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Current Immunology
Reviews
ISSN: 1573-3955
Current Immunology Reviews
Volume 1, Number 3, November 2005
Contents
Playing with Fire: Manipulation of Macrophage Proinflammatory
Signal Transduction by the Intracellular Protozoan Toxoplasma
gondii Pp. 213
Leesun Kim, Barbara A. Butcher and Eric Y. Denkers
[Abstract]
Hepatitis C Virus’s Immune Evasion Strategies
Pp.223
Michael W. Cruise, John R. Lukens and Young S. Hahn
[Abstract]
Chemokines: Central Mediators of the Innate
Response to Sepsis Pp.237
Traci L. Ness, Steven L. Kunkel and Cory M. Hogaboam
[Abstract]
The Role of Natural Killer T Cells in Atherosclerosis
Pp.261
Amy S. Major and Luc Van Kaer
[Abstract]
Recognition and Function of Human γδ T
Cells: Application for Tumor Immunotherapy Pp.275
Yoshimasa Tanaka, Yu Kato, Shoichi Kita and Nagahiro
Minato
[Abstract]
Molecular Functions of BCL10 and MALT1 in
Normal and Neoplastic Lymphocytes Pp. 287
Jürgen Ruland
[Abstract]
Eosinophilic Esophagitis: New Pathogenic Insights
Pp. 297
Alex Straumann, Dagmar Simon and Hans-Uwe Simon
[Abstract]
Abstracts
[Back to top]
Playing with Fire: Manipulation of Macrophage
Proinflammatory Signal Transduction by the Intracellular Protozoan
Toxoplasma gondii
Leesun Kim, Barbara A. Butcher and Eric Y. Denkers
The protozoan Toxoplasma gondii is an enormously
successful parasite that asymptomatically infects 10-50 percent
of the human population worldwide. During immunodeficiency,
Toxoplasma emerges as a virulent pathogen causing
lethal disease if untreated. The normally innocuous nature
of infection is dependent upon the parasite’s ability
to trigger protective immunity enabling host survival, at
the same time avoiding an excessively strong immune response
that could cause excessive host pathology. Recent data from
our laboratory and others are revealing this key principle
in action within the innate immune system. Infection triggers
early activation of mitogen-activated protein kinase (MAPK),
nuclear factor (NF)κB
and signal transducer and activator of transcription (STAT)
pathways. Nevertheless, Toxoplasma suppresses other
components of proinflammatory signaling, and this is likely
to down-modulate effector functions of both macrophages and
dendritic cells. The ability of T. gondii to simultaneously
activate and suppress signal transduction in infected cells
is a likely consequence of the parasite’s need to manipulate
cellular immunity to achieve a stable interaction at the host-parasite
interface.
[Back to top]
Hepatitis C Virus’s Immune Evasion Strategies
Michael W. Cruise, John R. Lukens and Young S. Hahn
Hepatitis C virus (HCV) is a major problem in human health
infecting 200 million chronic carriers worldwide. The HCV
genome consists of a single strand of RNA and the most remarkable
feature of HCV is its ability to persist in the majority (>85%)
of infected individuals. Chronic HCV infection is associated
with liver cirrhosis, the development of hepatocellular carcinoma,
and extrahepatic autoimmune disease. This non-cytolytic virus
has developed several mechanisms by which it can evade or
subvert the host immune system. While the development of quasispecies
allows the virus to escape the immune surveillance, direct
interactions of HCV viral proteins with immune cells modulates
host immune responses. Recently, T regulatory cells have been
suggested to play a role in dampening HCV-specific T cell
responses during chronic HCV infection. In addition to the
virus-mediated modulation of immune response, the local environment
(i.e. liver) for HCV replication influences the control of
viral infection. Understanding the viral interaction with
host immune system within the liver environment will prove
useful to the design of new HCV therapeutics and vaccine strategies.
[Back to top]
Chemokines: Central Mediators of the Innate Response
to Sepsis
Traci L. Ness, Steven L. Kunkel and Cory M. Hogaboam
Sepsis represents a perplexing challenge for the innate
immune system. In response to microbial challenge, an immunocompetent
host initiates an immediate robust response to contain and
clear infection. However, if the infection is not controlled
and spreads beyond the local site, this pervasive immune response,
once systemic, often results in detrimental complications
such as systemic inflammatory response syndrome, multiple
organ failure, and immune paralysis, contributing to the high
mortality observed in sepsis. Resident tissue macrophages,
as sentinels of the host immune response to infection, are
responsible for recognition of infection through several pattern
recognition molecules and initiation of a complex cytokine/chemokine
cascade. Chemokines are central mediators involved in recruitment
of specific leukocyte populations to the site of infection,
differentiation of classically- and alternatively-activated
macrophages, and regulation of important processes such as
pathogen phagocytosis and killing, release of reactive oxygen
intermediates and proteases, and subsequent chemokine production.
This review explores the role of the peritoneal macrophage
and the importance of chemokines in macrophage activation
during septic peritonitis. Continued investigation of chemokines
and their mechanisms of action will provide valuable insight
into the development of effective clinical therapeutics for
the treatment of sepsis as well as other inflammatory disorders.
[Back to top]
The Role of Natural Killer T Cells in Atherosclerosis
Amy S. Major and Luc Van Kaer
Atherosclerosis is a chronic inflammatory disease characterized
by the progressive growth of lesions in the artery wall with
activation of both innate and adaptive immunity. Recently,
a unique group of immune cells, termed natural killer T (NKT)
cells, has emerged as playing a critical role in the regulation
of inflammation and immunity. NKT cells share characteristics
of conventional T lymphocytes and natural killer cells and
express an invariant T cell receptor, which recognizes glycolipid
antigen associated with the major histocompatibility complex
class I-like molecule CD1d. NKT cells play a role in protection
against many autoimmune, inflammatory diseases such as type
1 diabetes, multiple sclerosis and systemic lupus erythematosus.
Interestingly, new data is emerging that describes a role
for NKT cells in atherosclerosis. Recent studies have shown
that CD1d and NKT cells are present in the atherosclerotic
lesions of both humans and mice. Furthermore, we and others
have demonstrated that absence of CD1d in apolipoprotein E-deficient
(apoE-/-) mice ameliorates atherosclerosis and that specific
activation of NKT cells is proatherogenic. In addition, hyperlipidemic
apoE-/- mice exhibit defective NKT cell numbers and functions.
These findings and the well-established role of NKT cells
in regulating immunity make these cells attractive targets
for immunotherapy of atherosclerosis.
[Back to top]
Recognition and Function of Human γδ
T Cells: Application for Tumor Immunotherapy
Yoshimasa Tanaka, Yu Kato, Shoichi Kita and Nagahiro Minato
Human Vγ2Vδ2
T cells recognize nonpeptide antigens derived from microbial
pathogens in a TCR-dependent manner, such as isopentenyl pyrophosphate-related
metabolites and alkyl amines. Recent crystallographic analysis
of the γδ
TCR along with the site-directed mutagenesis studies has strongly
suggested that the γδ
TCR directly interacts with nonpeptide antigens via
a positively-charged pocket formed by CDR2 and CDR3 regions.
Full activation of γδ
T cells by nonpeptide antigens leading to proliferation and
cytokine production was suggested to require cognate cellular
interaction with the cells displaying the antigens via
specific adhesion molecules. Synthetic nitrogen-containing
bisphosphonate compounds such as pamidronate were also shown
to activate the same subset of γδ
T cells in a TCR-dependent manner. Most notably, these compounds
can efficiently sensitize a wide spectrum of human tumor cells
to the lysis by γδ
T cells. These characteristics of γδ
T cells confer them a unique role in cross-immunity in infection
and malignancy, and may provide a novel strategy for immunotherapy
of human cancer.
[Back to top]
Molecular Functions of BCL10 and MALT1 in Normal and Neoplastic
Lymphocytes
Jürgen Ruland
Antigen receptors on B and T lymphocytes utilize specific
adapter and scaffolding proteins to relay antigen recognition
at the cell surface to the activation of downstream signaling
pathways. One central pathway that is induced upon TCR and
BCR ligation cumulates in the activation of NF-κB.
This cascade is essential for the elicitation of proper immune
responses but when aberrantly activated can also promote diseases
including malignancy. Recent work identified the CARD protein
BCL10 and the paracaspase MALT1 as key regulators of antigen
receptor mediated NF-κB
induction. The genes encoding these proteins were originally
identified from recurrent chromosomal translocations in mucosa
associated lymphoid tissue (MALT) lymphoma associated with
advanced disease.
In physiological adaptive immune responses antigen receptor
proximal signaling and PKC activation induces recruitment
of BCL10 and MALT1 to the scaffold protein CARMA1 at the immunoreceptor.
Here BCL10 and MALT1 cooperate directly to assemble a multi
protein complex that mediates lysine-63-linked ubiquitination
of NEMO, the regulatory subunit of the IκB
kinase (IKK). This mechanism induces signal specific IKK activation,
leading to phosphorylation and degradation of the NF-κB
inhibitor IκB-α
and finally results in controlled activation of NF-κB.
However chromosomal translocations in MALT lymphoma uncouple
BCL10 or MALT1 from upstream stimuli and promote antigen independent
lymphoma growth with tumor progression. This review discusses
the mechanisms of BCL10 and MALT1 signal transduction and
their critical role in lymphocyte physiology and neoplasia.
[Back to top]
Eosinophilic Esophagitis: New Pathogenic Insights
Alex Straumann, Dagmar Simon and Hans-Uwe Simon
Eosinophilic esophagitis (EE), first recognized as a unique
entity some 12 years ago, is a chronic, TH2-type
inflammatory disorder of the esophagus. The diagnostic criterion
is a peak infiltration of the esophageal epithelium with >24
eosinophils/HPF. Though originally believed extremely rare,
EE is increasingly recognized and its prevalence may soon
equal chronic inflammatory bowel diseases. The main symptom
of EE is dysphagia for solid foods with imminent risk of food
impaction. Endoscopic abnormalities are varied but discreet,
with white exudates being the most prominent sign. Though
EE likely remains restricted to the esophagus, chronic inflammatory
processes may induce esophageal fibrosis. Therapeutic recommendations
include systemic or topical corticosteroids, leukotriene antagonists,
protein elimination diet and dilation. In EE, the inflammatory
pattern consists of eosinophils, T-cells and mast cells, together
with increased expression of IL-5 and TNF-α. Interestingly,
clinical data as well as animal studies show a striking association
of EE with allergic airway disorders. Immunologic interactions
between the airways and the esophagus might be transmitted,
at least in part, by IL-13. Adult EE patients are most frequently
sensitized to aeroallergens, whereas in children, sensitization
to food allergens is predominant. Despite enormous research
effort, many crucial questions remain unsolved requiring further
investigation.
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