Current
The Interaction of Fungi with Dendritic
Cells: Implications for Th Immunity and Vaccination Pp.507-524
Montagnoli
Claudia, Angela Bacci, Bozza Silvia, Roberta Gaziano, Antonio Spreca and
Luigina Romani
Microchimerism in Health and Disease Pp.525-535
Carol
M. Artlett
Cross-talk Between Hematopoiesis and
Angiogenesis Signaling Pathways
Pp.537-543
Domenico
Ribatti, Angelo Vacca, Beatrice Nico, Roberto Ria and Franco Dammacco
Toll-like Receptor 9, CpG DNA and Innate
Immunity Pp.545-556
Ali
A. Ashkar and Kenneth L. Rosenthal
Membrane Lipid Rafts: New Targets for
Immunoregulation Pp.557-570
F.
Van Laethem and O. Leo
Bisphosphonate Mechanism of Action Pp.571-577
Gideon
A. Rodan and Alfred A. Reszka
Oxidation of Low-Density Lipoprotein in
Atherosclerosis from Basic Biochemistry to Clinical Studies Pp.579-592
R.
Albertini, R. Moratti and G. De Luca
[Back to top] The Interaction of Fungi with Dendritic
Cells: Implications for Th Immunity and Vaccination
Montagnoli
Claudia, Angela Bacci, Bozza Silvia, Roberta Gaziano, Antonio Spreca and
Luigina Romani
Human beings are
continuously exposed to fungi, yet they rarely get fungal diseases. The
delicate balance between the host and these otherwise harmless pathogens may
turn into a parasitic relationship, resulting in the development of severe
infections. The ability to reversibly switch between unicellular and
filamentous forms, all of which can be found in infected tissues, is thought to
be important for virulence. Efficient responses to the different forms of fungi
require different mechanisms of immunity. Dendritic cells (DC) are uniquely
able at decoding the fungus-associated information and translating it in
qualitatively different T helper (Th) immune responses, in vitro and in vivo.
Myeloid DC phagocytosed yeasts and hyphae of Candida albicans and conidia and
hyphae of Aspergillus fumigatus, both in vitro and in vivo. Phagocytosis
occurred through distinct phagocytic morphologies, involving the engagement and
cooperativity of distinct recognition receptors. However, receptor engagement
and cooperativity were greatly modified by opsonization. The engagement of
distinct receptors translated into disparate downstream signaling events,
ultimately affecting cytokine production and costimulation. In vivo studies
confirmed that the choice of receptor and mode of entry of fungi into DC was
responsible for Th polarization and patterns of susceptibility or resistance to
infection. Adoptive transfer of different types of DC activated protective,
nonprotective and regulatory T cells, ultimately affecting the outcome of
infection. The conclusions are that the selective exploitation of receptors and
mode of entry into DC may determine the full range of host’s immune
relationships with fungi and have important implications in the design of
vaccine-based strategies.
[Back to top] Microchimerism in Health and Disease
Carol
M. Artlett
Microchimerism has
been defined by the presence of a low number of circulating cells transferred
from one individual to another. This transfer takes place naturally during
pregnancy, between mother and fetus and/or between fetuses in multi-gestational
pregnancies. Furthermore, the establishment of microchimerism can also occur
during blood transfusion and organ transplants. Microchimeric cells have been
implicated in health and disease. Microchimerism has been correlated with the
hyporesponsiveness of the maternal immune system towards the fetal allograft
and with the longevity of organ transplants. However, maternal microchimeric
cells have been implicated in diseases of the neonate including neonatal
graft-versus-host disease, severe combined immunodeficiency and erythema
toxicum neonatorum. And more recently, microchimeric cells have been implicated
in the pathogenesis of autoimmune diseases including systemic sclerosis and
myositis.
[Back to top] Cross-talk Between Hematopoiesis and
Angiogenesis Signaling Pathways
Domenico
Ribatti, Angelo Vacca, Beatrice Nico, Roberto Ria and Franco Dammacco
The relationship
between hematopoietic cells and endothelial cells has been seen as an
indication that a common progenitor, the hemangioblast, gives rise to both cell
types in the yolk sac, the initial site of hematopoiesis and blood vessel formation
during mammalian development. The existence of angioblast-like circulating
endothelial precursor cells in adults humans has recently been suggested. In
this review, we have summarized the principle mechanisms involved in the
cross-talk signaling pathway between hematopoiesis and angiogenesis in order to
further understand how the hematopoietic and vascular systems are established
during the development.
[Back to top] Toll-like Receptor 9, CpG DNA and Innate
Immunity
Ali
A. Ashkar and Kenneth L. Rosenthal
Innate immunity
provides the first line of defense against invading pathogens and is essential
for survival in the absence of adaptive immune responses. Innate immune
recognition relies on a limited number of germ-line encoded receptors, such as
Toll-like receptors (TLRs), that evolved to recognize conserved molecular
patterns of microbial origin. To date, ten transmembrane proteins in the TLR
family have been described. It is becoming increasingly clear that bacterial
CpG DNA and synthetic oligodeoxynucleotides (ODN) containing unmethylated CpG
are potent inducers of the innate immune system including dendritic cells
(DCs), macrophages, and natural killer (NK) and NKT cells. Recent studies
indicate that mucosal or systemic delivery of CpG DNA can act as a potent
adjuvant in a vaccine combination or act alone as an anti-microbial agent.
Recently, it was shown that TLR9 is essential for the recognition of
unmethylated CpG DNA since cells from TLR9-deficient mice are unresponsive to
CpG stimulation. Although the effects of CpG DNA on bone marrow-derived cells
are beginning to unfold, there has been little or no information regarding the
mechanisms of CpG DNA function on non-immune cells or tissues. This review
focuses on the recent advances in CpGDNA/ TLR9 signaling effects on the
activation of innate immunity.
[Back to top] Membrane Lipid Rafts: New Targets for
Immunoregulation
F.
Van Laethem and O. Leo
Engagement of
immune receptors by antigen may lead to activation, cell proliferation,
differentiation and effector functions. It has recently been proposed that the
initiation and propagation of the signaling events taking place in immune cells
occur in specialized membrane regions called lipid rafts. These
detergent-insoluble glycolipid domains are specialized membrane compartments
enriched in cholesterol and glycolipids. They also contain many lipid-modified
signaling proteins such as tyrosine kinases of the Src family, GPI
(glycosylphosphatidylinositol)-linked proteins as well as adaptor proteins. The
confinement of signaling molecules in membrane subdomains suggests that lipid
rafts function as platforms for the formation of multicomponent transduction
complexes. Indeed, upon receptor binding, immune receptors become
raft-associated and additional components of the signaling pathways are
recruited to rafts in order to form signaling complexes. It has been speculated
that the entry of immune receptors into rafts can regulate cell activation.
Accordingly, numerous experiments have provided substantial evidence that raft
integrity is crucial for the initiation and maintenance of intracellular
signals. Recent studies have also shown that the access and translocation of
immune receptors to lipid rafts are developmentally regulated (immature versus
mature cells, Th1 versus Th2 lymphocytes) and sensitive to pharmacological
agents. The aim of the present review is to summarize the current knowledge of
immune receptor signal transduction with particular emphasis on the role of
membrane compartments in immune activation. Finally, experimental evidences
indicating that these membrane structures may represent clinically relevant
potential targets for immune regulation, will be discussed.
[Back to top] Bisphosphonate Mechanism of Action
Gideon
A. Rodan and Alfred A. Reszka
Nitrogen-containing
bisphosphonates (N-BPs) are potent inhibitors of bone resorption widely used in
the treatment of osteoporosis and other bone degrading disorders. At the tissue
level, N-BPs reduce bone turnover, increase bone mass and mineralization,
measured clinically as a rise in bone mineral density, increase bone strength
and reduce fracture risk. At the cellular level, N-BPs, localize preferentially
at sites of bone resorption, where mineral is exposed, are taken up by
ostoclasts and inhibit osteoclast activity. The bone formation that follows
incroporates the N-BP in the matrix, where it becomes pharmacologically
inactive until released at a future time during bone remodeling. At the
molecular level, N-BPs inhibit an enzyme in the cholesterol synthesis pathway,
farnesyl diphosphate synthase. As a result, there is a reduction in the lipid
geranylgeranyl diphosphate, which prenylates GTPases required for cytoskeletal
organization and vesicular traffic in the osteoclast, leading to osteoclast
inactivation.
[Back to top] Oxidation of Low-Density Lipoprotein in
Atherosclerosis from Basic Biochemistry to Clinical Studies
R.
Albertini, R. Moratti and G. De Luca
Although it has
been known for long time that atherosclerosis is associated with lipid
deposition, only recently it has been accepted that the plasmatic concentration
of cholesterol, especially LDL cholesterol, is a risk factor for
atherosclerosis. However, chemically modified LDL, but not native LDL, is able
to induce the formation of foam cells, the hallmark of atherosclerosis. LDL
oxidation is likely to be the most important form of LDL modification in
humans. In biochemical terms, LDL oxidation is a free radical driven chain
reaction where polyunsaturated fatty acids are converted to lipid peroxides,
which easily decompose to many products, including biologically active
aldehydes. The assay of LDL oxidation in biological fluids is problematic;
direct assays detect a product of LDL oxidation whereas indirect assays give an
indicator of LDL oxidation susceptibility. In general, epidemiological studies
support the concept that the level of plasmatic lipophilic antioxidants,
tocopherols and carotenoids, is low in populations at increased risk for
atherosclerosis. However, clinical trials based on vitamin E as antioxidant
showed inconclusive results, suggesting that supplementation with vitamin E is
not generically recommended for atherosclerotic patients. These results,
however, do not contradict that oxidation of lipoprotein is involved in
atherosclerosis; rather, this negative outcome raises a number of
considerations such as the need for a reliable marker of lipoprotein oxidation
in plasma and a more complete information about the physiological triggers of
lipoprotein oxidation.