Pharmacological interaction of drugs with immune receptors: the p-i concept

Drug-induced hypersensitivity reactions have been explained by the hapten concept, according to which a small chemical compound is too small to be recognized by the immune system. Only after covalently binding to an endogenous protein the immune system reacts to this so called hapten-carrier complex, as the larger molecule (protein) is modified, and thus immunogenic for B and T cells. Consequently, a B and T cell immune response might develop to the drug with very heterogeneous clinical manifestations. In recent years, however, evidence has become stronger that not all drugs need to bind covalently to the MHC-peptide complex in order to trigger an immune response. Rather, some drugs may bind directly and reversibly to immune receptors like the major histocompatibility complex (MHC) or the T cell receptor (TCR), thereby stimulating the cells similar to a pharmacological activation of other receptors. This concept has been termed pharmacological interaction with immune receptors the (p-i) concept. While the exact mechanism is still a matter of debate, non-covalent drug presentation clearly leads to the activation of drug-specific T cells as documented for various drugs (lidocaine, sulfamethoxazole (SMX), lamotrigine, carbamazepine, p-phenylendiamine, etc.). In some patients with drug hypersensitivity, such a response may occur within hours even upon the first exposure to the drug. Thus, the reaction to the drug may not be due to a classical, primary response, but rather be mediated by stimulating existing, pre-activated, peptide-specific T cells that are cross specific for the drug. In this way, certain drugs may circumvent the checkpoints for immune activation imposed by the classical antigen processing and presentation mechanisms, which may help to explain the peculiar nature of many drug hypersensitivity reactions.

Consequences of depleted SERCA2-gated calcium stores in the skin

Sarco(endo)plasmic reticulum Ca2+-ATPase isoform 2 (SERCA2) pumps belong to the family of Ca2+-ATPases responsible for the maintenance of calcium in the endoplasmic reticulum. In epidermal keratinocytes, SERCA2-controlled calcium stores are involved in cell cycle exit and onset of terminal differentiation. Hence, their dysfunction was thought to provoke impaired keratinocyte cohesion and hampered terminal differentiation. Here, we assessed cultured keratinocytes and skin biopsies from a canine family with an inherited skin blistering disorder. Cells from lesional and phenotypically normal areas of one of these dogs revealed affected calcium homeostasis due to depleted SERCA2-gated stores. In phenotypically normal patient cells, this defect compromised upregulation of p21(WAF1) and delayed the exit from the cell cycle. Despite this abnormality it failed to impede the terminal differentiation process in the long term but instead coincided with enhanced apoptosis and appearance of chronic wounds, suggestive of secondary mutations. Collectively, these findings provide the first survey on phenotypic consequences of depleted SERCA-gated stores for epidermal homeostasis that explain how depleted SERCA2 calcium stores provoke focal lesions rather than generalized dermatoses, a phenotype highly reminiscent of the human genodermatosis Darier disease.

Feline caries in two cats from a 13th century archeological excavation

Mandibles of two cats containing carious lesions were discovered among the previously published findings of feline dental resorptive lesions from materials examined at an archaeological museum. These lesions were too small to be noted on radiographs, and consisted of two inconspicuous enamel lesions in a mandibular left first molar tooth (309), a clinically visible white spot area containing an enamel lesion in a mandibular left fourth premolar tooth (308), and a root surface caries in the 308 of a different specimen. Histologic examination using special stains and polarized light revealed both initial and early initial stage enamel caries, as well as root surface caries. Knoop hardness measurements confirmed these findings, considered the first documented cases of feline caries.

Daptomycin is more efficacious than vancomycin against a methicillin-susceptible Staphylococcus aureus in experimental meningitis

OBJECTIVES: To test the efficacy of daptomycin, a cyclic lipopeptide antibiotic, against a methicillin-susceptible Staphylococcus aureus strain in experimental rabbit meningitis and to determine its penetration into non-inflamed and inflamed meninges RESULTS: Over a treatment period of 8 h, daptomycin (15 mg/kg) was significantly superior to the comparator regimen vancomycin (-4.54 +/- 1.12 log(10)/mL for daptomycin versus -3.43 +/- 1.17 log(10)/mL for vancomycin). Daptomycin managed to sterilize 6 out of 10 CSFs compared with 4 out of 10 for vancomycin. The penetration of daptomycin into inflamed meninges was approximately 5% and approximately 2% into non-inflamed meninges. CONCLUSIONS: The superior bactericidal activity of daptomycin was confirmed in vivo and in time-killing assays in vitro.

Efficacy of telavancin against penicillin-resistant pneumococci and Staphylococcus aureus in a rabbit meningitis model and determination of kinetic parameters

The penetration of telavancin was 2% into inflamed meninges and ca. 1 per thousand into noninflamed meninges after two intravenous injections (30 mg/kg of body weight). In experimental meningitis, telavancin was significantly superior to vancomycin combined with ceftriaxone against a penicillin-resistant pneumococcal strain. Against a methicillin-sensitive staphylococcal strain, telavancin was slightly but not significantly superior to vancomycin.

Interferon-inducible expression of APOBEC3 editing enzymes in human hepatocytes and inhibition of hepatitis B virus replication

Hypermutations in hepatitis B virus (HBV) DNA by APOBEC3 cytidine deaminases have been detected in vitro and in vivo, and APOBEC3G (A3G) and APOBEC3F (A3F) have been shown to inhibit the replication of HBV in vitro, but the presumably low or even absent hepatic expression of these enzymes has raised the question as to their physiological impact on HBV replication. We show that normal human liver expresses the mRNAs of APOBEC3B (A3B), APOBEC3C (A3C), A3F, and A3G. In primary human hepatocytes, interferon alpha (IFN-alpha) stimulated the expression of these cytidine deaminases up to 14-fold, and the mRNAs of A3G, A3F, and A3B reached expression levels of 10%, 3%, and 3%, respectively, relative to GAPDH mRNA abundance. On transfection, the full-length protein A3B(L) inhibited HBV replication in vitro as efficiently as A3G or A3F, whereas the truncated splice variant A3B(S) and A3C had no effect. A3B(L) and A3B(S) were detected predominantly in the nucleus of uninfected cells; however, in HBV-expressing cells both proteins were found also in the cytoplasm and were associated with HBV viral particles, similarly to A3G and A3F. Moreover, A3G, A3F, and A3B(L), but not A3B(S), induced extensive G-to-A hypermutations in a fraction of the replicated HBV genomes. In conclusion, the editing enzymes A3B(L), A3F, and most markedly A3G, which are expressed in liver and up-regulated by IFN-alpha in hepatocytes, are candidates to contribute to the noncytolytic clearance of HBV.