The United States and Canadian Academy of Pathology Lippincott Williams and Wilkins publishes Laboratory Investigation

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		THE IMPORTANCE OF GPI ANCHORAGE IN DEVELOPMENT: Glycosylphosphatidylinositol (GPI) anchorage of membrane proteins to the cell membranes of cells is a mode of linkage utilized by a wide variety of proteins. Defects in the GPI-anchor biosynthetic pathway are known to give rise to specific pathological conditions, including paroxysmal nocturnal hemoglobinuria (PNH) in which the defect is restricted to hematopoietic cells. Other GPI-anchored proteins include the uPA receptor. This protein modulates the activity of uPA, an enzyme thought to be involved in proteolysis of a wide variety of proteins including other enzymes and extracellular matrix components, and thus would affect cell migration, adhesion, proliferation, and differentiation Another GPI-anchored protein is the folic acid receptor, whose ligand, folic acid, is known to be involved in neural tube development. In this issue, Nozaki et al (Lab Invest 1999;79:293) evaluated the developmental abnormalities associated with GPI-anchor deficient embryos using the Cre/loxP system. Their findings of developmental arrest at Day 9 post coitus in embryos having a complete knockout of the Pig-a gene, illustrate the importance of GPI-anchored proteins during this stage of development. Interestingly, the arrest of yolk sac vascular development and failure of neural tube closure observed in this study have also been observed in a variety of knockout mice including Ephrin2B-/-, Tie1-/-, and vimentin-/- among others, and in rodent conceptuses cultured in high D-glucose containing media. A potential, common abnormality among these diverse knockout mice may be a failure or dysregulation in cell-cell and cell-extracellular matrix interactions, which would lead to failures of migration, differentiation, and, ultimately, integrity of a variety of organs/tissues. Abnormalities of facial primordia noted in both completely and partially disrupted Pig-a embryos are also consistent with defects in cell-cell, cell-extracellular matrix, and/or receptor-ligand interactions. These results underscore the importance of GPI-anhored proteins in both early and later phases of development and may perhaps lead to a more complete understanding of selected developmental abnormalities in the human population. Developmental Abnormalities of Glycosylphosphatidylinositol-Anchor\NDeficient Embryos Revealed by Cre/loxP System Masami Nozaki, Kazuhito Ohishi, Naoko Yamada, Taroh Kinoshita, Andras Nagy, and Junji Takeda ORGAN DIFFERENCES IN SYSTEMIC AUTOIMMUNITY: The MRL mouse is a widely studied model of human systemic lupus erythematosis, especially those animals that display a severe form of the disease due to the concomitant presence of the lprmutation which inactivates the Fas gene product (CD95). One of the advantages of having a mouse model, such as MRL/lprmice, is the opportunity to test treatment strategies in a preclinical setting. Neonatal thymectomy is protective in MRL animals, implying that autoimmunity in this model depends on regulatory T cells as well as on antibody-secreting B cells. Therefore, inhibition of T-cell activation would be expected to ameliorate the disease. A major tenet of modern immunology is the two signal hypothesis of lymphocyte activation. For T cells, this hypothesis states that effective activation depends on recognition both of antigen (Signal 1), which delivers signals through the T cell receptor for antigen, and of a costimulator molecule (Signal 2), such as B7-1(CD80) or B7-2(CD86) on an antigen-presenting cell, which deliver signals through the CD28 molecule on the T cell. Activated T cells normally turn off Signal 2 by de novo expression of CTLA-4, an inhibitory surface receptor that binds B7-1 or B7-2 with higher affinity than does CD28. Soluble CTLA-4, administered as an immunoglobulin fusion protein (CTLA-4-Ig), can block Signal 2 from being delivered and prevent T cell activation. Thus one would predict that treatment of young MRL/lprmice with soluble CTLA-4-Ig will prevent the development of autoimmunity. In the current issue of the journal (Lab Invest 1999;79;317-326) Takiguchi and colleagues have tested this idea. As expected, the characteristic lupus-like disease in the kidneys is inhibited by CTLA-4-Ig treatment. Surprisingly, lung disease, a less well studied target of autoimmunity in these mice, was found to progress at indistinguishable rates in treated and untreated animals. These data suggest that different organs may be injured by different mechanisms in the sae autoimmune animal, a hypothesis supported by the observation that kidney disease is, at least in part, mediated by autoantibodies, whereas lung disease seems to be mediated by activated macrophages. This study also points out the value of careful and thorough histopathologic examination in evaluating therapy in preclinical animal models, a lesson that should apply equally well to patient-based clinical research. Blockade of CD28/CTLA4-B7 Pathway Prevented Autoantibody-Related Diseases but Not Lung Disease in MRL/lpr Mice Mitsuyoshi Takiguchi, Masaaki Murakami, Izumi Nakagawa, Akira Yamada, Shunsuke Chikuma, Yoshinori Kawaguchi, Akira Hashimoto, and Toshimitsu Uede EXPRESSION OF CELL CYCLE GENES IN HEAD AND NECK CANCER: The study by Lai and El Naggar is one of the first to report the simultaneous analysis of the expression of three key proteins for the regulation of tumor cell growth in squamous cell carcinomas of the head and neck. Western blotting allows the authors to compare the relative levels of expression for each of the following proteins: Rb, p16, and cyclinD. The results appearing in this issue (Lab Invest 1999;79:255-260) herald a new era of molecular characterization of tumors. The time is coming when we will obtain massive data on the profiles of gene expression. Advances in high throughput gene expression analysis and detection of mutations, combined with the development of bioinformatics, make it possible to gather what, by recent standards, was an unmanageable amount of information. Studies like that of Lai and El Naggar represent the forefront of this type of approach. Destined to become superseded in the near future, these studies are important because they establish the feasibility and interest of the approach. Parenthetically, the paper also illustrates the importance of studying both cell lines and primary tumor tissue, because some of the results indicate significant differences exist between both, presumably the result of the adaptation or selection of the cells to grow in vitro conditions. Differential Expression of Key Cell Cycle Genes (p16/cyclin D1/ pRb) in Head and Neck Squamos Carcinomas Syeling Lai and Adel K. El-Naggar PHYTOSTEROLS PROTECT APO-E DEFICIENT MICE: The pathologic sequelae of disordered cholesterol metabolism constitute the single most serious threat to health in all modern Western cultures. Although many factors contribute, one accepted risk factor is the so-called Western diet, rich in saturated fat and cholesterol. A second major input into whole-body pools of cholesterol is its denovo biosynthesis. Thus, over the years, a variety of dietary and pharmacological strategies have been devised that focus on reducing dietary cholesterol and saturated fat, controlling its absorption, or blocking its synthesis. In humans, dietary factors influencing cholesterol synthesis are manifold and include caloric intake, meal frequency, fat type, and cholesterol content. Of increasing interest is the effect of dietary phytosterols on cholesterol absorption and metabolism. Phytosterols (plant sterols) are abundant in the fat-soluble fractions of plants and are typically consumed at levels of 200-400 mg/day in Western diets. Chemically resembling cholesterol, phytosterols inhibit the absorption of cholesterol and have been proposed to be of therapeutic benefit in dietary plans aimed at reducing cholesterol levels. However, their mechanism of action and impact on other biologic functions is relatively unexplored. In this issue (Lab Invest 1999;79:355-364), Moghadasian and colleagues add intriguing new observations to our understanding of phytosterol action. Mice genetically altered to delete the apolipoprotein-E gene do not appropriately regulate endogenous cholesterol synthesis, and as such are particularly prone to diet induced atherosclerosis. Using such animals fed a high fat and high cholesterol diet, they demonstrate that the addition of a mixture of sitosterol and campesterol not only lowers circulating cholesterol and enhances HMG-CoA reductase activity, but also prevents the other adverse consequences of hypercholesterolemia, including erythrocyte fragility and cutaneous xanthomas. These are encouraging observations. However, there are also caveats. Whereas the min action of the phytosterols may be to impair absorption of dietary cholesterol (hence the dramatic effects observed here in a dietary induced animal model of atherosclerosis) other workers have, on occasion, noted estrogenic like effects of such agents, manifested as testicular damage in rabbits and albino rats. In the present study, some testicular and seminiferous tubule atrophy was noted, although its extent was variable and may have been exacerbated by Apo-E deficiency. Although the extent of such changes is unclear and may not be of major health significance relative to the vascular complications of hypercholesterolemia, this observation does suggest that other pathways of steroid metabolism might be impacted by the phytosterols. It will thus be important in future studies to consider the longer term impacts of such dietary agents and whether they can alter hormonal function. Histologic, Hematologic, and Biochemical Characteristics of Apo E-Deficient Mice: Effects of Dietary Cholesterol and Phytosterols Mohammed H. Moghadasian, Lien B. Nguyen, Sarah Shefer, Bruce M. McManus, and Jiri J. Frohlich