited JNK activation, but not p38 MAPK or ERK activation, stimulated by LPS, while PI3K p110α siRNA did not affect LPS-induced JNK, p38 MAPK, or ERK activation in both cell types. Transfection of siRNA against JNK1, JNK2, and both decreased LPS-induced IL-12 production. Furthermore, PI3K p110β siRNA attenuated LPS-induced JNK1 phosphorylation, while not affecting JNK2 phosphorylation. Our findings indicate that PI3K p110β positively controls LPS-induced IL-12 production through the JNK1-dependent pathway in human macrophages and DCs.

Inhalation of asbestos increases the risk of lung cancer and pulmonary fibrosis. It is difficult to directly assess the distribution and content of inhaled particles in lung tissue sections. The purpose of this study is to employ an in-air micro particle induced X-ray emission (in-air micro-PIXE) system for assessment of the spatial distribution and content of asbestos and other metals in lung tissue. A proton ion-microbeam from this system was applied to irradiate lung tissue of patients with or without asbestosis, tumor tissue from both groups, and asbestos fibers (in vitro). The content of each element composing asbestos and those of other metals were calculated and their distribution was assessed from the characteristic X-ray pattern for each element obtained after irradiation. This in-air micro-PIXE system could identify the location of asbestos bodies composed of Si, Mg, and Fe in lung tissue sections. Macrophage and lymphocytes accumulated in that area. This new system also revealed deposits of titanium, nickel, and cobalt in the lung tissues, in addition to asbestos bodies. The Si and Fe content were higher in lungs with asbestosis than in lungs without asbestosis or in tumor tissue. Analysis of asbestos fibers composed of chrysotile, crocidolite, and amosite showed that the ratios of Si, Fe, and Mg corresponded with those for the chemical structures. In-air micro-PIXE analysis is useful for assessing the distribution and quantities of asbestos bodies and also other metals in lung tissue comparing to immune-related cell localizations, and is also useful for analysis of standard asbestos fibers.

A 65-year-old man experienced cough and shortness of breath 3 days after receiving the first dose of the Pfizer-BioNTech coronavirus disease 2019 (COVID-19) vaccine. Chest X-ray revealed bilateral infiltrates, and the desaturation deteriorated rapidly. The symptoms and radiographic abnormalities rapidly improved after the initiation of corticosteroid therapy. Intradermal testing of the Pfizer-BioNTech COVID-19 vaccine showed a delayed positive reaction. Based on these findings, the patient was diagnosed with COVID-19 vaccineinduced pneumonitis. The timing of the onset of pneumonitis after vaccination and the results of intradermal testing suggest that Type IV hypersensitivity against COVID-19 vaccine may have been responsible for this clinical condition.