Immunogenetics of drug-induced skin blistering disorders. Part I: Perspective

The overall immunopathogenesis relevant to a large series of disorders caused by a drug or its associated hyperimmune condition is discussed based upon the examination of the genetics of severe drug-induced bullous skin problems (sporadic idiosyncratic adverse events, including Stevens-Johnson syndrome and toxic epidermal necrolysis). An overarching pharmacogenetic schema is proposed. Immune cognition and early-effector processes are focused upon and a challenging synthesis around systems evolution is explained by a variety of projective analogies. Etiology, human leukocyte antigen-B, immune stability, clysiregulation, pharmacomimicry, viruses and an aggressive ethnically differentiated 'karmic' response are discussed.

Altered expression of cell cycle proteins and prolonged duration of cardiac myocyte hyperplasia in p27KIP1 knockout mice

The precise role of cell cycle-dependent molecules in controlling the switch from cardiac myocyte hyperplasia to hypertrophy remains to be determined. We report that loss of p27(KIP1) in the mouse results in a significant increase in heart size and in the total number of cardiac myocytes. In comparison to p27(KIP1)+/+ myocytes, the percentage of neonatal p27(KIP1)-/- myocytes in S phase was increased significantly, concomitant with a significant decrease in the percentage of G(0)/G(1) cells. The expressions of proliferating cell nuclear antigen, G(1)/S and G(2)/M phase-acting cyclins, and cyclin-dependent kinases (CDKs) were upregulated significantly in ventricular tissue obtained from early neonatal p27(KIP1)-/- mice, concomitant with a substantial decrease in the expressions of G(1) phase-acting cyclins and CDKs. Furthermore, mRNA expressions of the embryonic genes atrial natriuretic factor and alpha-skeletal actin were detectable at significant levels in neonatal and adult p27(KIP1)-/- mouse hearts but were undetectable in p27(KIP1)+/+ hearts. In addition, loss of p27(KIP1) was not compensated for by the upregulation of other CDK inhibitors. Thus, the loss of p27(KIP1) results in prolonged proliferation of the mouse cardiac myocyte and perturbation of myocyte hypertrophy.

Non-promoting diterpene esters can induce Epstein-Barr Virus early antigen expression in the Raji cell line

A range of diterpene ester ligands with selective biological activity (e.g., irritant but not tumour promoting) were tested for their ability to induce Epstein-Barr virus (EBV) early antigen expression in the lymphoblastoid Raji cell line. All substituted compounds were found to be capable of inducing some antigen expression at nM−μM levels, including desacetyl-α-sapinine, a compound largely devoid of biological activity. The non-promoting, fluorescent compound, sapintoxin A, was virtually equipotent with promoting compounds. It was concluded that, although the assay has relevance to the specific condition of chronic diterpene ester exposure occurring in conjunction with high EBV infection rates, there was relatively poor correlation with mouse skin tumour promoting potential.

Carnauba wax nanoparticles enhance strong systemic and mucosal cellular and humoral immune responses to HIV-gp140 antigen

Induction of humoral responses to HIV at mucosal compartments without inflammation is important for vaccine design. We developed charged wax nanoparticles that efficiently adsorb protein antigens and are internalized by DC in the absence of inflammation. HIV-gp140-adsorbed nanoparticles induced stronger in vitro T-cell proliferation responses than antigen alone. Such responses were greatly enhanced when antigen was co-adsorbed with TLR ligands. Immunogenicity studies in mice showed that intradermal vaccination with HIV-gp140 antigen-adsorbed nanoparticles induced high levels of specific IgG. Importantly, intranasal immunization with HIV-gp140-adsorbed nanoparticles greatly enhanced serum and vaginal IgG and IgA responses. Our results show that HIV-gp140-carrying wax nanoparticles can induce strong cellular/humoral immune responses without inflammation and may be of potential use as effective mucosal adjuvants for HIV vaccine candidates.

Studies into the role of the SEF14 fimbrial antigen in the pathogenesis of Salmonella enteritidis

To investigate the role of the SEF14 fimbrial antigen in pathogenesis, a single defined sefA (SEF14(-)) inactivated mutant of Salmonella enteritidis strain LA5 was constructed and tested in a number of biological assay systems. There was no significant difference between the wild-type strain and the isogenic SEF14(-) mutant in their abilities to adhere to and invade HEp-2 epithelial cells or their survival in mouse peritoneal macrophages, whereas the SEF14(-) mutant was ingested more rapidly by isolated human PMN. Both the strains colonized the intestine, invaded and spread systemically in 1 day-old chicks, laying hens and BALB/c mice equally well. A significantly greater number of chicks excreted the wildtype SEF14(+) strain during the first week following infection as compared to those infected with the SEF14(-) mutant. However, similar numbers of chicks excreted the two strains between 2 and 7 weeks after infection. These results indicate that possession of SEF14 fimbriae alone do not appear to play a significant role in the pathogenesis of S. enteritidis although its contribution to virulence may be dependent on the host species infected. (C) 1996 Academic Press Limited