Stimulatory MAIT cell antigens reach the circulation and are efficiently metabolised and presented by human liver cells.

OBJECTIVE Mucosal-associated invariant T (MAIT) cells are the most abundant T cells in human liver. They respond to bacterial metabolites presented by major histocompatibility complex-like molecule MR1. MAIT cells exert regulatory and antimicrobial functions and are implicated in liver fibrogenesis. It is not well understood which liver cells function as antigen (Ag)-presenting cells for MAIT cells, and under which conditions stimulatory Ags reach the circulation. DESIGN We used different types of primary human liver cells in Ag-presentation assays to blood-derived and liver-derived MAIT cells. We assessed MAIT cell stimulatory potential of serum from healthy subjects and patients with portal hypertension undergoing transjugular intrahepatic portosystemic shunt stent, and patients with inflammatory bowel disease (IBD). RESULTS MAIT cells were dispersed throughout healthy human liver and all tested liver cell types stimulated MAIT cells, hepatocytes being most efficient. MAIT cell activation by liver cells occurred in response to bacterial lysate and pure Ag, and was prevented by non-activating MR1 ligands. Serum derived from peripheral and portal blood, and from patients with IBD stimulated MAIT cells in MR1-dependent manner. CONCLUSION Our findings reveal previously unrecognised roles of liver cells in Ag metabolism and activation of MAIT cells, repression of which creates an opportunity to design antifibrotic therapies. The presence of MAIT cell stimulatory Ags in serum rationalises the observed activated MAIT cell phenotype in liver. Increased serum levels of gut-derived MAIT cell stimulatory ligands in patients with impaired intestinal barrier function indicate that intrahepatic Ag-presentation may represent an important step in the development of liver disease

Prophylactic intraperitoneal onlay mesh following midline laparotomy—long-term results of a randomized controlled trial

OBJECTIVES: Incisional hernia, a serious complication after laparotomy, is associated with high morbidity and costs. This trial examines the value of prophylactic intraperitoneal onlay mesh to reduce the risk of incisional hernia after a median follow-up time of 5.3 years. METHODS: We conducted a parallel group, open-label, single center, randomized controlled trial (NCT01003067). After midline incision, the participants were either allocated to abdominal wall closure according to Everett with a PDS-loop running suture reinforced by an intraperitoneal composite mesh strip (Group A) or the same procedure without the additional mesh strip (Group B). RESULTS: A total of 276 patients were randomized (Group A = 131; Group B = 136). Follow-up data after a median of 5.3 years after surgery were available from 183 patients (Group A = 95; Group B = 88). Incisional hernia was diagnosed in 25/95 (26%) patients in Group A and in 46/88 (52%) patients in Group B (risk ratio 0.52; 95% CI 0.36-0.77; p < 0.001). Eighteen patients with asymptomatic incisional hernia went for watchful waiting instead of hernia repair and remained free of symptoms after of a median follow-up of 5.1 years. Between the second- and fifth-year follow-up period, no complication associated with the mesh could be detected. CONCLUSION: The use of a composite mesh in intraperitoneal onlay position significantly reduces the risk of incisional hernia during a 5-year follow-up period. TRIAL REGISTRATION NUMBER: Ref. NCT01003067 (clinicaltrials.gov)

Differential effects of 17beta-estradiol on function and expression of estrogen receptor alpha, estrogen receptor beta, and GPR30 in arteries and veins of patients with atherosclerosis

Venous complications have been implicated in the adverse effects of hormone replacement therapy. This study investigated acute effects of the natural estrogen, 17beta-estradiol, on function, estrogen receptors/GPR30 expression, and kinase activation in vascular rings and cultured smooth muscle cells from arteries and veins of patients with coronary artery disease. Changes in vascular tone of internal mammary arteries and saphenous veins exposed to the steroid were recorded. 17Beta-estradiol caused concentration-dependent, endothelium-independent relaxation in arteries (P<0.05 versus solvent control) but not in veins (P not significant). 17Beta-estradiol enhanced contractions to endothelin-1 in veins but not in arteries. The novel membrane estrogen receptor GPR30 was detected in both vessels. Moreover, gene expression of estrogen receptor beta was 10-fold higher than that of estrogen receptor alpha or GPR30 (P<0.05). Expression of all 3 of the receptors was reduced after exposure to 17beta-estradiol in arteries but not in veins (P<0.05). Basal phosphorylation levels of extracellular signal-regulated kinase were higher in venous than in arterial smooth muscle cells and were increased by 17beta-estradiol in arterial cells only. In summary, this is the first study to report that, in human arteries but not in veins, 17beta-estradiol acutely affects vascular tone, estrogen receptor expression, including GPR30, and extracellular signal-regulated kinase phosphorylation. These data indicate that effects of natural estrogens in humans differ between arterial and venous vascular beds, which may contribute to the vascular risks associated with menopause or hormone therapy