熊谷 仁

Uncontrolled type 2 immunity by type 2 helper T (Th2) cells causes intractable allergic diseases; however, whether the interaction of CD4+ T cells shapes the pathophysiology of allergic diseases remains unclear. We identified a subset of Th2 cells that produced the serine proteases granzyme A and B early in differentiation. Granzymes cleave protease-activated receptor (Par)-1 and induce phosphorylation of p38 mitogen-activated protein kinase (MAPK), resulting in the enhanced production of IL-5 and IL-13 in both mouse and human Th2 cells. Ubiquitin-specific protease 7 (USP7) regulates IL-4-induced phosphorylation of STAT3, resulting in granzyme production during Th2 cell differentiation. Genetic deletion of Usp7 or Gzma and pharmacological blockade of granzyme B ameliorated allergic airway inflammation. Furthermore, PAR-1+ and granzyme+ Th2 cells were colocalized in nasal polyps from patients with eosinophilic chronic rhinosinusitis. Thus, the USP7-STAT3-granzymes-Par-1 pathway is a potential therapeutic target for intractable allergic diseases.

Aging is believed to induce insulin resistance in humans. However, when and how insulin sensitivity changes with aging remain unclear in both humans and mice. In this study, groups of male C57BL/6N mice at 9-19 weeks (young), 34-67 weeks (mature adult), 84-85 weeks (presenile) and 107-121 weeks (aged) of age underwent hyperinsulinemic-euglycemic clamp studies with somatostatin infusion under awake and non-restrained conditions. The glucose infusion rates for maintaining euglycemia were 18.4±2.9, 5.9±1.3, 20.3±7.2 and 25.3±4.4 mg/kg/min in young, mature adult, presenile and aged mice, respectively. Thus, compared with young mice, mature adult mice exhibited the expected insulin resistance. In contrast, presenile and aged mice showed significantly higher insulin sensitivity than the mature adult mice. These age-related changes were mainly observed in glucose uptake into adipose tissue and skeletal muscle (rates of glucose disappearance were 24.3±2.0, 17.1±1.0, 25.5±5.2 and 31.8±2.9 mg/kg/min in young, mature adult, presenile and aged mice, respectively). Epididymal fat weight and hepatic triglyceride levels were higher in mature adult mice than those in young and aged mice. Our observations indicate that, in male C57BL/6N mice, insulin resistance appears at the mature adult stage of life but subsequently improves markedly. These alterations in insulin sensitivity are attributable to changes in visceral fat accumulations and age-related factors.

Tissue-resident memory T cells (TRM cells) are crucial mediators of adaptive immunity in nonlymphoid tissues. However, the functional heterogeneity and pathogenic roles of CD4+ TRM cells that reside within chronic inflammatory lesions remain unknown. We found that CD69hiCD103lo CD4+ TRM cells produced effector cytokines and promoted the inflammation and fibrotic responses induced by chronic exposure to Aspergillus fumigatus. Simultaneously, immunosuppressive CD69hiCD103hiFoxp3+ CD4+ regulatory T cells were induced and constrained the ability of pathogenic CD103lo TRM cells to cause fibrosis. Thus, lung tissue-resident CD4+ T cells play crucial roles in the pathology of chronic lung inflammation, and CD103 expression defines pathogenic effector and immunosuppressive tissue-resident cell subpopulations in the inflamed lung.

Brown adipose tissue (BAT) plays a role in energy expenditure and is involved in nutrient metabolism. C-X-C chemokine ligand 12 (CXCL12)-CXCR4 pathway regulates the immune, nervous, and cardiovascular systems and affects the adipose tissue. Here, we investigated the role of this pathway as an activator of BAT. Uncoupling protein 1 mRNA and protein levels and oxygen consumption increased in the brown adipocytes treated with 100 nM CXCL12 peptide. CXCL12-mediated upregulation in P38 and extracellular signal-regulated kinase (ERK) levels was reduced by each inhibitor. Thus, the CXCL12-CXCR4 pathway activated the brown adipocytes through P38 and ERK that acted downstream of this pathway. Mice with CXCR4 defects only in the brown adipocytes were generated and fed with high-fat diet (HFD). Body weight and blood glucose after glucose injection increased in these mice. Long-term exposure to HFD deteriorated blood glucose level after glucose injection. Insulin sensitivity was exacerbated in the knockout mice fed with HFD. Serum lipid parameters and CXCL12 level in knockout mice were similar to those in control mice. These results suggest that the CXCL12-CXCR4 pathway induces brown adipocyte activity and affects nutrient metabolism under HFD load.

House dust mites (HDMs), Dermatophagoides sp., are one of the most widespread aeroallergens worldwide and cause various allergic diseases, including asthma. The pathophysiology of asthma has been intensively investigated using murine models of allergic airway inflammation induced by exposure to D. pteronyssinus. However, the pathogenic roles of D. farinae in the allergic airway inflammation remains unclear. We herein report that repetitive exposure to D. farinae resulted in neutrophil-dominant airway inflammation together with fibrotic changes and the formation of lymphoid clusters. Both type 1 and type 2 inflammatory cytokines were induced. The pathogenic changes in the airway were dependent on both the frequency and dose of D. farinae exposure. Our study provides novel procedures and insight into the pathogenesis of D. farinae-induced airway inflammation in vivo.

The primary function of the lung is efficient gas exchange between alveolar air and alveolar capillary blood. At the same time, the lung protects the host from continuous invasion of harmful viruses and bacteria by developing unique epithelial barrier systems. Thus, the lung has a complex architecture comprising a mixture of various types of cells including epithelial cells, mesenchymal cells, and immune cells. Recent studies have revealed that Interleukin (IL-)33, a member of the IL-1 family of cytokines, is a key environmental cytokine that is derived from epithelial cells and induces type 2 inflammation in the barrier organs, including the lung. IL-33 induces allergic diseases, such as asthma, through the activation of various immune cells that express an IL-33 receptor, ST2, including ST2+ memory (CD62LlowCD44hi) CD4+ T cells. ST2+ memory CD4+ T cells have the capacity to produce high levels of IL-5 and Amphiregulin and are involved in the pathology of asthma. ST2+ memory CD4+ T cells are maintained by IL-7- and IL-33-produced lymphatic endothelial cells within inducible bronchus-associated lymphoid tissue (iBALT) around the bronchioles during chronic lung inflammation. In this review, we will discuss the impact of these immune cells-epithelial/mesenchymal interaction on shaping the pathology of chronic allergic inflammation. A better understanding of pathogenic roles of the cellular and molecular interaction between immune cells and non-immune cells is crucial for the development of new therapeutic strategies for intractable allergic diseases.

AIMS: Women with a history of gestational diabetes mellitus (GDM) are likely to develop postpartum diabetes mellitus (DM). We examined women in the early stages of pregnancy who were at high risk of postpartum DM progression to establish a follow-up method for early detection. METHODS: We performed the oral glucose tolerance test (OGTT) and identified predictive factors for postpartum impaired glucose tolerance (IGT) or DM in 77 women after GDM, for 2 years after delivery, retrospectively. Cutoff values for each factor were determined. We classified these women with GDM into four groups using these predictive factors and evaluated postpartum glucose intolerance (GI) in each group. RESULTS: In total, 44.1% of the women with a GDM history had developed postpartum GI within 2 years. We determined three risk factors for postpartum GI: elevated glucose level 120 min after a 75-g OGTT (Glu120), elevated glycated hemoglobin (HbA1c) level at diagnosis, and perinatal complications. The cutoff Glu120 and the HbA1c level were 155 mg/dl and 5.3% (34 mmol/mol), respectively. Type 2 DM developed in 53.8% of women, and IGT developed in 38.5% of women within 2 years in groups with high Glu120 and high HbA1c. CONCLUSIONS: High-risk groups require careful follow-up observation.

The lung develops an unique epithelial barrier system to protect host from continuous invasion of various harmful particles. Interleukin (IL-)33 released from epithelial cells in the lung drives the type 2 immune response by activating ST2- expressed immune cells in various allergic diseases. However, the involvement of memory-type ST2+CD4+ T cells in such lung inflammation remains unclear. Here we demonstrated that intratracheal administration of IL-33 resulted in the substantial increase of numbers of tissue-resident memory-type ST2+CD4+ T cells in the lung. Following enhanced production of IL-5 and IL-13, eosinophilic lung inflammation sequentially developed. IL-33-mediated eosinophilic lung inflammation was not fully developed in T cell-deficient Foxn1 nu mice and NSG mice. Dexamethasone treatment showed limited effects on both the cell number and function of memory-type ST2+CD4+ T cells. Thus our study provides novel insight into the pathogenesis of eosinophilic lung disease, showing that memory-type ST2+CD4+ T cells are involved in IL-33-induced eosinophilic inflammation and elicited steroid-resistance.

CD4(+) T cells play central roles to appropriate protection against pathogens. While, they can also be pathogenic driving inflammatory diseases. Besides the classical model of differentiation of T helper 1 (Th1) and Th2 cells, various CD4(+) T cell subsets, including Th17, Th9, T follicular helper (Tfh) and T regulatory (Treg) cells, have been recognized recently. In this review, we will focus on how these various CD4(+) T cell subsets contribute to the pathogenesis of immune-mediated inflammatory diseases. We will also discuss various unique subpopulations of T helper cells that have been identified. Recent advancement of the basic immunological research revealed that T helper cells are plastic than we imagined. So, we will focus on the molecular mechanisms underlying the generation of the plasticity and heterogeneity of T helper cell subsets. These latest finding regarding T helper cell subsets has pushed us to reconsider the etiology of immune-mediated inflammatory diseases beyond the model based on the conventional Th1/Th2 balance. Toward this end, we put forward another model, "the pathogenic Th population disease induction model", as a possible mechanism for the induction and/or persistence of immune-mediated inflammatory diseases.

A 74-year-old woman visited an otolaryngology clinic with pharyngeal pain, and was diagnosed with a peritonsillar abscess. She received antibiotics and underwent incisional drainage, but displayed high white blood cell and blast cell counts, and was referred to our hospital. Gram-negative rods (Leptotrichia trevisanii) were detected in blood cultures performed on admission. She was diagnosed with bacteremia and acute myelogenous leukemia (FAB classification: M1). After antibiotic therapy, she temporarily recovered from the bacteremia, but subsequently died on day 34. Although Leptotrichia trevisanii bacteremia is extremely rare, clinicians should consider it in cases involving immunocompromised patients with oral lesions.