Type III (Arthus) allergic reactions and endotoxin toxicity in guinea-pigs.

Lipoplysaccharide (endotoxin) from E. coli cells produced lethal effects in guinea-pigs. Endotoxin caused no visible dermal change in normal animals, but produced skin reactions characterized by specific Arthus-type (Type III immune hypersensitivity) vascular inflammation in immunized animals. It is concluded that Arthus allergic reactions were evoked by endotoxin, however, endotoxin lethal toxicity appears independent of this process.     

An extragalactic supernebula confined by gravity

Little is known about the origins of globular clusters, which contain hundreds of thousands of stars in a volume only a few light years across. Radiation pressure and winds from luminous young stars should disperse the star-forming gas and disrupt the formation of the cluster. Globular clusters in our Galaxy cannot provide answers; they are billions of years old. Here we report the measurement of infrared hydrogen recombination lines from a young, forming super star cluster in the dwarf galaxy NGC5253. The lines arise in gas heated by a cluster of about one million stars, including 4,000-6,000 massive, hot 'O' stars. It is so young that it is still enshrouded in gas and dust, hidden from optical view. The gases within the cluster seem bound by gravity, which may explain why the windy and luminous O stars have not yet blown away those gases. Young clusters in 'starbursting' galaxies in the local and distant Universe may also be gravitationally confined and cloaked from view.     

Mutations in the gene encoding peroxisomal alpha-methylacyl-CoA racemase cause adult-onset sensory motor neuropathy

Sensory motor neuropathy is associated with various inherited disorders including Charcot-Marie-Tooth disease, X-linked adrenoleukodystrophy/adrenomyeloneuropathy and Refsum disease. In the latter two, the neuropathy is thought to result from the accumulation of specific fatty acids. We describe here three patients with elevated plasma concentrations of pristanic acid (a branched-chain fatty acid) and C27-bile-acid intermediates. Two of the patients suffered from adult-onset sensory motor neuropathy. One patient also had pigmentary retinopathy, suggesting Refsum disease, whereas the other patient had upper motor neuron signs in the legs, suggesting adrenomyeloneuropathy. The third patient was a child without neuropathy. In all three patients we discovered a deficiency of alpha-methylacyl-CoA racemase (AMACR). This enzyme is responsible for the conversion of pristanoyl-CoA and C27-bile acyl-CoAs to their (S)-stereoisomers, which are the only stereoisomers that can be degraded via peroxisomal beta-oxidation. Sequence analysis of AMACR cDNA from the patients identified two different mutations that are likely to cause disease, based on analysis in Escherichia coli. Our findings have implications for the diagnosis of adult-onset neuropathies of unknown aetiology.     

Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis

Atopic disease, including atopic dermatitis (eczema), allergy and asthma, has increased in frequency in recent decades and now affects approximately 20% of the population in the developed world. Twin and family studies have shown that predisposition to atopic disease is highly heritable. Although most genetic studies have focused on immunological mechanisms, a primary epithelial barrier defect has been anticipated. Filaggrin is a key protein that facilitates terminal differentiation of the epidermis and formation of the skin barrier. Here we show that two independent loss-of-function genetic variants (R510X and 2282del4) in the gene encoding filaggrin (FLG) are very strong predisposing factors for atopic dermatitis. These variants are carried by approximately 9% of people of European origin. These variants also show highly significant association with asthma occurring in the context of atopic dermatitis. This work establishes a key role for impaired skin barrier function in the development of atopic disease.     

Identification of a putative second T-cell receptor

Framework monoclonal antibodies have identified a population of human lymphocytes that express the T3 glycoprotein but not the T-cell receptor (TCR) alpha- and beta-subunits. Chemical crosslinking experiments reveal that these lymphocytes express novel T3-associated polypeptides, one of which appears to be the product of the T gamma gene. The other polypeptide may represent a fourth TCR subunit, designated T delta.     

Cloning and sequencing of human cholesteryl ester transfer protein cDNA

The transfer of insoluble cholesteryl esters among lipoprotein particles is a vital step in normal cholesterol homeostasis and may be involved in the development of atherosclerosis. Extrahepatic tissues lack the enzymes required for the degradation of sterols to the excretable form of bile acids. Cholesterol synthesized in these tissues in excess of that needed for the synthesis of cell membranes or steroid hormones must accordingly be returned through the plasma to the liver for catabolism. The series of reactions involved has been termed reverse cholesterol transport. Catalysed steps of this pathway are believed to include an efflux from peripheral cells, which generates a diffusion gradient between these membranes and extracellular fluid; esterification of this cholesterol by lecithin-cholesterol acyltransferase (LCAT) (phosphatidylcholine-sterol acyltransferase) acting on species of high-density lipoproteins; transfer of the cholesteryl esters formed (largely to low- and very low-density lipoproteins) (LDL and VLDL) by a cholesteryl ester transfer protein (CETP); and removal of these lipoproteins, together with their cholesteryl ester content, by the liver through receptor-mediated and nonspecific endocytosis. Of these steps, the CETP reaction is the least characterized. Several laboratories have reported the purification from human plasma of proteins active on cholesteryl ester transfer between lipoprotein particles and possibly between cells and plasma. However, the reported relative molecular mass (Mr), abundance and specificity of the purified activities have differed considerably. We have recently described the preparation of a highly active CETP of Mr 74,000 purified about 100,000-fold from human plasma, which may represent the functional component of earlier preparations. Using a partial amino-acid sequence from this purified protein, CETP complementary DNA derived from human liver DNA has been cloned and sequenced and the cloned DNA used to detect CETP messenger RNA in a number of human tissues.     

Two forms of the T-cell receptor gamma protein found on peripheral blood cytotoxic T lymphocytes

The T-cell receptor (TCR) gamma polypeptide is expressed associated with CD3 (T3) on the surface of normal human peripheral blood lymphocytes. These cells function as non-MHC-restricted cytotoxic T lymphocytes (CTL)and thus may play an important role in host immune defence. The TCR gamma polypeptide occurs as a dimer in at least two molecular forms based on the absence or presence of disulphide linkage. These forms use TCR gamma polypeptides with strikingly different peptide backbone sizes.     

Type III (Arthus) allergic reactions and endotoxin toxicity in guinea-pigs

Summary Lipopolysaccharide (endotoxin) fromE. coli cells produced lethal effects in guinea-pigs. Endotoxin caused no visible dermal change in normal animals, but produced skin reactions characterized by specific Arthus-type (Type III immune hypersensitivity) vascular inflammation in immunized animals. It is concluded that Arthus allergic reactions were evoked by endotoxin, however, endotoxin lethal toxicity appears independent of this process.Acknowledgment. Supported by a grant from the National Health and Medical Research Council of Australia.