Phospholipase A2 (PLA2) comprises a superfamily of enzymes that hydrolyse the ester bond of phospholipids at the sn-2 position. Among the members of this superfamily, cytosolic PLA2 has attracted attention because it preferentially hydrolyses arachidonoyl phospholipids and is activated by submicromolar concentrations of Ca2+ ions and by phosphorylation by mitogen-activated protein kinases (MAP kinases). Here we investigate the function of cytosolic PLA2 in vivo by using homologous recombination to generate mice deficient in this enzyme. These mice showed a marked decrease in their production of eicosanoids and platelet-activating factor in peritoneal macrophages. Their ovalbumin-induced anaphylactic responses were significantly reduced, as was their bronchial reactivity to methacholine. Female mutant mice failed to deliver offspring, but these could be rescued by administration of a progesterone-receptor antagonist to the mother at term. Considered together with previous findings, our results indicate that cytosolic PLA2 plays a non-redundant role in allergic responses and reproductive physiology.

The interleukin 7 receptor (IL-7R) plays a crucial role in early B-and T-cell development. It consists of a unique a chain and a common y chain [IL-2 receptor y chain (IL-2Ry)]. Gene inactivation of IL-7, IL-7R, and IL-2Ry resulted in severe impairment of B and T lymphopoiesis in mice. In addition, IL-2Ry-deficient mice lack yS T cells in the skin and have the impaired development of natural killer (NK) cells and intraepithelial lymphocytes. To explore the role of IL-7/IL-7R system in yS T-and NK-cell development, we have generated and analyzed IL-7R-deficient mice. y6 T cells were absent from skin, gut, liver, and spleen in the deficient mice. In contrast, c43 T and B cells were detected in reduced, but certain, numbers, and NK cells developed normally. The y6 T-cell development in fetal and adult thymus was also completely blocked. These results clearly demonstrate that the signal from IL-7R is indispensable for y6 T-cell development in both thymic and extrathymic pathways. On the contrary, it is suggested that NK-cell development requires cytokine(s) other than IL-7.Interleukin 7 (IL-7) is a growth factor for early B-and T-cell precursors. It was first characterized by its ability to support the growth of B-cell precursors. Subsequently, it has been shown to support survival and growth of early thymocytes and promote rearrangement of T-cell receptor (TCR) ,B and -y chains in fetal thymus and fetal liver cultures (1, 2). In vivo administration of neutralizing antibodies to IL-7 and IL-7 receptor (IL-7R) resulted in the inhibition of both B and T lymphopoiesis (3, 4). IL-7R consists of two polypeptides: a unique a chain (IL-7Ra) and a common -y chain (IL-2R 'y chain, IL-2R-y) (5, 6). IL-7R shares the IL-2R-y with the receptors for IL-2, IL-4, IL-9, and IL-15 (7 and V-y4 but not of V-y3 or V-y5 genes and sustained expression of RAG-1 and RAG-2 genes (1, 2). Collectively, these results strongly suggest that IL-7 may be also involved in the development and the maintenance of 'y6 T cells in the thymus and the periphery. Gene inactivation studies have been carried out to elucidate the in vivo function of various cytokines and their receptors. In IL-2R-y-deficient mice, numbers of T, B, and natural killer (NK) cells are reduced (15,16). In addition, DETCs are absent from the skin and the development of IELs is severely diminished. In contrast, mice deficient for IL-2, IL-4, or both cytokines have normal numbers of mature T and B cells (17, 18). On the other hand, in both IL-7-and IL-7R-deficient mice, the numbers of lymphocytes are reduced (19,20), suggesting that the impairment of T and B lymphopoiesis in IL-2Ry-deficient mice is caused by depletion of the signal by IL-7. However, studies have not been reported on the development of y8 T and NK cells in IL-7R-deficient mice.To elucidate the role of IL-7/IL-7R system in y8 T-cell development, we have generated and analyzed IL-7R-deficient mice. yS T cells were absent from these mice, while decreased, but certain, numbers of mature af3 T cells were detected. ...

Reactive arthritis (ReA) is typically preceded by sexually transmitted disease or gastrointestinal infection. An association has also been reported with bacterial and viral respiratory infections. Herein, we report the first case of ReA after the he severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. This male patient is in his 50s who was admitted with COVID-19 pneumonia. On the second day of admission, SARS-CoV-2 PCR was positive from nasopharyngeal swab specimen. Despite starting standard dose of favipiravir, his respiratory condition deteriorated during hospitalisation. On the fourth hospital day, he developed acute respiratory distress syndrome and was intubated. On day 11, he was successfully extubated, subsequently completing a 14-day course of favipiravir. On day 21, 1 day after starting physical therapy, he developed acute bilateral arthritis in his ankles, with mild enthesitis in his right Achilles tendon, without rash, conjunctivitis, or preceding diarrhoea or urethritis. Arthrocentesis of his left ankle revealed mild inflammatory fluid without monosodium urate or calcium pyrophosphate crystals. Culture of synovial fluid was negative. Plain X-rays of his ankles and feet showed no erosive changes or enthesophytes. Tests for syphilis, HIV, anti-streptolysin O (ASO), Mycoplasma, Chlamydia pneumoniae, antinuclear antibody, rheumatoid factor, anticyclic citrullinated peptide antibody and Human Leukocyte Antigen-B27 (HLA-B27) were negative. Gonococcal and Chlamydia trachomatis urine PCR were also negative. He was diagnosed with ReA. Nonsteroidal Anti-Inflammatory Drug (NSAID)s and intra-articular corticosteroid injection resulted in moderate improvement.

ObjectivesEvaluation of rituximab and glucocorticoids as therapy to induce remission after relapse in ANCA-associated vasculitis (AAV) in a prospective observational cohort of patients enrolled into the induction phase of the RITAZAREM trial.MethodsPatients relapsing with granulomatosis with polyangiitis or microscopic polyangiitis were prospectively enrolled and received remission-induction therapy with rituximab (4×375 mg/m2) and a higher or lower dose glucocorticoid regimen, depending on physician choice: reducing from either 1 mg/kg/day or 0.5 mg/kg/day to 10 mg/day by 4 months. Patients in this cohort achieving remission were subsequently randomised to receive one of two regimens to prevent relapse.Results188 patients were studied: 95/188 (51%) men, median age 59 years (range 19–89), prior disease duration 5.0 years (range 0.4–34.5). 149/188 (79%) had previously received cyclophosphamide and 67/188 (36%) rituximab. 119/188 (63%) of relapses had at least one major disease activity item, and 54/188 (29%) received the higher dose glucocorticoid regimen. 171/188 (90%) patients achieved remission by 4 months. Only six patients (3.2% of the study population) did not achieve disease control at month 4. Four patients died in the induction phase due to pneumonia (2), cerebrovascular accident (1), and active vasculitis (1). 41 severe adverse events occurred in 27 patients, including 13 severe infections.ConclusionsThis large prospective cohort of patients with relapsing AAV treated with rituximab in conjunction with glucocorticoids demonstrated a high level of efficacy for the reinduction of remission in patients with AAV who have relapsed, with a similar safety profile to previous studies.

We have previously shown that following oral administration of myelin basic protein (MBP), regulatory T cells are generated from gut-associated lymphoid tissue and that these cells suppress experimental allergic encephalomyelitis (EAE). These regulatory T cells produce transforming growth factor-beta (TGF-beta) with various amounts of IL-4 and IL-10 and these TGF-beta-secreting T cells have been termed Th3 cells. T cells in lymphoid organs drained by mucosal sites secrete IL-4 as a primary T cell growth factor. In the present study, we examined the role of IL-4 on oral tolerance and in the generation of TGF-beta secreting cells. Treatment of (PLJ x SJL)F1 mice with intraperitoneal (i. p.) IL-4 and low-dose oral MBP (0.5 mg) given three times reduced the severity of EAE, whereas i.p. injection of IL-4 alone or oral MBP alone given in these suboptimal doses, showed no protection. Spleen cells from protected mice produced increased amounts of TGF-beta and reduced IFN-gamma upon stimulation with MBP in vitro. Mucosal MBP-specific IgA production was significantly increased in IL-4 plus MBP fed animals. Moreover, oral administration of IL-4 (1 microg per feeding) also enhanced the suppression of EAE by oral MBP and this protective effect was reversed by administration of anti-TGF-beta antibody in vivo. Reverse transcription-PCR showed enhanced suppression of IFN-gamma in Peyer's patch in animals fed MBP and IL-4 versus those fed MBP alone. We then investigated the role of IL-4 in the generation of TGF-beta-secreting cells using MBP Ac1-11 TCR transgenic animals. Cells were cultured with IL-2, IL-4, or IFN-gamma in the presence of MBP and limiting dilution analysis for cytokine-secreting cells performed. We found that IL-4, but not IL-2 or IFN-gamma, generated TGF-beta-secreting T cells from naive splenic T cells and that these cells provided help for IgA production. These findings demonstrate that IL-4 is a differentiation factor for TGF-beta-secreting Th3 cells and oral IL-4 has a synergistic effect on low-dose oral tolerance that is associated with increased TGF-beta secretion.