Human intrahepatic regulatory T cells are functional, require IL-2 from effector cells for survival, and are susceptible to Fas ligand-mediated apoptosis.

UNLABELLED: Regulatory T cells (Treg ) suppress T effector cell proliferation and maintain immune homeostasis. Autoimmune liver diseases persist despite high frequencies of Treg in the liver, suggesting that the local hepatic microenvironment might affect Treg stability, survival, and function. We hypothesized that interactions between Treg and endothelial cells during recruitment and then with epithelial cells within the liver affect Treg stability, survival, and function. To model this, we explored the function of Treg after migration through human hepatic sinusoidal-endothelium (postendothelial migrated Treg [PEM Treg ]) and the effect of subsequent interactions with cholangiocytes and local proinflammatory cytokines on survival and stability of Treg . Our findings suggest that the intrahepatic microenvironment is highly enriched with proinflammatory cytokines but deficient in the Treg survival cytokine interleukin (IL)-2. Migration through endothelium into a model mimicking the inflamed liver microenvironment did not affect Treg stability; however, functional capacity was reduced. Furthermore, the addition of exogenous IL-2 enhanced PEM Treg phosphorylated STAT5 signaling compared with PEMCD8. CD4 and CD8 T cells are the main source of IL-2 in the inflamed liver. Liver-infiltrating Treg reside close to bile ducts and coculture with cholangiocytes or their supernatants induced preferential apoptosis of Treg compared with CD8 effector cells. Treg from diseased livers expressed high levels of CD95, and their apoptosis was inhibited by IL-2 or blockade of CD95. CONCLUSION: Recruitment through endothelium does not impair Treg stability, but a proinflammatory microenvironment deficient in IL-2 leads to impaired function and increased susceptibility of Treg to epithelial cell-induced Fas-mediated apoptosis. These results provide a mechanism to explain Treg dysfunction in inflamed tissues and suggest that IL-2 supplementation, particularly if used in conjunction with Treg therapy, could restore immune homeostasis in inflammatory and autoimmune liver disease. (Hepatology 2016;64:138-150).

Domestic violence in the Solomon Islands.

The Solomon Islands has one of the highest rates of family and sexual violence (FSV) in the world with 64% of women aged 15-49 have reported physical and/or sexual abuse by a partner. The National Referral Hospital (NRH) in the capital, Honiara, is the only tertiary hospital for the country. Our 4-week medical elective at the NRH was spent reflecting on healthcare challenges including FSV, with the aim of identifying cases of FSV and assessing on the current strategies to improve care for victims. Throughout our placement, we encountered many cases of probable FSV, particularly in the Emergency Department and Obstetrics and Gynecology. These patients were often not managed effectively, largely due to time pressures and overcrowding in the hospital. However, we identified a number of strategies, which have recently been implemented in order to help FSV victims in the Solomon Islands. These include strategies within the healthcare setting, in particular, the commencement of FSV reporting within the hospital, and the production of a manual to enable healthcare worker education on the issue. Strategies within the criminal justice system are also in place. These include recent changes in legislation and the work of the volunteer police force, Royal Assist Mission to the Solomon Islands, to improve attitudes toward FSV. These approaches to tackle the problem of FSV are currently in their early stages and have largely stemmed from Western policies and ideals. This report concludes that more time is needed to accurately assess the impact of the current changes before further recommendations are made.