Regulation of cytotoxic T lymphocyte triggering by PIR-B on dendritic cells

Priming of cytotoxic T lymphocytes (CTLs) by dendritic cells (DCs) is crucial for elimination of pathogens and malignant cells. To activate CTLs, DCs present antigenic peptide-complexed MHC class I molecules (MHC-I) that will be recognized by the CTLs with T cell receptors and CD8 molecules. Here we show that paired Ig-like receptor (PIR)-B, an MHC-I receptor expressed on antigen-presenting cells, can regulate CTL triggering by blocking the access of CD8 molecules to MHC-I. PIR-B-deficient DCs evoked CTLs more efficiently, leading to accelerated graft and tumor rejection. PIR-B(+) non-DC transfectant cells served as less efficient stimulators and targets for CTLs than PIR-B(-) cells at the effector phase in vitro. On surface plasmon resonance analysis, PIR-B and CD8alpha alpha were revealed to compete in binding to MHC-I. Our results may provide a novel strategy for regulating CTL-mediated immunity and diseases in a sterical manner.     

Changes in coronary resistance related to the stages of the female life cycle.

BACKGROUNDS: Estrogen is known to dilate the coronary vascular system mainly through nitric oxide (NO) release. However, it has not been determined whether or not this effect occurs equally throughout all stages of the female life cycle. We examined the changes in coronary flow properties in adolescent, adult and ovariectomized (OVX) female rats using the endothelial NO synthetase blocker, L-N (omega) nitroarginine (L-NNA). METHODS AND RESULTS: Female rats were divided into 3 groups: adolescent (13 weeks, n=6), adult (19 weeks, n=8) and OVX (20 weeks, n=7, 12 weeks after oophorectomy). Coronary effluent was measured using the Langendorff non-working heart model before and 15 min after the use of L-NNA. In OVX rats, coronary effluent was significantly decreased in comparison with adolescent and adult rats (adolescent vs OVX: p<0.001; adult vs OVX: p<0.05). After treatment with L-NNA, coronary effluent was significantly higher in the adolescent group compared with the adult and OVX groups (adolescent vs adult: p<0.01; adolescent vs OVX: p<0.0005). CONCLUSIONS: Oophorectomy brought about an increase in coronary vascular resistance. L-NNA exacerbated coronary vascular resistance in relation to maturation. It is suggested that the effect of estrogen on vascular dilatation in adolescents is largely dependent on a non-NO pathway, whereas adults are largely dependent on an NO pathway.     

CD28 signals the differential control of regulatory T cells and effector T cells

One possible means of driving antigen‐specific immune suppression is to expand or induce antigen‐specific FoxP3‐expressing Treg cells. One way of activating and expanding these specialized cells, both in vitro and in vivo, is by strong costimulation via CD28 with an agonistic anti‐CD28 monoclonal antibody, called anti‐CD28 superagonist (CD28SA). However, CD28SA also strongly activates conventional T (Tconv) cells to secrete proinflammatory cytokines and, under certain conditions, causes serious cytokine release syndrome. In this issue of European Journal of Immunology, Tabares et al. [Eur. J. Immunol. 2014. 44: 1225–1236] address how CD28SA can be used for the differential control of human Treg and Tconv cells to suppress immune responses without serious adverse effects. They show that, depending on the dose of the antibody or by comedication of cortico‐steroid, the selective expansion of Treg cells can be achieved without significantly activating Tconv cells to produce inflammatory cytokines. This difference in CD28 signal sensitivity between the two populations can be exploited for better control of immune responses.     

Plasminogen activator inhibitor 1--insulin-like growth factor binding protein 3 cascade regulates stress-induced senescence

Cellular senescence is widely believed to play a key role in tumor suppression, but the molecular pathways that regulate senescence are only incompletely understood. By using a secretome proteomics approach, we identified insulin-like growth factor binding protein 3 (IGFBP3) as a secreted mediator of breast cancer senescence upon chemotherapeutic drug treatment. The senescence-inducing activity of IGFBP3 is inhibited by tissue-type plasminogen activator-mediated proteolysis, which is counteracted by plasminogen activator inhibitor 1 (PAI-1), another secreted mediator of senescence. We demonstrate that IGFBP3 is a critical downstream target of PAI-1-induced senescence. These results suggest a role for an extracellular cascade of secreted proteins in the regulation of cellular senescence.     

LecT-hepa, a glyco-marker derived from multiple lectins, as a predictor of liver fibrosis in chronic hepatitis C patients

Assessment of liver fibrosis in patients with chronic hepatitis C (CHC) is critical for predicting disease progression and determining future antiviral therapy. LecT-Hepa, a new glyco-marker derived from fibrosis-related glyco-alteration of serum alpha 1-acid glycoprotein, was used to differentiate cirrhosis from chronic hepatitis in a single-center study. Herein, we aimed to validate this new glyco-marker for estimating liver fibrosis in a multicenter study. Overall, 183 CHC patients were recruited from 5 liver centers. The parameters Aspergillus oryzae lectin (AOL) / Dature stramonium lectin (DSA) and Maackia amurensis lectin (MAL)/DSA were measured using a bedside clinical chemistry analyzer in order to calculate LecT-Hepa levels. The data were compared with those of seven other noninvasive biochemical markers and tests (hyaluronic acid, tissue inhibitor of metalloproteases-1, platelet count, aspartate aminotransferase-to-platelet ratio index [APRI], Forns index, Fib-4 index, and Zeng's score) for assessing liver fibrosis using the receiver-operating characteristic curve. LecT-Hepa correlated well with the fibrosis stage as determined by liver biopsy. The area under the curve (AUC), sensitivity, and specificity of LecT-Hepa were 0.802, 59.6%, and 89.9%, respectively, for significant fibrosis; 0.882, 83.3%, and 80.0%, respectively, for severe fibrosis; and 0.929, 84.6%, and 88.5%, respectively, for cirrhosis. AUC scores of LecT-Hepa at each fibrosis stage were greater than those of the seven aforementioned noninvasive tests and markers. Conclusion: The efficacy of LecT-Hepa, a glyco-marker developed using glycoproteomics, for estimating liver fibrosis was demonstrated in a multicenter study. LecT-Hepa given by a combination of the two glyco-parameters is a reliable method for determining the fibrosis stage and is a potential substitute for liver biopsy. (HEPATOLOGY 2012).     

Omental patch repair effectively treats perforated marginal ulcer following Roux-en-Y gastric bypass

Background

Marginal ulcer formation remains a significant complication of Roux-en-Y gastric bypass (RYGB). Up to 1 % of all RYGB patients will develop free perforation of a marginal ulcer. Classically, this complication has required anastomotic revision; however, this approach is associated with significant morbidity. Several small series have suggested that omental patch repair may be effective. The aim of this study was to examine the management of perforated marginal ulcers following RYGB.

Methods

All patients who underwent operative intervention for perforated ulcers between 2003 and 2011 were reviewed. Those with a history of RYGB with perforation of a marginal ulcer were included in the analysis. Data collected included operative approach, operative time, blood loss, length of hospital stay, complications, smoking history, and steroid or NSAID use.

Results

From January 2003 to December 2011, a total of 1,760 patients underwent RYGB at our institution. Eighteen (0.85 %) developed perforation of a marginal ulcer. Three patients’ original procedure was performed at another institution. Eight patients (44 %) had at least one risk factor for ulcer formation. Treatment included omental patch repair (laparoscopic, n = 7; open, n = 9) or anastomotic revision (n = 2). Compared to anastomotic revision, omental patch repair had shorter OR time (101 ± 57 vs. 138 ± 2 min), decreased estimated blood loss (70 ± 72 vs. 250 ± 71 mL), and shorter total length of stay (5.6 ± 1.4 vs. 11.0 ± 5.7 days).

Conclusions

Perforated marginal ulcer represents a significant complication of RYGB. Patients should be educated to reduce risk factors for perforation, as prolonged proton pump inhibitor therapy may not prevent this complication in a patient with even just one risk factor. In our sample population we found laparoscopic or open omental patch repair to be a safe and effective treatment for this condition and it was associated with decreased operative time, blood loss, and length of stay.