Physiology and Pathology of Drug Hypersensitivity: Role of Human Leukocyte Antigens

Drug Hypersensitivity reactions can be distinguished in adverse drug events and adverse drug reactions. They represent a major problem in the medical scheme, since they are often underestimated. Pharmacogenetic analysis demonstrated significant associations between emerging hypersensitivity reactions and distinct genes of the HLA complex. HLA-mediated hypersensitivity reactions particularly affect skin and liver, however, impairment of the bone marrow and kidney function could also be observed. These life threatening medical conditions can be attributed to the activation of autologous drug-specific T-cells. Severe drug hypersensitivity reactions that resemble acute GvHD are linked to certain specific HLA alleles. The most common hypersensitivity reactions occur after the treatment of HLA-B*57:01+ HIV patients with abacavir and HLA-A*31:01+ or B*15:02+ epileptic patients with carbamazepine (CBZ)

Peptide Presentation Is the Key to Immunotherapeutical Success

Positive and negative selection in the thymus relies on T-cell receptor recognition of peptides presented by HLA molecules and determines the repertoire of T cells. Immune competent T-lymphocytes target cells display nonself or pathogenic peptides in complex with their cognate HLA molecule. A peptide passes several selection processes before being presented in the peptide binding groove of an HLA molecule; here the sequence of the HLA molecule’s heavy chain determines the mode of peptide recruitment. During inflammatory processes, the presentable peptide repertoire is obviously altered compared to the healthy state, while the peptide loading pathway undergoes modifications as well. The presented peptides dictate the fate of the HLA expressing cell through their (1) sequence, (2) topology, (3) origin (self/nonself). Therefore, the knowledge about peptide competition and presentation in the context of alloreactivity, infection or pathogenic invasion is of enormous significance. Since in adoptive cellular therapies transferred cells should exclusively target peptide-HLA complexes they are primed for, one of the most crucial questions remains at what stage of viral infection viral peptides are presented preferentially over self-peptides. The systematic analyzation of peptide profiles under healthy or pathogenic conditions is the key to immunological success in terms of personalized therapeutics

Frustration - how it can be measured

A misfit parameter is used to characterize the degree of frustration of ordered and disordered systems. It measures the increase of the ground-state energy due to frustration in comparison with that of a relevant reference state. The misfit parameter is calculated for various spin-glass models. It allows one to compare these models with each other. The extension of this concept to other combinatorial optimization problems with frustration, e.g. p-state Potts glasses, graph-partitioning problems and coloring problems is given.Comment: 10 pages, 1 table, no figures, uses revtex.st

Constraints on the χ_(c1) versus χ_(c2) polarizations in proton-proton collisions at √s = 8 TeV

The polarizations of promptly produced χ_(c1) and χ_(c2) mesons are studied using data collected by the CMS experiment at the LHC, in proton-proton collisions at √s=8  TeV. The χ_c states are reconstructed via their radiative decays χ_c → J/ψγ, with the photons being measured through conversions to e⁺e⁻, which allows the two states to be well resolved. The polarizations are measured in the helicity frame, through the analysis of the χ_(c2) to χ_(c1) yield ratio as a function of the polar or azimuthal angle of the positive muon emitted in the J/ψ → μ⁺μ⁻ decay, in three bins of J/ψ transverse momentum. While no differences are seen between the two states in terms of azimuthal decay angle distributions, they are observed to have significantly different polar anisotropies. The measurement favors a scenario where at least one of the two states is strongly polarized along the helicity quantization axis, in agreement with nonrelativistic quantum chromodynamics predictions. This is the first measurement of significantly polarized quarkonia produced at high transverse momentum