HLA-B⁎27 subtype specificity determines targeting and viral evolution of a hepatitis C virus-specific CD8+ T cell epitope

Background & Aims: HLA-B⁄27 is associated with spontaneous HCV genotype 1 clearance. HLA-B⁄27-restricted CD8+ T cells target three NS5B epitopes. Two of these epitopes are dominantly targeted in the majority of HLA-B⁄27+ patients. In chronic infection, viral escape occurs consistently in these two epitopes. The third epitope (NS5B2820) was dominantly targeted in an acutely infected patient. This was in contrast, however, to the lack of recognition and viral escape in the large majority of HLA-B⁄27+ patients. Here, we set out to determine the host factors contributing to selective targeting of this epitope. Methods: Four-digit HLA class I typing and viral sequence analyses were performed in 78 HLA-B⁄27+ patients with chronic HCV genotype 1 infection. CD8+ T cell analyses were performed in a subset of patients. In addition, HLA/peptide affinity was compared for HLA-B⁄27:02 and 05. Results: The NS5B2820 epitope is only restricted by the HLA-B⁄27 subtype HLA-B⁄27:02 (that is frequent in Mediterranean populations), but not by the prototype HLA-B⁄27 subtype B⁄27:05. Indeed, the epitope is very dominant in HLA-B⁄27:02+ patients and is associated with viral escape mutations at the anchor position for HLA-binding in 12 out of 13 HLA-B⁄27:02+ chronically infected patients. Conclusions: The NS5B2820 epitope is immunodominant in the context of HLA-B⁄27:02, but is not restricted by other HLA-B⁄27 subtypes. This finding suggests an important role of HLA subtypes in the restriction of HCV-specific CD8+ responses. With minor HLA subtypes covering up to 39% of specific populations, these findings may have important implications for the selection of epitopes for global vaccines.

Logical omniscience as infeasibility

Logical theories for representing knowledge are often plagued by the so-called Logical Omniscience Problem. The problem stems from the clash between the desire to model rational agents, which should be capable of simple logical inferences, and the fact that any logical inference, however complex, almost inevitably consists of inference steps that are simple enough. This contradiction points to the fruitlessness of trying to solve the Logical Omniscience Problem qualitatively if the rationality of agents is to be maintained. We provide a quantitative solution to the problem compatible with the two important facets of the reasoning agent: rationality and resource boundedness. More precisely, we provide a test for the logical omniscience problem in a given formal theory of knowledge. The quantitative measures we use are inspired by the complexity theory. We illustrate our framework with a number of examples ranging from the traditional implicit representation of knowledge in modal logic to the language of justification logic, which is capable of spelling out the internal inference process. We use these examples to divide representations of knowledge into logically omniscient and not logically omniscient, thus trying to determine how much information about the reasoning process needs to be present in a theory to avoid logical omniscience.

Definitions and outcome measures for mucous membrane pemphigoid: recommendations of an international panel of experts

Mucous membrane pemphigoid encompasses a group of autoimmune bullous diseases with a similar phenotype characterized by subepithelial blisters, erosions, and scarring of mucous membranes, skin, or both. Although knowledge about autoimmune bullous disease is increasing, there is often a lack of clear definitions of disease, outcome measures, and therapeutic end points. With clearer definitions and outcome measures, it is possible to directly compare the results and data from various studies using meta-analyses. This consensus statement provides accurate and reproducible definitions for disease extent, activity, outcome measures, end points, and therapeutic response for mucous membrane pemphigoid and proposes a disease extent score, the Mucous Membrane Pemphigoid Disease Area Index.

Probabilistic Justification Logic

We present a probabilistic justification logic, PPJ, to study rational belief, degrees of belief and justifications. We establish soundness and completeness for PPJ and show that its satisfiability problem is decidable. In the last part we use PPJ to provide a solution to the lottery paradox.