山本 健

＜文献概要＞アレルギー性結膜疾患とアレルギー性鼻炎は,ともにアレルギー検査が診断の根拠となる.両疾患とも重症度に応じて抗アレルギー薬や局所ステロイド薬を用いるが,重症例や治療抵抗性の場合には速やかに眼科医や耳鼻科医への紹介が必要である.

＜文献概要＞アレルギー性結膜疾患とアレルギー性鼻炎は,ともにアレルギー検査が診断の根拠となる.両疾患とも重症度に応じて抗アレルギー薬や局所ステロイド薬を用いるが,重症例や治療抵抗性の場合には速やかに眼科医や耳鼻科医への紹介が必要である.

In serum proteomics using mass spectrometry, the number of detectable proteins is reduced due to high-abundance proteins, such as albumin. However, recently developed data-independent acquisition mass spectrometry (DIA-MS) proteomics technology has made it possible to remarkably improve the number of proteins in a serum analysis by removing high-abundance proteins. Using this technology, we analyzed sera from patients with systemic juvenile idiopathic arthritis (sJIA), a rare pediatric disease. As a result, we identified 2727 proteins with a wide dynamic range derived from various tissue leakages. We also selected 591 proteins that differed significantly in their active phases. These proteins were involved in many inflammatory processes, and we also identified immunoproteasomes, which were not previously found in serum, suggesting that they may be involved in the pathogenesis of sJIA. A detailed high-depth DIA-MS proteomic analysis of serum may be useful for understanding the pathogenesis of sJIA and may provide clues for the development of new biomarkers.

<title>Abstract</title> Systemic juvenile idiopathic arthritis (sJIA) is an autoinflammatory disease caused by high production of inflammatory cytokines. Conventional biomarkers, such as IL-18 are reportedly not always associated with frequent relapses or complication with macrophage activation syndrome (MAS). As few specific biomarkers that can indicate and evaluate the sJIA disease activity have been identified, the discovery of biomarkers is very important. We performed a deep proteomic analysis of serum samples from nine patients with sJIA using highly sensitive mass spectrometry, and identified differentially expressed proteins in various disease phases. We selected 68 proteins (URPs) that were highly expressed in the active phase from total of 2,727 proteins. Pathway analysis revealed that the URPs included proteins related to many immune process and proteasome proteins, which might be associated with the pathogenesis of sJIA. Based on these results, four proteins (leucine aminopeptidase 3; LAP3, guanylate-binding protein 1; GBP1, Heme oxygenase 1; HMOX1, and bone morphogenetic protein 10; BMP10), which exhibit high fold changes during the active phase or which might be core proteins in the functional network were selected as candidate biomarkers. These proteins may be clinically useful for diagnostic and therapeutic purposes and might help determine the pathogenesis of the disease.

Immunological memory is central to adaptive immunity and protection from disease. Changing metabolic demands as antigen-specific T cells transition from effector to memory cells have been well documented, but the cell-specific pathways and molecules that govern this transition are poorly defined. Here we show that genetic deletion of ACC1, a rate-limiting enzyme in fatty acid biosynthesis, enhances the formation of CD4+ T memory cells. ACC1-deficient effector helper T (Th) cells have similar metabolic signatures to wild-type memory Th cells, and expression of the gene encoding ACC1, Acaca, was inversely correlated with a memory gene signature in individual cells. Inhibition of ACC1 function enhances memory T cell formation during parasite infection in mice. Using single-cell analyses we identify a memory precursor-enriched population (CCR7hiCD137lo) present during early differentiation of effector CD4+ T cells. Our data indicate that fatty acid metabolism directs cell fate determination during the generation of memory CD4+ T cells.

ST2hi memory-type Th2 cells are identified as a pathogenic subpopulation in eosinophilic airway inflammation. These ST2hi pathogenic Th2 cells produce large amount of IL-5 upon T cell receptor stimulation, but not in response to IL-33 treatment. By contrast, IL-33 alone induces cytokine production in ST2+ group 2 innate lymphoid cells (ILC2). Here we show that a MAPK phosphatase Dusp10 is a key negative regulator of IL-33-induced cytokine production in Th2 cells. In this regard, Dusp10 is expressed by ST2hi pathogenic Th2 cells but not by ILC2, and Dusp10 expression inhibits IL-33-induced cytokine production. Mechanistically, this inhibition is mediated by DUSP10-mediated dephosphorylation and inactivation of p38 MAPK, resulting in reduced GATA3 activity. The deletion of Dusp10 renders ST2hi Th2 cells capable of producing IL-5 by IL-33 stimulation. Our data thus suggest that DUSP10 restricts IL-33-induced cytokine production in ST2hi pathogenic Th2 cells by controlling p38-GATA3 activity.

BACKGROUND: Bisphosphonates are recommended for use as first-line therapy for the prevention and treatment of glucocorticoid-induced osteoporosis in adults. However, the appropriate usage of bisphosphonates for the prevention or treatment of glucocorticoid-induced osteoporosis in children remains unclear. METHODS: We performed a cross-sectional study to clarify the factors associated with the development of glucocorticoid-induced bone loss and osteoporosis in patients with childhood-onset rheumatic disease and to investigate the impact of the early use of alendronate. We recruited 39 patients with childhood-onset rheumatic disease who were evaluated to detect bone loss or osteoporosis at 3 months to 1.5 years after the initiation of treatment. The primary outcome of the study was the presence of bone loss or osteoporosis at the initial evaluation of the bone mineral density after at least 3 months of glucocorticoid therapy. RESULTS: Bone loss and a history of fracture were found in 56 and 18% of the participants, respectively. Weekly oral alendronate therapy (median, 25.4 mg/m2) had been started by the time of the evaluation of osteoporosis in 46% of the participants and within 3 months after the start of glucocorticoid in 31% of the participants. There were no significant differences between the participants with bone loss (wBL group) and without bone loss (w/oBL group) in terms of gender, primary disease, or the age at the onset of primary disease. In terms of glucocorticoid use, there was no significant difference in the age at the start of glucocorticoid therapy, the length of glucocorticoid use, or the dose of glucocorticoids. The proportion of patients in the w/oBL group who received alendronate within 3 months after the start of glucocorticoid therapy was significantly greater than that in the wBL group. In the logistic regression analysis, only "alendronate therapy within 3 months after the start of glucocorticoid therapy" had a statistically significant effect on the development of bone loss (OR, 0.08; 95% CI, 0.02-0.43). The analysis did not reveal any factors associated with the development of osteoporosis. CONCLUSIONS: The early use of alendronate may have a preventive effect against the development of bone loss in glucocorticoid-treated patients with childhood-onset rheumatic disease.

To fulfil the bioenergetic requirements for increased cell size and clonal expansion, activated T cells reprogramme their metabolic signatures from energetically quiescent to activated. However, the molecular mechanisms and essential components controlling metabolic reprogramming in T cells are not well understood. Here, we show that the mTORC1-PPAR gamma pathway is crucial for the fatty acid uptake programme in activated CD4(+) T cells. This pathway is required for full activation and rapid proliferation of naive and memory CD4(+) T cells. PPAR gamma directly binds and induces genes associated with fatty acid uptake in CD4(+) T cells in both mice and humans. The PPAR gamma-dependent fatty acid uptake programme is critical for metabolic reprogramming. Thus, we provide important mechanistic insights into the metabolic reprogramming mechanisms that govern the expression of key enzymes, fatty acid metabolism and the acquisition of an activated phenotype during CD4(+) T cell activation.

Cutaneous polyarteritis nodosa (cutaneous PAN) is a form of necrotizing vasculitis of small- and medium-sized arteries, primarily involving the skin. In juvenile cases, cutaneous PAN is known to be frequently associated with Group A β-hemolytic Streptococcus (GAS) infections. We herein describe the first reported juvenile case of GAS-associated recurrent cutaneous PAN successfully improved with tonsillectomy. To avoid the use of steroids and immunosuppressive drugs, especially in juvenile cases, tonsillectomy is a possible treatment for GAS-associated recurrent cutaneous PAN.