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Common Themes Both plants and animals need to be able to distinguish between their own tissues and the cells and tissues of an invading pathogen. Across kingdoms there exists a range of pattern recognition systems that have become integral to the evolution of innate immune responses. Ronald and Beutler (p. 1061 ) synthesize recent intellectual progress to bring insights into shared features of animal immunology and plant pathology.

Herpes simplex virus-1 (HSV-1) encephalitis (HSE) is the most common form of sporadic viral encephalitis in western countries. Its pathogenesis remains unclear, as it affects otherwise healthy patients and only a small minority of HSV-1–infected individuals. Here, we elucidate a genetic etiology for HSE in two children with autosomal recessive deficiency in the intracellular protein UNC-93B, resulting in impaired cellular interferon-α/β and -λ antiviral responses. HSE can result from a single-gene immunodeficiency that does not compromise immunity to most pathogens, unlike most known primary immunodeficiencies. Other severe infectious diseases may also reflect monogenic disorders of immunity.

It has been reported by J. Trojan et al . (1 Jan. 1993, p. 94) ([1][1]) that antisense insulin-like growth factor I (IGF-I) messenger RNA induces curative immunotherapy of glioblastoma ([1][1]). We have determined the haplotypes of the glioma cell line and of the recipient rat strain used in this

Iron is vital for life but can be toxic when in excess, so the body has developed ways to carefully maintain stable iron levels. Although numerous proteins involved in iron homeostasis have been identified, it is not clear how they all fit together to regulate iron levels. Two new studies ([ Nemeth et al .][1]; [ Meyron-Holtz et al .][2]) fit several more pieces into the puzzle of iron regulation, as [Beutler][3] outlines in his Perspective. [1]: http://www.sciencemag.org/cgi/content/short/306/5704/2090 [2]: http://www.sciencemag.org/cgi/content/short/306/5704/2087 [3]: http://www.sciencemag.org/cgi/content/full/306/5704/2051

Gaucher disease is characterized by the accumulation of glucocerebroside, leading to enlargement of the liver and spleen and lesions in the bones. It is caused by an inherited deficiency of the enzyme glucocerebrosidase. Many mutations exist, but four of these account for over 97% of the mutations in Ashkenazi Jews, the population group in which Gaucher disease is the most common. Although there is a strong relation between the mutations and disease manifestations, genetic counseling is made difficult by the fact that within each genotype there is considerable variability in the severity of the disease. Intravenous infusion of glucocerebrosidase is an effective treatment, but the availability of enzyme replacement therapy is limited by its high cost. Marrow transplantation is also effective in treating the disease, but is rarely performed because of the risks involved. In the future gene transfer may become the treatment of choice.

Cachectin (tumor necrosis factor) is a macrophage hormone strongly implicated in the pathogenesis of endotoxin-induced shock. The availability of a DNA probe complementary to the cachectin messenger RNA (mRNA), as well as a specific antibody capable of recognizing the cachectin gene product, has made it possible to analyze the regulation of cachectin gene expression under a variety of conditions. Thioglycollate-elicited peritoneal macrophages obtained from mice contain a pool of cachectin mRNA that is not expressed as protein. When the cells are stimulated with endotoxin, large quantity of additional cachectin mRNA is produced, and immunoreactive cachectin is secreted. Macrophages from mice of the C3H/HeJ strain do not produce cachectin in response to endotoxin. A dual defect appears to prevent cachectin expression. First, a diminished quantity of cachectin mRNA is expressed in response to low concentrations of endotoxin. Second, a post-transcriptional defect prevents the production of cachectin protein. Macrophages from endotoxin-sensitive mice do not produce cachectin if they are first treated with dexamethasone, apparently for similar reasons. These findings give new insight into the nature of the C3H/HeJ mutation and suggest an important mechanism by which glucocorticoids may act to suppress inflammation.

Cachectin (tumor necrosis factor), a protein produced in large quantities by endotoxin-activated macrophages, has been implicated as an important mediator of the lethal effect of endotoxin. Recombinant human cachectin was infused into rats in an effort to determine whether cachectin, by itself, can elicit the derangements of host physiology caused by administration of endotoxin. When administered in quantities similar to those produced endogenously in response to endotoxin, cachectin causes hypotension, metabolic acidosis, hemoconcentration, and death within minutes to hours, as a result of respiratory arrest. Hyperglycemia and hyperkalemia were also observed after infusion. At necropsy, diffuse pulmonary inflammation and hemorrhage were apparent on gross and histopathologic examination, along with ischemic and hemorrhagic lesions of the gastrointestinal tract, and acute renal tubular necrosis. Thus, it appears that a single protein mediator (cachectin) is capable of inducing many of the deleterious effects of endotoxin.

A highly specific polyclonal rabbit antiserum directed against murine cachectin/tumor necrosis factor (TNF) was prepared. When BALB/c mice were passively immunized with the antiserum or with purified immune globulin, they were protected against the lethal effect of the endotoxin lipopolysaccharide produced by Escherichia coli. The prophylactic effect was dose-dependent and was most effective when the antiserum was administered prior to the injection of the endotoxin. Antiserum to cachectin/TNF did not mitigate the febrile response of endotoxin-treated animals, and very high doses of endotoxin could overcome the protective effect. The median lethal dose of endotoxin in mice pretreated with 50 microliters of the specific antiserum was approximately 2.5 times greater the median lethal dose for controls given nonimmune serum. The data suggest that cachectin/TNF is one of the principal mediators of the lethal effect of endotoxin.

Certain infections and malignancies in mammals cause the development of a condition known as cachexia in which the animal continues to lose weight, often while consuming an adequate diet. When macrophages are stimulated with an endotoxin, they produce a factor or factors, termed cachectin, that inhibits the activity of fat-producing (lipogenic) enzymes in cultured adipocytes. This effect may reflect one of the physiological bases for cachexia. In the present study, clones of complementary DNA from genes whose expression is increased during the differentiation of adipocytes were used to study the molecular basis of cachectin's actions. In the presence of cachectin, the expression of the corresponding genes was reversibly and specifically inhibited. Furthermore, when mature adipocytes were exposed to cachectin, the messenger RNA's of those genes diminished and rapidly approached the levels present before differentiation.

Absolute thresholds in response to red light were compared in nine normal subjects, six female carriers of protanopia (heterozygotes), and six male subjects with protanopia. The fovea and four peripheral retinal areas were tested, and all data were obtained before the occurrence of the rod-cone break. Elevated thresholds were found in all retinal areas tested in protanopic males, at the fovea in all carriers, and in some peripheral retinal areas in two carriers. The thresholds for carriers were far below those for the protanopic males, and no greater variability of threshold was found in the carriers when they were compared with the normal control group. The findings do not substantiate the occurrence of inactivation at the locus on the X chromosome for protanopia.

A specific method for starch-gel electrophoresis of galactose-1-phosphate uridyltransferase has been developed. Electrophoresis of red-cell hemolyzate from normal subjects and subjects homozygous for the Duarte variant has shown that the Duarte variant has a slightly faster electrophoretic mobility than the normal enzyme under the various conditions used. Molecular-weight estimation on Sephadex G-200 indicates that this observed difference in electrophoreticmobility of the Duarte variant is not due to difference in molecular size. Both enzymes have a molecular weigh of approximately 85,000.