Abstract
The cytosol of apoptotic cells contains a low molecular weight compound that markedly enhances generation of cytotoxic T lymphocyte responses to particulate human immunodeficiency gp120 antigen. By HPLC and mass spectroscopy, researchers identified the compound responsible for augmenting the CD8+ T cell response as uric acid. This identification was supported by the demonstration that treating mice with compounds that reduced uric acid accumulation (allopurinol or uricase) markedly suppressed the generation of gp120-specific cytotoxic T lymphocyte responses. Further studies indicated that the immunostimulatory form of uric acid was likely to be monosodium urate crystals that form at sites of cell injury. Uric acid apparently exerted its effect by stimulating dendritic cells to increase the expression of costimulatory molecules. Uric acid may be a “danger signal” released by dying cells that serves to promote immunity to pathogens. These studies suggest that uric acid may be a useful adjuvant for some vaccines.
Shi Y, Evans JE, Rock KL: Molecular identification of a danger signal that alerts the immune system to dying cells. Nature 425:516–521, 2003
Mice are often used as experimental animals to study airway remodeling in asthma. Canadian and American scientists recently developed a robust method for quantifying those changes in airway connective tissue and smooth muscle that serve as indices of airway remodeling. The technique consists of fixing lungs in formalin for 24 hours at a pressure of 20 cm of water, bisecting the left lung transversely, cutting 3-µm sections for staining with Masson's trichrome or for smooth muscle actin, and evaluation with a customized digital image analysis system. The best results were obtained by evaluating first generation airways at 20 µm below the epithelium. Using this technique, a significant difference between airways in control and experimental ovalbumin-sensitized mice could be detected with groups of only 8–10 mice. This appears to be a sensitive and reproducible technique for quantifying airway remodeling in mice.
Ellis R, Leigh R, Southam D, O'Byrne PM, Inman MD: Morphometric analysis of mouse airways after chronic allergen challenge. Lab Invest 83:1285–1291, 2003
Survey sequencing of the dog genome followed by assembly of contiguous segments and comparison to the mouse and human genomes has been completed. Of the more than 24,000 annotated human genes, putative orthologs for over 18,000 were identified in the dog genome. Based on these studies, it is clear that dogs and humans are more similar to each other than either is to the mouse. However, the dog was the first of the three species to diverge from a common ancestor. The mutation rates in dog and man appear to be similar and lower than the rate in mice. Approximately 31% of the dog genome consists of repetitive sequences and an additional 4% of lineage-specific repeat elements. The studies also identified many short repeat polymorphisms and single nucleotide polymorphisms that will be valuable for linkage analysis and gene mapping. Dogs represent a unique genetic resource, characterized by enormous genetic diversity among the different breeds but marked genetic homogeneity within each breed. Furthermore, dogs suffer from a variety of genetic defects similar to those in man. The detailed genetic information now available for the dog will enhance its usefulness as a model for human disease.
Kirkness EF, Bafna V, Halpern AL, Levy S, Remington K, Rusch DB, Delcher AL, Pop M, Wang W, Fraser CM, Venter JC: The dog genome: survey sequencing and comparative analysis. Science 301:1898–1903, 2003
It is increasingly apparent that the interaction of tumor cells with their microenvironment can be an important determinant of tumor behavior. California scientists recently demonstrated that ionizing radiation exposure can alter the ability of mammary epithelial cells to interact with each other and with the extracellular matrix in vitro. Irradiation altered the acinar organization of cells and the localization of molecules such as E-cadherin, β-catenin, and connexin-43 important in establishing cell polarity and intercellular communication. These changes were unlikely to be genetic, since most irradiated cells were affected; however, the changes persisted for several generations, indicating that they were heritable. These epigenetic changes in the way cells interact with their microenvironment may profoundly influence tumor development and behavior.
Park CC, Henshall-Powell RL, Erickson AC, Talhouk R, Parvin B, Bissell MJ, Barcellos-Hoff MH: Ionizing radiation induces heritable disruption of epithelial cell interactions. Proc Natl Acad Sci USA 100:10728–10733, 2003
To investigate the influence of previous respiratory viral infections on the response to subsequent infections with different viruses, mice were sequentially infected with a variety of unrelated viruses that either caused respiratory disease or spread via the respiratory route. The viruses employed included lymphocytic choriomeningitis, murine cytomegalo-virus, influenza A, and vaccinia viruses. These studies showed that previous viral infection dramatically altered the cytokine response, the pathology, and the viral clearance for subsequent viral infections. In general, two patterns of disease outcome were apparent. If previous immunity changed the nature of the response to the second virus from acute neutrophilic to lymphocytic, disease severity was reduced. However, a change from a mild lymphocytic to a severe lymphocytic response enhanced disease due to the second virus. These effects appear to be due to reactivation of memory T cells by cross-reactive peptides shared by different viruses.
Chen HD, Fraire AE, Joris I, Welsh RM, Selin LK: Specific history of heterologous virus infections determines anti-viral immunity and immunopathology in the lung. Am J Pathol 163:1341–1355, 2003