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Current Immunology
Reviews
ISSN: 1573-3955
Current Immunology Reviews
Volume 2, Number 1, February 2006
Contents
Editorial Pp. 1
BOB.1/OBF.1 – A Critical Regulator of B Cell
Function Pp. 3-12
Cornelia Brunner and Thomas Wirth
[Abstract]
Host Immune Responses to Aeromonas
Virulence Factors Pp. 13-26
Cristi L. Galindo, Jian Sha, Amin A. Fadl, Lakshmi L.
Pillai and Ashok K. Chopra
[Abstract]
Serotonin as a Modulator of Immune Function:
An Overview Pp. 27-35
Isabelle Cloëz-Tayarani
[Abstract]
OX40:OX40L Axis: Emerging Targets for Immunotherapy of Human
Disease Pp. 37-53
Shahram Salek-Ardakani, Aihua Song, Ian R. Humphreys
and Michael Croft
[Abstract]
Putative Immune Regulatory Role of Statins
Pp. 55-64
Hedwich F. Kuipers and Peter J. van den Elsen
[Abstract]
The Immunologic Barriers to Replacing Damaged
Organs Pp. 65-72
Marilia Cascalho and Jeffrey L. Platt
[Abstract]
The Biochemical Mechanisms of T-Cell Anergy Pp.
73-99
Alexandre D. Atfield, Peter Liu and Josef M. Penninger
[Abstract]
Sphingolipids in Cell Signaling: Their Function as
Receptor Ligands, Second Messengers, and Raft Constituents
Pp. 101-118
Thomas Baumruker and Andreas Billich
[Abstract]
Abstracts
[Back to top]
Editorial
One of the most challenging tasks in biomedical research
is keeping up with the immense literature in immunology. Recent
years have shown that the traditional definition of immunology
is no longer sufficient to encompass the relevant areas of
study, making the task even more difficult, especially to
the new investigator. Many (indeed it may be argued all) of
the greatest recent advances in cellular immunology have come
from areas not traditionally studied by immunologists (until
now!). For example, immunology has had the benefit of cell
biology in the elucidation of lymphocyte activation and the
access to insights from protein structural chemistry to explain
T cell receptor - MHC interactions.
The situation is no simpler for those wishing to do the most
medically relevant studies on immune development and function.
Indeed, not all immunologists have the time to benefit from
a medical education. While the mouse model, in all its forms
including transgenic and knockout strains, has been a traditional
focus of much basic immunology, there are considerable species
differences between mouse and human. Mouse models of human
disease unfortunately frequently fail to provide a faithful
representation of clinical pathophysiology. Thus, a strong
argument could be made that basic immunology research would
greatly benefit from some clear guides as to the most relevant
features of human clinical immunology and pathophysiology.
Conversely, clinical research would similarly benefit from
clear explanations of the latest advances in molecular immunology
in a context that links molecular mechanisms to medical physiology.
It is for these reasons we hope to provide researchers with
a new source of review articles to bridge the gap between
basic immunology and clinical application. Moreover, in addition
to providing reviews covering specific application of research
in basic mechanisms to the understanding of complex clinical
diseases, we hope to highlight areas in which studies in other
biomedical topics have major significance to basic and clinical
immunology mechanisms.
In this issue, to kick off the second year of the publication
of Current Immunology Reviews, we include several
articles that provide us with important insights into the
clinical application of basic immunology research. I would
highlight in particular a few articles in areas of study not
considered mainstream immunology yet with profound consequence
in immune responses in normal and disease settings. The article
by Cloëz-Tayarani (page 27) presents an interesting overview
of the important effects of serotonin – mainly viewed
as a neurotransmitter – on immune function. Similarly,
Kuipers and van den Elsen (page 55) provide some insights
into the possible important effects of statins in immune mediated
diseases such as Multiple Sclerosis.
This last paper also highlights the importance of understanding
basic cell biology mechanisms in the context of immune responses.
To this point, we also have papers by Atfield, Liu, and Penninger
(page 73) on the molecular mechanisms involved in T cell anergy,
an especially comprehensive overview by Baumruker and Billich
(page 101) on the biochemistry of sphingolipids in cell signaling,
and from Brunner and Wirth (page 3) a review of the important
role of the B cell transcription factor BOB.1/OBF.1 in B cell
function.
The practical clinical applications of basic immunology research
are presented in three articles. In the article by Galindo
et al. (page 13), the immune response to Aeromonas virulence
factors is examined, with important lessons in host response
to infectious agents. Salek-Ardakani et al. (page
37) present a compelling argument for the use of the OX40:OX40L
axis as a target for therapeutics in a variety of immune mediated
inflammatory conditions. Finally, Cascalho and Platt (page
65) present a cautionary tale on the immunologic barriers
to replacement of damaged organs.
With these articles we continue an impressive series of publications
with reviews bridging the gap between basic immunology research
and their application to standard-of-care clinical medicine.
We invite our readers to continue to offer their outstanding
articles on these topics.
David D. Lo
(Editor-in-Chief)
Developmental Immunology
La Jolla Institute for Allergy and Immunology
10355 Science Center Drive
San Diego
CA 92121
USA
E-mail: dlo@liai.org
[Back to top]
BOB.1/OBF.1 – A Critical Regulator of B Cell
Function
Cornelia Brunner and Thomas Wirth
The transcriptional coactivator BOB.1/OBF.1 binds as a ternary
complex with the transcription factors Oct-1 and Oct-2 to
DNA and induces octamer-dependent transcription. BOB.1/OBF.1
was shown to be necessary at multiple stages of B cell development,
in the bone marrow as well as at late stages in secondary
lymphoid organs. Bone marrow B cells from BOB.1/OBF.1-deficient
mice show increased apoptosis accompanied with decreased expression
levels of the anti-apoptotic protein Bcl2. Although transgenic
B cell-specific expression of Bcl2 rescued the numbers and
maturation of BOB.1/OBF.1-deficient B cells in the bone marrow
as well as in peripheral lymphoid organs, the B cell function
was still severely impaired. The most prominent characteristic
of BOB.1/OBF.1 knock-out mice is the complete failure to form
germinal centers upon immunization with thymic-dependent antigens
and consequently a massive defect in production of secondary
Ig isotypes. In addition, the marginal zone B cell compartment,
first line defence against blood born antigens, is virtually
absent in BOB.1/OBF.1 -/- animals. A large number of genes
specifically expressed in B cells contain octamer motifs in
their regulatory regions, but only a small number of BOB.1/OBF.1
dependent genes are described yet. To understand the molecular
basis of BOB.1/OBF.1 function in B cell development we and
others searched for BOB.1/OBF.1 target genes. A large number
of BOB.1/OBF.1-dependent genes were identified, which are
involved in different aspects of lymphocyte development and
signaling, supporting the critical regulatory role of BOB.1/OBF.1
for lymphocyte function. Here we summarize recent developments
highlighting the central role that BOB.1/OBF.1 plays in B
lymphocytes.
[Back to top]
Host Immune Responses to Aeromonas Virulence
Factors
Cristi L. Galindo, Jian Sha, Amin A. Fadl, Lakshmi L.
Pillai and Ashok K. Chopra
Aeromonas species are emerging human pathogens,
which produce an array of virulence factors and cause diseases
ranging from gastroenteritis to systemic infections. These
bacteria can be found in food and water and grow well and
produce toxins at refrigeration temperatures, which greatly
increase the risk of food poisoning. A detailed understanding
of host responses to Aeromonas virulence factors
is paramount to developing better treatment strategies. One
of the important virulence factors of Aeromonas is
the cytotoxic enterotoxin, Act, which induces potent inflammatory
responses in host cells and is lethal when injected intravenously
into mice. Microarray analyses of Act-treated host cells by
our laboratory revealed that Act induced host cell signaling
and apoptosis of macrophages and colonic epithelial cells.
We furthered showed that Act production is regulated by glucose
inhibited division gene A (gidA) and an iron-regulated
ferric uptake regulatory (fur) gene. In addition
to Act, our laboratory recently discovered new virulence factors/mechanisms,
including the plasminogen-activating enzyme enolase and a
type III secretion system, which contribute to Aeromonas-associated
diseases. Current knowledge concerning host responses to these
and other Aeromonas virulence factors is discussed.
[Back to top]
Serotonin as a Modulator of Immune Function: An Overview
Isabelle Cloëz-Tayarani
The CNS and immune system interact in a reciprocal manner
through a wide variety of common mediators including neurotransmitters
and cytokines. Among the former, serotonin (5-Hydroxytryptamine
= 5-HT) plays a major role in the control of neuronal activity.
It may also control the level of cytokines and lymphocyte
proliferation. 5-HT is synthesized and released in the circulation
by enterochromaffin cells from gastric and intestinal mucosa.
Under inflammatory conditions such as thrombosis and ischemia,
the activated platelets release 5-HT at the site of inflammation
and lead to an increase in its local concentration. In addition
to its possible interaction with blood cells, 5-HT may also
interact with the inflamed tissue macrophages through its
various receptors. Accordingly, 5-HT transporters and 5-HT
receptor subtypes have been characterized in different blood
cells. This review provides an overview of reported data on
the regulatory role of 5-HT on the activity of peripheral
blood cells. Such role includes both immunostimulatory and
immunoinhibitory effects based on 5-HT concentration and its
cellular target. In the light of recent data, this review
also speculates on the intracellular processes (i.e. MAP kinases),
which are activated by 5-HT suggesting neuromodulatory function.
[Back to top]
OX40:OX40L Axis: Emerging Targets for Immunotherapy of
Human Disease
Shahram Salek-Ardakani, Aihua Song, Ian R. Humphreys
and Michael Croft
Recent advances in our understanding of the mechanisms through
which T cells are activated have led to new therapeutic approaches
in the treatment of immunological disorders. An emerging target
for selective immune intervention has been the manipulation
of T cell costimulatory pathways. Impressive results in animal
models have shown that the tumor-necrosis-factor receptor
(TNFR) family member, OX40 (CD134), and its binding partner
OX40L, are key co-stimulatory molecules involved in the regulation
of many T cell mediated immune disorders. In this review we
will highlight these new findings with a particular emphasis
on their potential implications for immunotherapy of human
disease.
[Back to top]
Putative Immune Regulatory Role of Statins
Hedwich F. Kuipers and Peter J. van den Elsen
Statins, which are mainly used for treatment of hypercholesterolemia
because of their lipid-lowering effects, may also display
many immunomodulatory properties. Statins interfere in the
mevalonate pathway through inhibition of HMG-CoA reductase
activity and thereby affect isoprenylation of proteins and
cholesterol biosynthesis. Besides lowering blood cholesterol
levels, statins inhibit the production of pro-inflammatory
cytokines and reduce membrane expression of several immunoregulatory
molecules, including major histocompatibility complex class
II (MHC-II) molecules. In this review we discuss the putative
immunomodulatory role of statins and the mechanism by which
simvastatin reduces the membrane expression of MHC-II molecules
on several cell types, emphasizing on the disruption of cholesterol-containing
microdomains, or lipid rafts, which transport and concentrate
MHC-II molecules to the cell surface. Because glycosylphosphatidylinositol
(GPI)-linked proteins are in general characteristic components
of biochemically defined lipid rafts, and rely for transport
and function at the cell surface on the integrity of these
cholesterol-containing vesicles, we argue that statins, by
disrupting these vesicles, also affect the expression of other
immunoregulatory molecules. In addition, we also argue that
statins inhibit the activation and intracellular transport
of various proteins by interfering in protein isoprenylation.
The interference in these processes results in reduced expression
and function of membrane-bound molecules, which play important
roles in the initiation and effector function of the immune
response. Finally, we discuss the potential role of statins
in the treatment of neuroinflammatory diseases.
[Back to top]
The Immunologic Barriers to Replacing Damaged Organs
Marilia Cascalho and Jeffrey L. Platt
The recent years have brought breathtaking advances in the
biomedical sciences and biomedical engineering. These advances
offer the promise that diseases responsible for most disability
and early death may soon be addressed by replacing damaged
organs with bio-engineered substitutes. Application of these
technologies, however, is impeded by the immune response directed
against foreign cells and tissues. Here we consider the potentiality
and the limitations of these new technologies and how the
technologies might be combined to generate novel approaches
to organ replacement that overcome immunological barriers
to success.
[Back to top]
The Biochemical Mechanisms of T-Cell Anergy
Alexandre D. Atfield, Peter Liu and Josef M. Penninger
T-cells are thought to play important roles in the coordination
and development of immune responses in both health and disease.
A key checkpoint in the prevention of inappropriate activation
of T-cells is the requirement for co-stimulation by professional
APCs via receptors such as CD28. Several in vivo
and in vitro methods of experimental anergy induction
have been developed and are in popular use today. However,
the biochemical events that determine T-cell fate following
the application of activating vs. anergizing stimuli
remain poorly understood. We present a survey of T-cell signal
transduction in productive encounters with antigen-presenting
cells, as well as the molecular mechanisms that are thought
to alter these signaling pathways in T-cell anergy and the
conceptual and experimental context in which this understanding
has been developed. A strong possibility is that the program
of anergy induction involves the upregulation of one or more
‘anergy factors’ and over the years, several possible
mechanisms of T-cell anergy have been proposed. Amongst these,
E3 ubiquitin ligases such as Cbl-b, Itch and GRAIL have recently
emerged as being essential players in T-cell tolerance, as
well as host survival.
[Back to top]
Sphingolipids in Cell Signaling: Their Function as
Receptor Ligands, Second Messengers, and Raft Constituents
Thomas Baumruker and Andreas Billich
Sphingolipids have lately been recognized as important signaling
molecules with an unexpected multitude of actions and mechanisms.
While we are currently just uncovering the tip of the iceberg,
the available data give us an unprecedented understanding
of how membrane rearrangements translate into the generation
of intracellular lipid signaling molecules and further into
secreted bioactive lipids. Furthermore, new concepts such
as the rheostat of sphingolipids show that fundamental principles
in signaling also do apply to this class of molecules. The
plethora of sphingolipids as well as sphingolipid modifying
enzymes seem to comprise many novel, attractive, and pharmaceutically
exploitable targets beyond sphingolipidoses, in applications
ranging from autoimmune diseases and neurodegenerative conditions
to cancer. In this review, we summarize the mechanistic triad
of action of sphingolipids as membrane/raft components, intracellular
signaling molecules and secreted mediators.
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