The AP-2 clathrin adaptor mediates endocytosis of an inhibitory killer cell Ig-like receptor in human NK cells

Copyright © 2014 by The American Association of Immunologists, Inc. All rights reserved. Stable surface expression of human inhibitory killer cell Ig-like receptors (KIRs) is critical for controlling NK cell function and maintaining NK cell tolerance toward normal MHC class I+ cells. Our recent experiments, however, have found that Ab-bound KIR3DL1 (3DL1) readily leaves the cell surface and undergoes endocytosis to early/recycling endosomes and subsequently to late endosomes. We found that 3DL1 internalization is at least partially mediated by an interaction between the μ2 subunit of the AP-2 clathrin adaptor complex and ITIM tyrosine residues in the cytoplasmic domain of 3DL1. Disruption of the 3DL1/μ2 interaction, either by mutation of the ITIM tyrosines in 3DL1 or mutation of μ2, significantly diminished endocytosis and increased surface expression of 3DL1 in human primary NK cells and cell lines. Furthermore, we found that the 3DL1/AP-2 interaction is diminished upon Ab engagement with the receptor, as compared with untreated cells. Thus, we have identified AP-2-mediated endocytosis as a mechanism regulating the surface levels of inhibitory KIRs through their ITIM domains. Based on our results, we propose a model in which nonengaged KIRs are internalized by this mechanism, whereas engagement with MHC class I ligand would diminish AP-2 binding, thereby prolonging stable receptor surface expression and promoting inhibitory function. Furthermore, this ITIM-mediated mechanism may similarly regulate the surface expression of other inhibitory immune receptors

Acetate Causes Alcohol Hangover Headache in Rats

Background: The mechanism of veisalgia cephalgia or hangover headache is unknown. Despite a lack of mechanistic studies, there are a number of theories positing congeners, dehydration, or the ethanol metabolite acetaldehyde as causes of hangover headache. Methods: We used a chronic headache model to examine how pure ethanol produces increased sensitivity for nociceptive behaviors in normally hydrated rats. Results: Ethanol initially decreased sensitivity to mechanical stimuli on the face (analgesia), followed 4 to 6 hours later by inflammatory pain. Inhibiting alcohol dehydrogenase extended the analgesia whereas inhibiting aldehyde dehydrogenase decreased analgesia. Neither treatment had nociceptive effects. Direct administration of acetate increased nociceptive behaviors suggesting that acetate, not acetaldehyde, accumulation results in hangover-like hypersensitivity in our model. Since adenosine accumulation is a result of acetate formation, we administered an adenosine antagonist that blocked hypersensitivity. Discussion: Our study shows that acetate contributes to hangover headache. These findings provide insight into the mechanism of hangover headache and the mechanism of headache induction

Racism and hate speech – A critique of Scanlon’s Contractual Theory

The First Amendment is an important value in American liberal polity. Under this value, racism, hate speech and offensive speech are protected speech. This article scrutinizes one of the clear representatives of the American liberal polity - Thomas Scanlon. The paper tracks the developments in his theory over the years. It is argued that Scanlon’s arguments downplay tangible harm that speech might inflict on its target victim audience. Scanlon’s distinction between participant interests, audience interests, and the interests of bystanders is put under close scrutiny. The article criticizes viewpoint neutrality and suggests a balancing approach, further arguing that democracy is required to develop protective mechanisms against harm-facilitating speech as well as profound offences. Both should be taken most seriously

A reflection on HIV/AIDS research after 25 years

Dr. Robert C. Gallo provides a personal reflection on the 25 year history of AIDS

Disability Policies in France: Changes and Tensions between the Category-based, Universalist and Personalized Approaches

In this article, the authors show that the current French disability policy is traversed by conflicts between three different approaches to disability which came about at different periods in history. They begin by looking at the origins of disability policy in France. This policy was developed during the 20th century, from notions of repair, indemnification and compensation through rehabilitation. It became institutionalized in 1975, when two laws were passed, giving it the form of a category-based policy. Between 1970 and 2000, affected by the international situation, this policy came into conflict with a universalist policy. More recently there has been a desire to develop a personalized approach. Finally, the authors use two examples (taken from recent debates on the implementation in France of the new law of 11 February 2005) to show the tensions that have led to the coexistence of these three approaches within current disability policy

Histo-Blood Group Antigen Null Phenotypes Associated With a Decreased Risk of Clinical Rotavirus Vaccine Failure Among Children <2 Years of Age Participating in the Vaccine Impact on Diarrhea in Africa (VIDA) Study in Kenya, Mali, and the Gambia

Background: Previously studied risk factors for rotavirus vaccine failure have not fully explained reduced rotavirus vaccine effectiveness in low-income settings. We assessed the relationship between histo-blood group antigen (HBGA) phenotypes and clinical rotavirus vaccine failure among children 4. Conclusions: Our study demonstrated a significant relationship between null HBGA phenotypes and decreased rotavirus vaccine failure in a population with P[8] as the most common infecting genotype. Further studies are needed in populations with a large burden of P[6] rotavirus diarrhea to understand the role of host genetics in reduced rotavirus vaccine effectiveness

The effect of industry consolidation and deposit insurance reform on the resiliency of the U.S. bank insurance fund

We examine the effects of structural change in the U.S. banking industry, as well as key regulatory changes, including recently enacted deposit insurance reform legislation, on the resiliency of the FDIC-administered bank insurance fund (BIF) by estimating and comparing the probability of BIF insolvency over time. We do this using a Markov-switching model that relies on historical patterns of BIF disbursements to define the probability of switching among three "states" of the banking industry's financial health. Monte Carlo simulations are then performed to project the financial condition of the BIF over a 50-year period. Our results indicate that the insolvency risk to the bank insurance fund has increased significantly due to industry consolidation, and is mainly due to the concentration of deposits in the 10 largest U.S. banking companies. We also find that recent deposit insurance reforms will cause only a marginal reduction in the risk of BIF insolvency. The increased risk associated with a more concentrated industry structure simply dominates the reform effect.Deposit insurance Bank insurance fund Markov-switching model Monte Carlo simulation