Sumito Jitsukawa

Alteration of circulating type 2 follicular helper T cells and regulatory B cells underlies the comorbid association of allergic rhinitis with bronchial asthma.

Allergic rhinitis (AR), the most common allergic disorder of the airway, is often accompanied by bronchial asthma. However, little is known about the mechanism by which AR advances to AR comorbid with bronchial asthma (AR+Asthma). To determine the pathophysiologic features of AR and AR+Asthma, we examined subsets of follicular helper T (Tfh) cells and regulatory B (Breg) cells in peripheral blood from AR and AR+Asthma patients. The results showed polarization of Tfh2 cells within Tfh cell subsets in both AR and AR+Asthma cases. Interestingly, the %Breg cells in total B cells were decreased in AR cases and, more extensively, in AR+Asthma cases. Moreover, we found significant correlations of fractional exhaled nitric oxide and blood eosinophil levels with the index %Tfh2 cells per %Breg cells. Our findings indicate that relative decrease in Breg cells under the condition of Tfh2 cell skewing is a putative exaggerating factor of AR to bronchial asthma.

Cutting Edge: A Critical Role of Lesional T Follicular Helper Cells in the Pathogenesis of IgG4-Related Disease

IgG4-related disease (IgG4-RD) is a newly recognized systemic chronic fibroinflammatory disease. However, the pathogenesis of IgG4-RD remains unknown. To determine the pathophysiologic features of IgG4-RD, we examined T follicular helper (Tfh) cells in lesions and blood from patients with IgG4-RD. Patients with IgG4-related dacryoadenitis and sialadenitis (IgG4-DS) showed increased infiltration of Tfh cells highly expressing programmed death 1 and ICOS in submandibular glands. Tfh cells from IgG4-DS submandibular glands had higher expression of B cell lymphoma 6 and a greater capacity to help B cells produce IgG4 than did tonsillar Tfh cells. We also found that the percentage of programmed death 1hi circulating Tfh cells in IgG4-DS patients was higher than that in healthy volunteers and was well correlated with clinical parameters. Our findings indicate that anomalous Tfh cells in tissue lesions of IgG4-RD have features distinct from those in lymphoid counterparts or blood and potentially regulate local IgG4 production in IgG4-RD.

Clinical Evaluation of Sinonasal Lesions in Patients With Immunoglobulin G4-Related Disease

Objectives: Immunoglobulin G4-related disease (IgG4-RD) is a systemic disease entity characterized by elevated serum IgG4 and extensive IgG4-positive plasma cell infiltration of various organs. Patients with IgG4-RD show nasal manifestations with chronic rhinosinusitis. The objective of this study was to evaluate the clinical characteristics of sinonasal lesions in patients with IgG4-RD. Methods: We evaluated radiological findings of sinonasal lesions in 79 patients with IgG4-RD who were divided into 3 groups according to severity. We also compared serological findings, including serum IgG4 and IgE levels, and eosinophil counts. Results: Rhinosinusitis was found in 41 patients (51.9%). Although there were no significant differences in the serum IgG4 and IgE levels of the groups, there was a significant increase in eosinophil counts (445 ± 311.9/mm3) in Group C. Furthermore, 14 of the 41 patients with rhinosinusitis (34.1%) showed improvement after prednisolone administration. Patients with IgG4-RD and serum eosinophilia tend to also have sinonasal lesions. Conclusions: Rhinosinusitis is common in patients with IgG4-RD, and its pathogenesis can be similar to eosinophilic chronic rhinosinusitis.

The clinical characteristics of patients with IgG4-related disease with infiltration of the labial salivary gland by IgG4-positive cells.

Abstract Objectives. Mikuliczs disease (MD) is an immunoglobulin (Ig) G4-related disease with systemic symptoms. Submandibular gland (SMG) biopsy is recommended for patients with possible IgG4-related MD for accurate differential diagnosis; however, it is difficult for certain patients to undergo this procedure. In contrast, labial salivary gland (LSG) biopsy is more convenient. Here we present an analysis of patients with IgG4-related MD whose LSG specimens were infiltrated with abundant IgG4-positive plasma cells. Methods. Sixteen patients diagnosed with IgG4-related MD underwent simultaneous SMG and LSG biopsies. We evaluated patients’ serological and 18F-fluoro-2-deoxyglucose-positron emission tomography/computed tomography (18F-FDG-PET/CT) and grouped them as LSG+ (LSG specimens with > 40% IgG4-positive plasma cells/IgG-positive plasma cells, 11 patients) or LSG− (LSG specimens with < 40% IgG4-positive plasma cells/IgG-positive plasma cells, 6 patients). Results. There were not significant differences in serum IgG and IgG4 levels between the two groups; however, serum concentrations of soluble interleuikin-2 receptor (sIL-2R) were significantly higher in the LSG+ group. All patients with increased 18F-FDG uptake in their parotid glands were a part of the LSG+ group. Conclusions. When a SMG biopsy is not possible, the serum concentration of sIL-2R and 18F-FDG-PET/CT findings may predict whether LSG biopsy will facilitate the diagnosis of IgG4-related MD.

Lipid mediators foster the differentiation of T follicular helper cells

Lipid mediators such as leukotrienes and lipoxines broadly regulate innate and acquired immunity, and their dysfunction causes various immune-mediated disorders. We previously reported a salient feature of arachidonate 5-lipoxyganase (Alox5), which is responsible for the production of such lipid mediators, in the regulation of high affinity antibodies in vivo. The aim of this study was to determine the functional significance of Alox5-related lipid mediators during the processes of acquired humoral responses. The results of in vitro experiments using lymphocytes in tonsils and blood specimens showed that lipoxin A4 (LXA4) and leukotriene B4 (LTB4) have the capacity to differentiate naïve CD4+ T cells into T follicular helper (Tfh) cells, which activate naïve B cells to form germinal centers. Such a function of LXA4 was further supported by results of in vitro studies using BML-111 and BOC-2, which are an agonist and an antagonist, respectively, of FPR2 of an LXA4-specific cell-surface receptor. The results suggest that such lipid mediators have a potential role in the development of lymphoid follicles through the regulation of Tfh cell differentiation.

Novel Mechanisms of Compromised Lymphatic Endothelial Cell Homeostasis in Obesity: The Role of Leptin in Lymphatic Endothelial Cell Tube Formation and Proliferation

Leptin is a hormone produced by adipose tissue that regulates various physiological processes. Recent studies have shown that the level of circulating leptin is elevated in obese patients and have suggested a relationship between obesity and postoperative lymphedema. However, the mechanisms by which postoperative lymphedema develops in obese patients and the mechanisms by which leptin regulates lymphatic endothelial cell homeostasis such as tube formation and cell proliferation remain unknown. Here we report that leptin regulates tube formation and cell proliferation in human dermal lymphatic endothelial cells (HDLECs) by activation of the signal transducer and activator of transcription 3 pathway, which is downstream signaling of the leptin receptor. Additionally, we found that upregulation of suppressor of cytokine signaling 3 underlies the mechanisms by which a high dose of leptin inhibits cell proliferation and tube formation. Leptin also enhanced expression of the proinflammatory cytokine IL-6 in HDLECs. Interestingly, IL-6 rescues the compromised cell proliferation and tube formation caused by treatment with a high dose of leptin in an autocrine or paracrine manner. Taken together, our findings reveal a novel mechanism by which compromised HDLECs maintain their homeostasis during inflammation mediated by leptin and IL-6. Thus, regulating the level of leptin or IL-6 may be a viable strategy to reduce the incidence of postoperative lymphedema.

Bob1 limits cellular frequency of T‐follicular helper cells

T follicular helper (Tfh) cells are involved in specific humoral immunity at initial and recall phases. The fact that the transcription repressors B‐cell lymphoma‐6 and Blimp‐1 determine lineages of Tfh cells and other types of effector CD4+ T cells, respectively, suggests that there are unique mechanisms to establish Tfh‐cell identity. In this study, we found that Tfh cells preferentially express the transcriptional coactivator Bob1. Bob1 of Tfh cells was dispensable for the expression of B‐cell lymphoma‐6 and the functional property of the cells for B cell help. However, upon initial immunization of foreign antigens, the percentages of Tfh cells in Bob1−/− mice were much higher than those in wild‐type (WT) mice. In addition, expansion of Tfh cells within Bob1−/−CD4+ T cells transferred into WT mice revealed that the high frequency of Tfh cells was caused by a T‐cell‐intrinsic mechanism. These findings were further supported by the results of in vitro studies demonstrating that Bob1−/− Tfh cells had greater proliferative activity in response to stimuli by CD3/CD28 monoclonal antibody and were also refractory to CD3‐induced cell death in comparison to WT Tfh cells. These results suggest that Tfh cells harbor a Bob1‐related mechanism to restrict numerical frequency against stimulation of TCRs.

Keratinocytes in atopic dermatitis express abundant ΔNp73 regulating thymic stromal lymphopoietin production via NF-κB

BACKGROUND Atopic dermatitis (AD) is a chronic inflammatory skin disease that often cannot be completely controlled by modern medicine. Since multiple factors are intricately involved in the pathogenesis of AD, wide-ranging research is required for further advancement of AD treatment. Epidermal keratinocytes are the forefront to the external environment and play a pivotal role in the initiation of immune reaction against exogenous invasion. OBJECTIVE Thymic stromal lymphopoietin (TSLP) is a keratinocyte-derived cytokine that induces differentiation and activation of type 2 helper T cells and innate lymphoid cells, cardinal effectors in pathophysiology of AD. We previously reported that ΔNp63, a p53-related molecule, regulates the expression of TSLP receptors and suggested the entity of a potential TSLP autocrine loop in the AD epidermis. In this study, we further explored the significance of p53 family transcription factors in TSLP production from human keratinocytes. METHOD Expression profile of p73, a p53-related molecule, was evaluated in human AD tissue by immunohistochemistry. In addition, the function of p73 in producing TSLP was investigated with in vitro cultured keratinocytes via molecular biological analysis. RESULTS ΔNp73 was abundantly expressed in the AD epidermis and increased the release of TSLP via NF-κB activation. Furthermore, the Toll-like receptor 3 signal enhanced ΔNp73 expression and thereby induced TSLP expression. CONCLUSION Our results indicate that ΔNp73 is an additional participant in the mechanism of TSLP production. Amending the aberrant state of keratinocytes, represented by overexpression of ΔNp73, can be a novel therapeutic target of AD.

Expression and Localization of Human Defensins in Palatine Tonsils

Defensins are small antimicrobial peptides and effector components of innate immune responses. Recent studies have shed light on their beneficial functions for the prevention of infection and potential for development of new drugs. Here, we showed the expression profiles of human defensins in palatine tonsils with 3 different diseases: tonsillar hypertrophy, recurrent tonsillitis and focal infection of the tonsil. RT-PCR analysis and immunofluorescence revealed that the expression of human α-defensin 4 and β-defensin 3 (β3) in palatine tonsils with tonsillar hypertrophy was lower than that in recurrent tonsillitis and focal infection of the tonsil, suggesting that chronic inflammation induces defensin expression. Interestingly, β2 and β3 mRNAs were specifically expressed by palatine tonsil tissues but not in human peripheral blood mononuclear cells and mucosa of the small intestine. Additionally, we observed that exposure to a Toll-like receptor 4 ligand, lipopolysaccharide, which is used as a bacterial infection model, increases the production of β2 in culture supernatants from tonsillar epithelial cells in a dose-dependent manner. Taken together, these results indicate that β2 produced by tonsillar epithelial cells plays an important role in the innate immune response for bacterial infections.

Loss of sorting nexin 5 stabilizes internalized growth factor receptors to promote thyroid cancer progression

Thyroid carcinoma is the most common endocrine malignancy and its prevalence has recently been increasing worldwide. We previously reported that the level of sorting nexin 5 (Snx5), an endosomal translocator, is preferentially decreased during the progression of well‐differentiated thyroid carcinoma into poorly differentiated carcinoma. To address the functional role of Snx5 in the development and progression of thyroid carcinoma, we established Snx5‐deficient (Snx5−/−) mice. In comparison to wild‐type (Snx5+/+) mice, Snx5−/− mice showed enlarged thyroid glands that consisted of thyrocytes with large irregular‐shaped vacuoles. Snx5−/− thyrocytes exhibited a higher growth potential and higher sensitivity to thyroid‐stimulating hormone (TSH). A high content of early endosomes enriched with TSH receptors was found in Snx5−/− thyrocytes, suggesting that loss of Snx5 caused retention of the TSH receptor (TSHR) in response to TSH. Similar data were found for internalized EGF in primary thyrocytes. The increased TSH sensitivities in Snx5−/− thyrocytes were also confirmed by results showing that Snx5−/− mice steadily developed thyroid tumors with high metastatic potential under high TSH. Furthermore, a thyroid cancer model using carcinogen and an anti‐thyroidal agent revealed that Snx5−/− mice developed metastasizing thyroid tumors with activation of MAP kinase and AKT pathways, which are postulated to be major pathways of malignant progression of human thyroid carcinoma. Our results suggest that thyrocytes require Snx5 to lessen tumorigenic signaling driven by TSH, which is a major risk factor for thyroid carcinoma. Copyright