Histone
Acetylation/Deacetylation and Cancer: An “Open” and “Shut” Case? Pp.
401-429
Cellular
and Molecular Mechanisms of Vaccine-induced Protection against Retroviral
Infections Pp. 431-436
Biology
of gd T Cells in Tuberculosis
and Malaria Pp. 437-446
Restoring
the Phenotype of Fragile X Syndrome: Insight from the Mouse Model Pp.
447-455
Continuing Education of the Immune System - Dendritic Cells, Immune Regulation and Tolerance Pp. 457-468
Genetic
Bases and Medical Relevance of Capsular Polysaccharide Biosynthesis in
Pathogenic Streptococci Pp. 475-491
Gastric
Toxicity and Mucosal Ulceration Induced by Oxygen-derived Reactive Species:
Protection by Melatonin Pp. 501-513
Making
the Animal Model for AIDS Research More Precise: The Impact of Major Histocompatibility
Complex (MHC) Genes on Pathogenesis and Disease Progression in SIV-Infected
Monkeys Pp. 515-522
[Back to top] Histone
Acetylation/Deacetylation and Cancer: An “Open” and “Shut” Case?
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.
[Back to top] Cellular and
Molecular Mechanisms of Vaccine-induced Protection against Retroviral
Infections
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.
[Back to top] Biology of gd T Cells in Tuberculosis and Malaria
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 ab
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 Vg9/Vd2
T cells may play an important role in the immune responses against
Mycobacterium tuberculosis and Plasmodium falciparum. Vg9/Vd2
T cells represent about 75% of all circulating gd T cells while
they can be greatly expanded during the acute phase of Mycobacterium
tuberculosis and Plasmodium falciparum malaria. Vg9/Vd2
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 Vg9/Vd2 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 Vg9/Vd2
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 Vg9/Vd2
T cells can contribute to the killing of microorganisms residing in
intracellular compartments.
[Back
to top] Restoring the Phenotype of Fragile X Syndrome: Insight from the Mouse
Model
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.
[Back to top] Continuing Education of
the Immune System - Dendritic Cells, Immune Regulation and Tolerance
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 represents 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 one’s 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.
[Back to top] Genetic Bases and Medical Relevance of Capsular Polysaccharide Biosynthesis in Pathogenic Streptococci
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.
[Back to top] Gastric Toxicity and Mucosal Ulceration Induced by Oxygen-derived Reactive Species: Protection by Melatonin
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.
[Back to top] Making the Animal Model for AIDS Research
More Precise: The Impact of Major Histocompatibility Complex (MHC) Genes on
Pathogenesis and Disease Progression in SIV-Infected Monkeys
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.