Current Molecular Medicine - Volume 1, Issue 4, 2001

DNA in eukaryotic cells is packaged into chromatin. The main packaging component of chromatin is the nucleosome, and this is composed of proteins known as histones. Histones can be reversibly modified in several ways, and the best characterized of these modifications is histone acetylation. This is a reversible modification, which is carried out by two families of enzymes, the histone acetyltransferases (HATs), and the histone deacetylases (HDACs). These enzymes have important activities in many cellular processes including transcription, DNA replication and cell cycle progression.The mechanisms underlying tumor formation are multifaceted, and often involve mutations or alterations of genes involved with the regulation and control of the cell cycle or cell death. Because of their important roles in the regulation of such events, enzymes that affect histone acetylation status are increasingly being associated with tumors. This article describes some of the current knowledge about histone acetyltransferases and histone deacetylases, and how their multitudinal roles in cellular events may have important roles in tumorigensis.

More than 15 years after the discovery of human immunodeficiency virus (HIV), researchers are still struggling to design a protective AIDS vaccine. A remaining problem is a lack of basic knowledge about the immunological requirements for protection against retroviruses. Infection of macaque monkeys with simian immunodeficiency virus is still the best model for HIV vaccine research. However, in this model it remains difficult to determine protective immunological mechanisms because of limited numbers of experimental animals and their genetic heterogeneity. Thus, fundamental concepts in retroviral immunology have to be defined in other ways such as mouse models. This minireview summarizes new findings on cellular and molecular mechanisms in protection of mice against Friend murine retrovirus infection. It has been shown that complex immune responses, including B and T cell responses, are required for efficient protection in this model. Multiple viral antigens are necessary to elicit such broad immune reactivity. Efficacious vaccines must protect not only against acute disease, but also against the establishment of persistent infections or the host is at serious risk of virus reactivation. The minireview closes with a discussion on the relevance of findings from the mouse model on the design of a protective vaccine against HIV.

Tuberculosis and malaria remain the leading causes of mortality among human infectious diseases in the world. It is estimated that 3 to 5 million people die from tuberculosis and malaria each year. Although it is traditionally believed that CD4 and CD8 alpha-beta T lymphocytes are mandatory for protective immune responses against Mycobacterium tuberculosis and Plasmodium falciparum (the ethiologic agents of tuberculosis and the most severe form of malaria, respectively), there is still incomplete understanding of the mechanisms of immune protection and of the causes of its failure in the affected patients. Several studies in humans and animal models have suggested that V gama9 / V delta2 T cells may play an important role in the immune responses against Mycobacterium tuberculosis and Plasmodium falciparum. V gama9 / V delta2 T cells represent about 75percent of all circulating gama-delta T cells while they can be greatly expanded during the acute phase of Mycobacterium tuberculosis and Plasmodium falciparum malaria. V-gama9 / V delta2 T recognize a new class of antigenic molecules which are nonpeptidic in nature and contain critical phosphate moieties (phosphoantigens). Interestingly, phosphoantigens isolated from Mycobacterium tuberculosis and Plasmodium falciparum share strong structural homology and are probably identical. However, despite a large body of data reported in the literature, it is not yet clear whether V-gama9 / V delta2 T cells play a protective or pathogenic role in immune responses against Mycobacterium tuberculosis and Plasmodium falciparum. In this review we summarize our current knowledge of the biology of V-gama9 / V-delta2 T cells in response to the two pathogens, Mycobacterium tuberculosis and Plasmodium falciparum, and provide evidence suggesting definition of a novel and important protective role through which V gama9 / V delta2 T cells can contribute to the killing of microorganisms residing in intracellular compartments.

A mouse model for the fragile X syndrome, the most common form of inherited mental retardation, was generated a number of years ago. It shows characteristics compatible with the clinical symptoms of human patients. These include pathological changes such as macroorchidism, behavioral problems, and diminished visuo-spatial abilities. To investigate whether the fragile X syndrome is a potentially correctable disorder, several groups attempted to rescue the knockout mutation by introduction of an intact copy of the FMR1 gene in the knockout mouse. Two different types of rescue mice have been created by injection of constructs based on FMR1 cDNA or on FMR1 genomic DNA. Several pathological, behavioral and cognitive function tests were performed on these two different rescue mouse lines to compare their characteristics with those of the knockout and control littermates. Each rescue line resembled the control in some aspects though neither of the 2 lines was a full rescue, e.g. resemble the control in all aspects investigated. Thus, rescue of some aspects of the phenotype has been achieved by introduction of FMR1 constructs in the fragile X knockout mice. The results implicate that, even if FMR1 production is cell type specific, the quantity of the FMRP expression is highly critical as overproduction may have a harmful effect.

T cells, as they develop in the thymus come to express antigen receptors. The specificity of these receptors cannot be predicted and must include many with potential anti-self reactivity. Those that encounter self-antigens, in association with self-MHC (major histocompatibility complex), with high affinity are inactivated and do not leave the thymus. Not all self-antigens however are expressed in the thymus and thus many potentially self-reactive T cells enter the periphery. It poses therefore a fundamental immunological question: how peripheral self-tolerance is maintained in health?Dendritic cells (DC) play a central role in the activation of T cells, especially naïve T cells. Their importance in initiating immune responses against pathogens has been well established. However, DC represent complex populations of cells. Recent advances in our knowledge including molecular understanding of DC / T cell interactions have begun to reveal another important dimension of DC functions in the periphery, being not only initiators but also regulators of the immune system. This review summarises recent findings on the roles of DC in the regulation of immune responses and the maintenance of peripheral tolerance, in an attempt to explain how break down of this may lead to immunopathologies and autoimmunity. The concept of a regulatory DC and its possible role in the generation of T regulatory cells in health and in diseases are also discussed. Based on these, the need for a continuing education of the immune system throughout ones life, in which DC are again the tutors, is postulated.

The mannose receptor (MR) recognizes a range of carbohydrates present on the surface and cell walls of micro-organisms. The MR is primarily expressed on macrophages and dendritic cells and is involved in MR-mediated endocytosis and phagocytosis. In addition, the MR plays a key role in host defense and provides a link between innate and adaptive immunity. Herein, we will review the role of the MR in innate host defense as well as the recent evidence for its role in the adaptive response, for both humoral and cellular immune responses.

Many streptococci are human and / or animal pathogens and the frequent cause of life-threatening diseases. Among various streptococcal virulence factors, capsular polysaccharides (CPs) are recognized as essential to prevent phagocytosis by macrophages and neutrophils. In the last decade, an impressive advance on the knowledge of the genetic bases underlying capsule formation has been achieved. The capsular gene cluster driving the formation of the CP of Streptococcus pyogenes and other hyaluronate-producing streptococci, represents one of the simplest cases of gene organization to synthesize a capsule. A more complex situation has been found in Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus suis, and other streptococci. On the whole, there exists a direct relationship between the structural and chemical complexity of the repeating unit of the polysaccharide and the number of genes found in the corresponding capsular locus. Streptococcal vaccines, either polysaccharide or conjugate, are currently being tested in clinical trials to overcome the rise of worldwide antibiotic resistance, although, for different reasons, none of these vaccines are expected to provide the required full coverage in a near future. This concern has prompted to explore alternative possibilities with an improved therapeutic potential against streptococcal diseases.

One factor critical to successful human gene therapy is development of efficient gene delivery systems. Although numerous vector systems for gene transfer have been developed, a perfect vector system has not yet been constructed. Difficulties of in vivo gene transfer appear to result from resistance of living cells to invasion by foreign materials and from interference of cellular functions. We should analyze what barriers in tissues affect in vivo gene transfection and how to solve these problems for gene therapy. In this review article, the biological barriers to in vivo gene transfection are discussed and possible solutions to each barrier are discussed with respect to construction of a perfect gene therapy vector system.

Uncontrolled hydrochloric acid secretion and ulceration of the stomach mucosa due to various factors are serious global problems. Although the mechanism of acid secretion from the parietal cell is now well understood, the processes involved in gastric ulceration are still not clear. Among various causes of gastric ulceration, lesions caused by stress, alcohol consumption, Helicobacter pylori infection and due to use of nonsteroidal antiinflammatory drugs have been shown to be mediated largely through the generation of reactive oxygen species, especially the hydroxyl radical. A number of excellent drugs have proven useful in controlling hyperacidity and ulceration but their long-term use is associated with disturbing side-effects. Hence, the search is still on to find a compound possessing antisecretory, antiulcer and antioxidant properties which will serve as a therapeutic agent to reduce gastric hyperacidity and ulcers. This article describes the role of reactive oxygen species in gastric ulceration, drugs controlling them with their merits and demerits and, the role of melatonin, a pineal secretory product, in protecting against gastric lesions. In experimental studies, melatonin has been shown to be effective in reducing mucosal breakdown and ulcer formation in a wide variety of situations. Additionally, the low toxicity of melatonin supports further investigation of this molecule as a gastroprotective agent. Finally, we include a commentary on how melatonin research with respect to gastric pathophysiology can move forward with a view of eventually using this indole as a therapeutic agent to control gastric ulceration in humans.

Experimentally infected rhesus monkeys serve as an indispensable animal model to assess the pathogenesis, to validate therapy approaches and to develop vaccination strategies against viral diseases such as AIDS threatening the human population. Upon infection with simian immunodeficiency virus (SIV), a retrovirus closely related to the human immunodeficiency virus (HIV), macaques develop clinical manifestations similar to those of HIV-infected humans. As in humans, the disease course is variable. Polymorphic genes of the major histocompatibility complex (MHC) are required for the initiation and regulation of a specific immune response and represent a major host factor accounting for the differential outcome of infection. During the last few years, our understanding of the structure and function of the rhesus macaque MHC has increased substantially. Functional studies have led to the identification of specific SIV and HIV peptide epitopes presented by rhesus macaque MHC molecules. The subsequent development of MHC class I tetramers has allowed further insight into the cellular immune response following SIV-infection. Detailed studies demonstrated that viral escape mutants are generated during the acute and chronic phase of infection and explain why control of viral replication ultimately fails. Furthermore, particular MHC haplotypes which influence disease progression have been discovered. Thus, MHC-typing can have a prognostic potential. The further elucidation of the rhesus macaque MHC and the search for other relevant genes will remain an important task for future research and will stimulate all immunologically-related investigations in macaques.