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 1 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.

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Objective The aim was to study the pathological role of lymphocytes with a peripheral T helper-cell-like phenotype (PD-1 + CXCR5 − CD4 + ) in IgG4-related disease (IgG4-RD). Methods PD-1 + CXCR5 − CD4 + T cells in the blood of patients with IgG4-RD ( n = 53), patients with SS ( n = 16) and healthy volunteers ( n = 34) as controls were analysed by flow cytometry. Correlations between results obtained by flow cytometry and clinical parameters relevant to IgG4-RD were also analysed. Results The percentage and absolute number of PD-1 + CXCR5 − cells within total CD4 + T cells in IgG4-RD patients were significantly increased compared with those in healthy volunteers. Further analysis showed that there were marked positive correlations of the percentage of PD-1 + CXCR5 − CD4 + T cells with the serum level of IgG4 and the number of organs involved. Interestingly, granzyme A (GZMA) + cells were enriched in PD-1 + CXCR5 − CD4 + T cells, and the percentage and absolute number of GZMA + PD-1 + CXCR5 − CD4 + T cells were significantly elevated in IgG4-RD patients. Although no obvious change was observed in the percentage of total CD4 + T cells, the percentage and absolute number of PD-1 + CXCR5 − CD4 + T cells decreased in accordance with a reduction of serum IgG4 level after treatment with glucocorticoids. Conclusion In IgG4-RD, circulating CD4 + T-cell populations were composed of PD-1 + CXCR5 − cells, and the ratios of these cells were correlated with clinical manifestations of IgG4-RD. Further analysis of GZMA + PD-1 + CXCR5 − CD4 + T cells might lead to a deeper understanding of the pathogenesis of ectopic lymphoid follicles and the persistent inflammation in IgG4-RD.

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 © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

The present research showed that significant adverse effects on mental health were observed among women who experienced IPV with sexual violence compared with the ones without. These findings provide important implications for considering the specific approaches to meet the needs of those women experiencing sexual IPV and the need for timely and effective interventions, including healthcare, social services, and primary prevention.