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Current Protein & Peptide
Science
ISSN: 1389-2042
Current Protein and Peptide
Science
Volume 7, Number 4, August 2006
Contents
Immune Receptors for Glycoconjugates
Guest Editor: Dapeng Zhou
Editorial Pp. 281
Dapeng Zhou
C-Type Lectins on Dendritic Cells and Their
Interaction with Pathogen-Derived and Endogenous Glycoconjugates
Pp. 283-294
Karlijn Gijzen, A. Cambi, R. Torensma and Carl G. Figdor
[Abstract]
Differential Regulation of Protein- and Polysaccharide-Specific
Ig Isotype Production In Vivo in Response to Intact
Streptococcus pneumoniae Pp. 295-305
Clifford M. Snapper
[Abstract]
Immunology of O-Glycosylated Proteins: Approaches
to the Design of a MUC1 Glycopeptide-Based Tumor Vaccine Pp.
307-315
Franz-Georg Hanisch and Tanja Ninkovic
[Abstract]
Interaction of Human Immunodeficiency Virus (HIV)
Glycans with Lectins of the Human Immune System Pp.
317-324
Xin Ji, Ying Chen, Jonathan Faro, Henry Gewurz, James
Bremer and Gregory T. Spear
[Abstract]
The Immunological Function of iGb3 Pp.
325-333
Dapeng Zhou
[Abstract]
General Articles
Structure-Activity Relationship Studies: Methods
and Ligand Design for G-Protein Coupled Peptide Receptors
Pp. 335-353
Manja Lang and Annette G. Beck-Sickinger
[Abstract]
Rho GTPase Activating Proteins in Cancer Phenotypes
Pp. 355-365
Raj P. Kandpal
[Abstract]
Abstracts
[Back to top]
Editorial
Dapeng Zhou
I would like to thank Prof. Ben M. Dunn, Editor
in Chief of CPPS, for supporting my proposal in organizing
this special issue on Immune receptors for glycoconjugates.
The aim of this issue is to highlight the rapid progress in
our understanding of glycoconjugate-mediated communication
in the context of immune responses.
Only after this project was completed did I recognize what
a precious chance it was for me to serve the community of
glycobiology and immunology. In retrospect, I am so thankful
to all the authors and reviewers for their excellent contribution.
Many of them sacrificed weekends or holidays, as evidenced
by my records of dates in receiving emails. I am greatly encouraged
by the brilliance of every article after these synergized
efforts. I have very much enjoyed the learning from each author
and each reviewer.
The selected topics have been based on my personal view of
the important questions. These include the dendritic cell
lectins, the lectins that interact with HIV, the glycopeptide
antigens, the immune responses to bacteria polysaccharides,
and the glycolipid antigens. These articles cover the carbohydrate
recognition in both the innate immunity and the adaptive immunity.
In every article, the power of biochemistry and glyco-chemistry
is highlighted.
I hope the concepts and strategic designs proposed by our
authors will be helpful for the readers in understanding the
rules of glyco-immunology. Glycoconjugates are extremely structurally
diverse, with the unique central dogma being storage of information
through the action of glyco-enzymes instead of genetic codes.
My sincere hope is that readers will be excited enough by
these articles to follow this area of research closely, and
perhaps will even join us in making contributions to this
very promising field of study.
Dapeng Zhou, M.D., Ph.D.
Assistant Professor
Guest Editor
Current Protein and Peptide Science
Department of Melanoma Medical Oncology
M.D. Anderson Cancer Center
University of Texas
USA
E-mail: dzhou@mdanderson.org
[Back to top]
C-Type Lectins on Dendritic Cells and Their
Interaction with Pathogen-Derived and Endogenous Glycoconjugates
Karlijn Gijzen, A. Cambi, R. Torensma and Carl G. Figdor
Human C-type lectin receptors (CLRs) characteristically
bind glycosylated ligands in a Ca2+-dependent
way via their carbohydrate recognition domain (CRD). Their
carbohydrate preference is dependent on the amino acid sequence
in the CRD domain and on the ability and flexibility of the
CRD domain to accommodate sugar moieties that are located
at different distances from each other in the glycoconjugate.
Although microbial and vertebrate cells are able to produce
similar polysaccharide chains, the density of carbohydrates
on microbes is much higher compared to vertebrate cells. Despite
this difference, carbohydrates present on both cell types
can be recognized by the CLRs. These receptors are pre-dominantly
expressed by antigen presenting cells such as dendritic cells.
In addition to the Toll-like receptor family, CLRs function
as pattern recognition receptors by recognizing glycosylated
patterns on pathogens. This usually results in internalization
of the pathogen, lysosomal degradation and subsequent loading
of pathogen-derived peptides into major histo-compatibility
complex molecules for antigen presentation. However, several
pathogens have developed ways to exploit the CLRs to evade
immune eradication by for example escaping from the lysosomal
degradation pathway or by inducing anti-inflammatory cytokines.
When CLRs bind endogenous glycosylated ligands they mediate
several processes like cell-cell adhesion and clearance of
aberrant cells like tumor cells or apoptotic cells.
[Back to top]
Differential Regulation of Protein- and Polysaccharide-Specific
Ig Isotype Production In Vivo in Response to Intact
Streptococcus pneumoniae
Clifford M. Snapper
Adaptive humoral immunity to extracellular bacteria is
largely mediated by antibody specific for both protein and
polysaccharide antigens. Proteins and polysaccharides are
biochemically distinct, and as a result are processed differently
by the immune system, leading to different mechanistic pathways
for eventual elicitation of specific Ig isotypes. Much of
our current knowledge concerning the parameters underlying
anti-protein and anti-polysaccharide Ig responses have come
from studies using soluble, purified antigens. However, the
lessons learned from these studies are not entirely applicable
to the mechanisms underlying physiologic anti-protein and
anti-polysaccharide Ig responses to intact bacteria. Specifically,
unlike isolated, soluble antigens, intact bacteria are complex
particulate immunogens in which multiple protein and polysaccharide
antigens, and bacterial adjuvants (e.g. Toll-like receptor
ligands) are co-expressed, indeed often physically linked.
In this review, data from a series of recent studies are discussed
in which heat-killed, intact Streptococcus pneumoniae
was used as an immunogen to study the mechanisms underlying
in vivo anti-protein and anti-polysaccharide Ig isotype
induction. An unexpected role for CD4+
T cells and dendritic cells for induction of IgG anti-polysaccharide
responses by intact bacteria is discussed, and shown to have
distinct mechanistic features from those that mediate anti-protein
responses. The further role of cytokines, Toll-like receptors,
and B cell receptor signaling in mediating these responses,
and its implications for the effectiveness of anti-pneumococcal,
polysaccharide-based vaccines, is also discussed.
[Back to top]
Immunology of O-Glycosylated Proteins: Approaches
to the Design of a MUC1 Glycopeptide-Based Tumor Vaccine
Franz-Georg Hanisch and Tanja Ninkovic
Until about 1990 there was general consent about the
assumption that only protein and peptide antigens have the
capacity of CD4+ or CD8+ T-cell stimulation. Since about ten
years evidence is now accumulating that carbohydrate-peptide
epitopes do play a role in classical MHC-mediated immune responses.
This holds true for glycopeptides, where the glycan chain
is short and not located at an “anchor residue”
needed for MHC interaction. T-cell recognition of O-glycosylated
peptides is potentially of high biomedical significance, because
it can mediate the immune protection against microorganisms,
the vaccination in anti-tumor therapies, but also some aspects
of autoimmunity.
The epithelial type 1 transmembrane mucin MUC1 is established
as a marker for monitoring recurrence of breast cancer and
is a promising target for immunotherapeutic strategies to
treat cancer by active specific immunization. Natural human
immune responses to the tumor-associated glycoforms of the
mucin indicate that antibody reactivities are more directed
to glycopeptide than to non-glycosylated peptide epitopes.
To overcome the weak immunogenicity of the natural target,
heavily O-glycosylated MUC1, the question was addressed whether
O-linked glycans remain intact during processing in the MHC
class II pathway and interfere with endosomal processing and
peptide presentation. Attempts were made to define on a biochemical
level the structural requirements for an efficient endosomal
proteolysis catalyzed by cathepsin L in antigen-presenting
cells. Evidence based on work with CD4+ T-hybridomas confirms
that O-glycopeptides can be effectively presented to T-cells
and that glycans can form integral parts of the TCR defined
epitopes. Similar approaches are currently followed in the
MHC class I pathway which aim at the identification of immunogenic
glycopeptides generated by immunoproteasomes.
[Back to top]
Interaction of Human Immunodeficiency Virus
(HIV) Glycans with Lectins of the Human Immune System
Xin Ji, Ying Chen, Jonathan Faro, Henry Gewurz, James
Bremer and Gregory T. Spear
Approximately half of the molecular mass of gp120, the
receptor-binding envelope protein of human immunodeficiency
virus (HIV), consists of N-linked glycans. Nearly half of
these glycans are of the high mannose type. These high mannose
glycans furnish a rich forest of mannose residues on the virus
surface making HIV a prime target for interaction with mannose-specific
lectins of the immune system. This review focuses on the known
interactions between gp120 and immune system lectins some
of which HIV appears to exploit. The effect of variation in
glycosylation of gp120, especially with respect to clades
of HIV, on binding of immune system lectins is highlighted.
[Back to top]
The Immunological Function of iGb3
Dapeng Zhou
The mechanistic studies on immune recognition of carbohydrates
have been paved by the synergized advances in identifying
the precise sugar structures recognized by the immune system,
in analyzing the cellular and humoral components bearing the
receptors for glycoconjugates, and production of the biological
relevant carbohydrate epitopes by synthetic chemistry. In
our current studies on natural antigenic glycolipids, we have
found that the activation as well as the development of natural
killer T cells (NKT) is guided by the information provided
by glycolipid metabolism pathways in antigen presenting cells
(APC). Based on genetic data and cellular immunological assays,
we propose a neutral glycosphingolipid isoglobotrihexosylceramide,
iGb3, as one of the candidates recognized by NKT cells under
patho-physiological conditions such as cancer and auto-immune
disease. New immunotherapy approaches might be explored by
interfering with glycolipid metabolism or by directly supplementing
rationally designed glycolipids.
[Back to top]
Structure-Activity Relationship Studies: Methods
and Ligand Design for G-Protein Coupled Peptide Receptors
Manja Lang and Annette G. Beck-Sickinger
The exchange of information between cells represents
an important regulatory mechanism for cellular activities.
Such regulation processes mainly occur by hydrophilic compounds,
unable to penetrate the cell membrane. Accordingly such signals
have to be transmitted into the cell that is performed by
transmembrane receptors. The widespread group of G-protein
coupled receptors plays a decisive role in extracellular signal
recognition and transition into cellular response. The importance
of this interaction is evidently shown by the severe diseases
that correlate with dysfunction of the interaction between
ligand and G-protein coupled receptor. The development of
drugs against these diseases needs the comprehension of signal
recognition and transition as well as the understanding of
intracellular signal pathways. In this review, we describe
concepts and methods to identify the structure-activity relationships
of G-protein coupled peptide receptors and their successful
application. Furthermore we provide an insight into peptide
based drug design. Examples are taken from the field of CGRP,
orexin and growth hormone secretagogue receptor ligands.
[Back to top]
Rho GTPase Activating Proteins in Cancer
Phenotypes
Raj P. Kandpal
Rho proteins belong to the Ras superfamily of small GTPases
and function as binary switches that shuttle between active
and inactive states based on the nature of bound guanine nucleotide.
Three sets of regulatory proteins, namely, guanine dissociation
inhibitors, guanine exchange factors, and GTPase activating
proteins (GAPs) control the balance between active and inactive
Rho proteins. There are more than 70 RhoGAPs encoded in the
human genome. The RhoGAP family is distinguished by the presence
of the RhoGAP domain. However, the majority of RhoGAPs contain
multiple additional domains. There are as many as eight domains
in some of these proteins. The modular structure of GAPs is
important for their interaction with other proteins. A significant
number of RhoGAPs have been shown to be present in altered
abundance in a variety of human cancers or cell lines. The
ability of RhoGAPs to modulate Rho mediated signaling pathways
may lend themselves as targets for small molecule therapeutic
agents against cancer.
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