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Background & Aims Drug-induced liver injury (DILI), especially from antimicrobial agents, is an important cause of serious liver disease. Amoxicillin-clavulanate (AC) is a leading cause of idiosyncratic DILI, but little is understood about genetic susceptibility to this adverse reaction. Methods We performed a genome-wide association study using 822,927 single-nucleotide polymorphism (SNP) markers from 201 White European and US cases of AC-DILI and 532 population controls, matched for genetic background. Results AC-DILI was associated with many loci in the major histocompatibility complex. The strongest effect was with a human leukocyte antigen (HLA) class II SNP (rs9274407, P=4.8×10−14), which correlated with rs3135388, a tag SNP of HLA-DRB1*1501-DQB1*0602 that was previously associated with AC-DILI. Conditioned on rs3135388, rs9274407 is still significant (P=1.1×10−4). An independent association was observed in the class I region (rs2523822, P=1.8×10−10), related to HLA-A*0201. The most significant class I and II SNPs showed statistical interaction (P=0.0015). High-resolution HLA genotyping (177 cases and 219 controls) confirmed associations of HLA-A*0201 (P=2×10−6) and HLA-DQB1*0602 (P=5×10−10), and their interaction (P=0.005). Additional, population-dependent effects were observed in HLA alleles with nominal significance. In an analysis of auto-immunerelated genes, rs2476601 in the gene PTPN22 was associated (P=1.3×10−4). Conclusions Class I and II HLA genotypes affect susceptibility to AC-DILI, indicating the importance of the adaptive immune response in pathogenesis. The HLA genotypes identified will be useful in studies of the pathogenesis of AC-DILI, but have limited utility as predictive or diagnostic biomarkers because of the low positive-predictive values.

Tumor immune escape variants can be identified in human and experimental tumors. A variety of different strategies are used by tumor cells to avoid recognition by different immune effector mechanisms. Among these escape routes, alteration of MHC class I cell surface expression is one of the mechanisms most widely used by tumor cells. In this review we focus our attention on the T-cell immune selection of MHC class I-deficient tumor variants. Different altered MHC class I phenotypes that originate from multiple molecular mechanisms can be identified in human tumors. MHC-deficient tumor clones can escape T-cell immune responses, but are in theory more susceptible to NK-cell-mediated lysis. In this context, we also review the controversial issue of the aberrant expression of nonclassical HLA class I molecules, particularly HLA-G, in tumors. This expression may be relevant in tumor cells that have lost the capacity to interact with NK inhibitory receptors-namely, those tumor cells with no HLA-B or HLA-C expression. Most published studies have not analyzed these possibilities and do not provide information about the complete HLA-A, HLA-B, or HLA-C molecule profiles of the tumors studied. In contrast, HLA-E has been reported to be expressed in some tumor cell lines with very low HLA-A, HLA-B, and HLA-C expression, suggesting that HLA-E may indeed, in some cases, play a role by inhibiting NK lysis of cells that otherwise would be destroyed by NK cells. Finally, we provide evidence that the status of the immune system in the tumor-bearing animal is capable of defining the MHC profile of the tumor cells. In other words, MHC class I-negative metastatic colonies are produced in immunocompetent animals, and MHC class I-positive colonies in T-cell immunodeficient individuals.

Interactions involving charged particles in the presence of multivalent ions are relevant in wide-range of phenomena, including condensation of nucleic acids, cement hardening, or water treatment. Here, we study such interactions by combining direct force measurements with atomic force microscopy (AFM) and aggregation studies with time-resolved light scattering for particles originating from the same colloidal suspension for the first time. Classical DLVO theory is found to be only applicable for monovalent and divalent ions. For ions of higher valence, charge inversion and additional non-DLVO attractive forces are observed. These attractive forces can be attributed to surface charge heterogeneities, which leads to stability ratios that are calculated from direct force measurements to be higher than the experimental ones. Ion-ion correlations are equally important as they induce the charge inversion in the presence of trivalent or tetravalent ions, and they enhance the surface charge heterogeneities. Such heterogeneities therefore play an essential role in controlling interactions in particle suspensions containing multivalent ions.

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The mechanisms that lead to loss of MHC class I expression in different types of tumors are not yet fully known. Accordingly, we studied colorectal carcinomas to elucidate the specific mechanisms of evasion of the T-cell immune response. We selected tumors with total loss of MHC class I expression and studied 124 colorectal carcinomas with immunohistochemical staining and anti-HLA monoclonal antibodies (mAb). Fourteen of 124 (11%) tumors exhibited a phenotype with HLA class I total loss. Microsatellite instability (MSI) analysis was also carried out in the same tumor samples. The expression of beta2-microglobulin (beta2m), HLA-A, B, and C antigens, transporter associated with antigen processing 1 (TAP1), TAP2, low-molecular-weight protein 2 (LMP2), and LMP7 were analyzed using reverse-transcription polymerase chain reaction (RT-PCR) in microdissected tumor samples. Four of 14 microsatellite instability-positive (MSI+) and W6/32 mAb-negative tumors showed biallelic inactivation of beta2m and accumulation of HLA class I heavy chain in the cytoplasm. MSI-negative (MSI-)/W6/32 mAb-negative tumors presented alterations in the expression of components of the antigen processing machinery (APM). Nine of 10 tumor samples showed LMP7 gene downregulation, and four of 10 presented TAP2 dysregulation. This group apparently expressed normal levels of heavy chain and beta2m mRNA. Two major mechanisms in colorectal cancer appear to be responsible for the total loss of MHC surface expression (beta2m mutations and LMP7/TAP2 downregulation) that may contribute to the failure of T lymphocyte recognition during an immune response. The precise identification of the molecular defects that underlie HLA class I abnormalities will have important implications for patients receiving T-cell-based specific immunotherapy.

Interaction forces between carboxylate colloidal latex particles of about 2 μm in diameter immersed in aqueous solutions of monovalent salts were measured with the colloidal probe technique, which is based on the atomic force microscope. We have systematically varied the ionic strength, the type of salt, and also the surface charge densities of the particles through changes in the solution pH. Based on these measurements, we have accurately measured the dispersion forces acting between the particles and estimated the apparent Hamaker constant to be (2.0 ± 0.5) × 10(-21) J at a separation distance of about 10 nm. This value is basically independent of the salt concentration and the type of salt. Good agreement with Lifshitz theory is found when roughness effects are taken into account. The combination of retardation and roughness effects reduces the value of the apparent Hamaker constant and its ionic strength dependence with respect to the case of ideally smooth surfaces.