| Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical Design
Volume 12, Number 29, 2006
Contents
Genome and Proteome Analyses of Autoimmune Diseases
Executive Editor: G. Neeck
Editorial Pp. 3697-3698
Spots, Blots, Peaks and Chips: Proteomic Approaches in Autoimmune
Diseases Pp. 3699-3706
H. Dotzlaw, M. Eggert, G. Neeck and M. Schulz
[Abstract]
Comparative Genomics for the Investigation of
Autoimmune Diseases Pp. 3707-3722
S. Möller, R. Goertsches, U.K. Zettl and P. Serrano-Fernández
[Abstract]
Resources and Tools for Investigating Biomolecular
Networks in Mammals Pp.3723-3724
S. Dietmann, D. Aguilar, M. Mader, M. Oesterheld, A. Ruepp,
V. Stuempflen and H.-W. Mewes
[Abstract]
New Analytical Tools for Studying Autoimmune Diseases
Pp. 3735-3742
M. Kalbas, A. Lueking, A. Kowald and S. Muellner
[Abstract]
The Role of HLA Promoters in Autoimmunity
Pp. 3743-3752
B. Müller-Hilke and N.A. Mitchison
[Abstract]
Dissecting the Genetic Basis of Rheumatoid Arthritis
in Mouse Models Pp. 3753-3759
S.M. Ibrahim and X. Yu
[Abstract]
Multiple Sclerosis Therapy Monitoring Based on
Gene Expression Pp. 3761-3779
R. Goertsches, P. Serrano-Fernández, S. Möller,
D. Koczan and U.K. Zettl
[Abstract]
Molecular Characteristics of Autoimmune Pancreatitis
Pp. 3781-3786
R. Jaster and J. Emmrich
[Abstract]
Functional Genome and Proteome Analyses of Cutaneous
Autoimmune Diseases Pp. 3787-3798
J. Trcka and M. Kunz
[Abstract]
Therapeutic Strategies in Autoimmune Diseases
by Interfering with Leukocyte Endothelium Interaction Pp.
3799-3806
J. Rychly and B. Nebe
[Abstract]
General Articles
No-Reflow: A Heterogeneous Clinical Phenomenon with Multiple
Therapeutic Strategies Pp. 3807-3815
L. Galiuto and F. Crea
[Abstract]
Electrically-Assisted Nucleic Acids Delivery to
Tissues In Vivo: Where Do We Stand? Pp.
3817-3825
M. Cemazar, M. Golzio, G. Sersa, MP. Rols and J. Teissié
[Abstract]
Abstracts
[Back
to top]
Editorial
Autoimmune diseases are multifactorial polygenic diseases
involving interactions between environmental and genetic factors.
Complex networks of interacting genes are affected. Sequencing
of the human genome and advances in novel screening technologies
of genomics and proteomics offer an opportunity of systematic
research to better understand the molecular mechanisms in
these diseases and to find new therapeutic targets and new
diagnostic tools. Therefore the aim of this volume is to discuss
this novel research strategy and experimental data derived
from this technology and methodology platform of a number
of autoimmune diseases by outstanding experts of different
aspects of the issue.
The volume starts with a contribution by Helmut Dotzlaw
et al. [1] Rostock and Giessen, Germany giving an overview
of the approaches used in the proteomic analyses of autoimmune
diseases: during the last years investigations employing a
variety of proteomic technologies have yielded a wealth of
information on a number of autoimmune diseases in humans and
animal models. Steffen Moeller et al. [2] Rostock,
Germany and Szcezin, Poland review reports on the role of
comparative genomics in research on autoimmune diseases. These
novel tools have proven to be successful in inferring functional
equivalence between loci of multiple genomes. Tools for projecting
experimental data sets onto known functional information are
a major need to support the analysis of samples produced in
clinical research of autoimmune diseases. Developing quantitative
and predictive models for interactions of regulatory DNA,
RNAs, and proteins is the ultimate goal of system biology.
Sabine Dietmann et al. [3] Neuherberg and Freising,
Germany describe advances related to the problem of integrating
heterogenous data sets into functional modules for animal
and human cellular networks based on publicly available data
resources. Protein biochips are emerging analytical tools
to follow DNA microarrays as a new screening technology to
identify protein-ligand interactions. The huge potential of
this technology as well as future requirements such as protein
microarray based diagnostics are presented by Mathias
Kalbas et al. [4], Dortmund, Germany. Population studies
reveal HLA class gene polymorphism associated with all the
common chronic autoimmune diseases. Brigitte Müller-Hilke,
and N. Avrion Mitchison [5], Rostock, Germany and London,
UK summarize the knowledge of HLA promoter polymorphisms and
how these translate into differential expression, T cell polarization
and inflammation. The authors also discuss current strategies
for pharmaceutical intervention in HLA expression. Rheumatoid
Arthritis, is the most common chronic inflammatory autoimmune
disorder that involves an interaction of genetic and environmental
factors. Combining genetic association studies in humans and
murine models with high throughput sequencing, RNA expression
profiling and proteome analysis have identified some promising
new targets. Saleh M. Ibrahim and Xinhua Yu [6],
Rostock, Germany review the advances made dissecting the genetics
of Rheumatoid Arthritis using mouse model. Multiple Sclerosis
is the most prevalent chronic autoimmune disorder of the central
nervous system. Goertsches et al. [7], Rostock, Germany
and Szcecin, Poland discuss the state of the art in Multiple
Sclerosis research at the transcriptomic level applying genomewide
screening methods. Their review discribes disease pathogenicity,
diagnostic markers, the identification of new therapeutic
targets and a classification of patients towards the advent
of tailored therapies. In the very last years, autoimmune
pancreatitis has been recognized as a new distinct entity.
Up to now, autoimmune pancreatitis is a rare disease, frequently
associated with other autoimmune diseases. Robert Jaster
and Joerg Emmrich [8], Rostock, Germany describe the
characteristic features of autoimmune pancreatitis focussing
on the molecular mechanisms of the disease. Jiri Trcka
and Manfred Kunz [9] Rostock, Germany summarize the current
knowledge about functional genome and proteome analyses addressing
cutaneous autoimmune diseases like psoriasis, lupus erythematosus,
systemic sclerosis, vitiligo, and alopecia areata. Leukocyte
extravasation are of central pathogenetic importance in all
inflammatory diseases. Joachim Rychly and Barbara Nebe
[10] Rostock, Germany discuss basic scientific data on the
mechanisms of leukocyte endothelial interaction, experiments
to prove therapeutic approaches to inhibit leukocyte extravasation
as well as clinical studies.
References
[1] Dotzlaw H, Eggert M, Neeck G, Schulz M. Spots, Blots,
Peaks and Chips: Proteomic Approach in Autimmune Diseases.
Curr Pharm Design 12(29): 3699-3706.
[2] Moeller S, Zettl UK, Serrano-Fernández P. Comparative
Genomics for the Investigation of Autoimmune Diseases. Curr
Pharm Design 12(29): 3707-3722.
[3] Dietmann S, Aguilar D, Mader M, Oesterheld M, Ruepp A,
Stuempflen V, Mewes H-W. Resources and Tools for Investigating
Biomolecular Networks in Mammals. Curr Pharm Design 12(29):
3723-3734.
[4] Kalbas M, Lueking A, Kowald A, Muellner S. New analytical
tools for studying Autoimmune Diseases. Curr Pharm Design
12(29): 3735-3742.
[5] Müller-Hilke B, Mitchison NA. The role of HLA promoters
in Autoimmunity. Curr Pharm Design 12(29): 3743-3752.
[6] Ibrahim S, Xinhua Yu. Dissecting the genetic basis of
rheumatoid arthritis in mouse models. Curr Pharm Design 12(29):
3753-3759.
[7] Goertsches R, Serrano-Fernández P, Möller
S, Koczan D, Zettl UK. Multiple Sclerosis therapy monitoring
based on gene expression. Curr Pharm Design 12(29): 3761-3779.
[8] Jaster R, Emmrich J. Molecular characteristics of autoimmune
pancreatitis. Curr Pharm Design 12(29): 3781-3786.
[9] Trcka J, Kunz M. Functional genome and proteome analyses
of cutaneous autoimmune diseases. Curr Pharm Design 12(29):
3787-3798.
[10] Rychly J, Nebe B. Therapeutic strategies in autoimmune
diseases by interfering with leukocyte endothelium interaction.
Curr Pharm Design 12(29): 3799-3806.
G. Neeck
BIOMEDRO Biomedical Research
and Development Rostock Ltd
at Rostock Clinic South
Suedring 81, D-18059 Rostock
Germany
[Back to top]
Spots, Blots, Peaks and Chips: Proteomic Approaches in Autoimmune
Diseases
H. Dotzlaw, M. Eggert, G. Neeck and M. Schulz
During the past five years, investigations employing a variety
of proteomic technologies have yielded a wealth of information
on a number of autoimmune disorders. Animal models of autoimmune
disease have been examined and have provided clues that can
be useful in elucidating molecular pathways and mechanisms
that play a role in autoimmune disorders. Human sera and body
fluids have been analyzed and have resulted in the identification
of autoantibodies that can be used as diagnostic markers in
specific autoimmune diseases, and proteomic fingerprints of
tissues and body fluids have resulted in the identification
of individual proteins or patterns of protein expression that
are deregulated in autoimmune diseases. The information provided
by these proteomic studies are of diagnostic and therapeutic
potential. This review provides an overview of the approaches
used in the proteomic analyses of autoimmune disease.
[Back to top]
Comparative Genomics for the Investigation of Autoimmune
Diseases
S. Möller, R. Goertsches, U.K. Zettl and P. Serrano-Fernández
The complete DNA sequence of the human genome and of several
related mammals are now available, due to the investments
of enormous resources and advances in sequencing technology.
Novel technologies have been developed to compare multiple
genomes with each other, thus specifying regions of sequence
similarity among mammals and with their pathogens. Larger
blocks of sequence similarity (syntenic regions) have been
determined and made publicly available. In many ways, novel
insights can be gained by such data when combining external
genetic or clinical information for these syntenic loci. These
novel tools have proven to be successful in inferring functional
equivalence between loci of multiple genomes.
This review reports on the role of comparative genomics in
research on autoimmune diseases, a field with strong dependencies
on animal models of human diseases and the problem of an adequate
information transfer between multiple organisms and research
areas.
[Back to top]
Resources and Tools for Investigating Biomolecular
Networks in Mammals
S. Dietmann, D. Aguilar, M. Mader, M. Oesterheld, A. Ruepp,
V. Stuempflen and H.-W. Mewes
Molecular databases serve as primary information resources
for the analysis of biological networks providing an essential
and invaluable treasure for information exploration. Tools
for projecting experimental data sets onto known functional
information are a major need to support the analysis of samples
produced in clinical research. A new concept is the notation
of functional modules, i.e. the characterisation of sets of
proteins that perform a defined biological function in cooperation.
The determination and analysis of functional modules overcome
the limitations of the analysis of individual genes and their
properties. Although functional modules are not suitable to
fully capture systems properties, they have the potential
to unify the information generated by different types of experiments.
We describe advances related to the problem of integrating
heterogeneous data sets into functional modules for mouse
and/or human cellular networks based on publicly available
data resources, including advances in the design of ontologies
for functional classification, problems of automatic protein
functional annotation and integration of microarray data.
[Back to top]
New Analytical Tools for Studying Autoimmune Diseases
M. Kalbas, A. Lueking, A. Kowald and S. Muellner
Protein microarrays with immobilised proteins on their surface
are new analytical tools to overcome the current limits with
respect to sample volume and throughput. They have a great
potential as well with respect to multiplexing of complex
samples, as a research tool and in diagnostics. Based on recent
advances in this technology, new applications for protein
microarrays in studying autoimmune diseases were described.
Required tools for bioinformatical analysis of protein microarrays
concerning normalisation, clustering and classification methods
are discussed. The huge potential of this technology as well
as future requirements such as protein microarray based diagnostics
are presented.
[Back to top]
The Role of HLA Promoters in Autoimmunity
B. Müller-Hilke and N.A. Mitchison
Population studies reveal HLA class I and class II gene
polymorphisms associated with all the common chronic autoimmune
diseases, notably spondylarthropathies, rheumatoid arthritis,
multiple sclerosis and type I diabetes. We here discuss the
exceptionally high levels of nucleotide diversity in the MHC
region likely to reflect not only balancing selection acting
on the epitope binding sites but also natural selection operating
on the promoter region. The latter possibility is supported
by functional studies with promoters, higher levels of diversity
in the promoters of class II than class I genes and the relatively
high frequency of single nucleotide polymorphisms around transcription
factor binding sites. This, we argue, reflects the need for
an appropriate level of signalling at the immunological synapse.
We here summarise our knowledge of HLA promoter polymorphisms
and how these translate into differential expression, T cell
polarisation and inflammation. We discuss current strategies
for pharmaceutical intervention in HLA expression.
[Back to top]
Dissecting the Genetic Basis of Rheumatoid Arthritis
in Mouse Models
S.M. Ibrahim and X. Yu
Rheumatoid Arthritis, RA, is a common polygenic multi-factorial
chronic inflammatory disorder that involves complex interactions
between genetic and environmental factors. Despite major advances,
the aetiology of the disease is still not completely understood.
In this post-genome era, the sequencing of the human and some
murine genomes as well as advances in global screening technologies
offer an opportunity to accelerate the search for new pathological
pathways and to identify new therapeutic targets. Animal models
of RA offer an opportunity to dissect the genetic basis of
disease in a simplified genome and controlled environment
with the aim of identifying new pathological pathways and
thus new therapeutic targets. Linkage analysis in the mouse
model has identified more than 60 Loci, controlling disease
pheno-types, immune response and cytokines. This indicates
that gene variations among inbred mice strains affect the
disease and that those polymorphic genes could be potential
therapeutic targets. However, progress in identification of
susceptibility genes in mouse models is slow. The progress
is hampered by the complexity of disease as well as the traditional
genetic dissection strategies. In this post-genome era, the
sequencing of the human and some murine genomes as well as
advances in global screening technologies offer an opportunity
to accelerate the progress.
[Back to top]
Multiple Sclerosis Therapy Monitoring Based on Gene
Expression
R. Goertsches, P. Serrano-Fernández, S. Möller,
D. Koczan and U.K. Zettl
Multiple sclerosis (MS) is the most prevalent chronic autoimmune,
neurodegenerative disorder of the central nervous system (CNS).
Despite substantial progress, treatment of MS and other autoimmune
diseases is only moderately effective. It is anticipated that
the treatment of autoimmune diseases with single drugs or
biological approaches will in the future be complemented,
or even replaced, by combination therapies, which include
immunomodulation, elimination of infectious triggers and tissue
repair. One proclaimed goal of biomedical research and clinical
practice is the discovery of sets of genes with expression
that correlates with successful outcomes of drug therapy,
or with unfortunate side effects. Such information has direct
consequences for selection, refinement or development of treatments
and will soon be translated into clinical trials. The genome-wide
RNA profile of an individual represents one complement to
the comprehensive determination of disease- or drug response-related
elements; comparable to a ‘sentinel’ method, it
serves as a large-scale approach to MS biology. This work
reviews the state of the art in MS research at the transcriptome
level applying genomewide screening methods. It discusses
implications in understanding disease pathogenicity, diagnostic
markers, the identification of new therapeutic targets and
a classification of patients towards the advent of tailored
therapies.
[Back to top]
Molecular Characteristics of Autoimmune Pancreatitis
R. Jaster and J. Emmrich
For many years, a pathological immune response has been implicated
in the development of chronic pancreatitis. However, only
in the last decade autoimmune pancreatitis (AIP) has been
recognized as a distinct entity with typical histopathological
and immunological findings. AIP is frequently associated with
other autoimmune diseases, such as Sjogren`s syndrome, sclerosing
extra-hepatic cholangitis and retroperitoneal fibrosis. Although
AIP is rare, improved diagnostics is of significant clinical
interest because of the prompt response to steroid treatment.
In this review, we describe the characteristic features of
AIP and focus on the molecular pathogenesis of the disease.
[Back to top]
Functional Genome and Proteome Analyses of Cutaneous
Autoimmune Diseases
J. Trcka and M. Kunz
The use of functional genomics and proteomics technologies
has dramatically increased through recent years with a special
emphasis on cancer biology. However, a series of more recent
reports has also addressed inflammatory diseases. These included
studies on different autoimmune diseases, such as rheumatoid
arthritis, lupus erythematosus, and systemic sclerosis. Gene
and protein expression profiles from these studies have emphasized
the role of cytokines, chemokines, and apoptosis-related molecules
for the pathogenesis of autoimmune diseases. Much less is
known about gene and protein patterns of these diseases in
dermatology. Here we provide an overview on current knowledge
about genomics and proteomics analyses of cutaneous autoimmune
diseases. These diseases include psoriasis, lupus erythematosus,
systemic sclerosis, vitiligo, and alopecia areata. The presented
findings not only provide deeper insights into the pathogenesis
of each individual disease but also show overlapping gene
patterns suggestive for common pathogenic mechanisms. However,
many open questions remain to be resolved since data about
local gene expression pattern in affected tissues are still
scarce.
[Back to top]
Therapeutic Strategies in Autoimmune Diseases by Interfering
with Leukocyte Endothelium Interaction
J. Rychly and B. Nebe
The interaction of leukocytes with the vessel endothelium
to facilitate the extravasation into the tissue represents
a key process of the body’s defense mechanisms. Excessive
recruitment of leukocytes into the inflamed tissue in chronic
diseases like autoimmune disorders could be prevented by interfering
with the mechanisms of leukocyte extravasation. Significant
progress in elucidating the molecular basis of the trafficking
of leukocytes from the blood stream to the extravascular tissue
has been achieved that enables new strategies for therapeutic
approaches. The multistep process of leukocyte rolling, firm
adhesion and transmigration through the endothelial wall is
facilitated by a dynamic interplay of adhesion receptors on
both leukocytes and endothelial cells as well as chemokines.
In preclinical studies using various animal models, promising
results have been received demonstrating that blocking of
adhesion receptors of the selectin and integrin families improved
the inflammation process in models of ulcerative colitis,
autoimmune encephalomyelitis or contact hypersensitivity.
In addition to the targeting of adhesion receptors by antibodies,
small molecules that mimic epitopes of adhesion receptor ligands
have been developed and successfully applied in animal models.
Clinical studies revealed a limited response using antibodies
to selectins or LFA-1 integrins compared with animal models.
However, using humanized antibodies to the α4-
integrin subunit significant efficacy has been demonstrated
in autoimmune diseases like psoriasis, multiple sclerosis
and inflammatory bowel disease.
[Back to top]
No-Reflow: A Heterogeneous Clinical Phenomenon with Multiple
Therapeutic Strategies
L. Galiuto and F. Crea
Previously defined as a shotcoming to achieve uniform intramyocardial
reperfusion after prolonged but reversible coronary occlusion,
only recently has no-reflow phenomenon been characterized
as a heterogeneous clinical condition. In fact, in about half
of post-infarct patients that show no-reflow after 24 hours
from coronary recanalization by either thrombolysis or PTCA,
no-reflow phenomenon is spontaneously reversible. Reversible
no-reflow is associated with favorable left ventricular remodeling
even in the absence of significant improvement in regional
contractile function. Thus, it may be a clinical marker of
yet unknown mechanisms, which may favorably affect myocardial
response to necrosis.
Based on the pathogenesis and on the time-course of no-reflow,
the phenomenon may be associated with lack of patency or with
loss of anatomic integrity of microvessels, with the former
being potentially reversible while the latter associated with
definitive tissue damage. As a consequence, possible therapeutic
strategies of no-reflow have to be designed according to not
only the main target [microvessel patency or integrity], but
also taking into account the timing of development of the
damage.
This “mini review” is focused on recent advances
on the pathogenesis and clinical presentation on no-reflow.
These data will give the opportunity to formulate novel interpretation
and classification of the phenomenon and consequently, to
propose adequate therapeutic strategies.
[Back to top]
Electrically-Assisted Nucleic Acids Delivery to Tissues
In Vivo: Where Do We Stand?
M. Cemazar, M. Golzio, G. Sersa, MP. Rols and J. Teissié
Electropulsation (electroporation) is a physical
method for delivery of various molecules into the cells in
vitro and in vivo. It is an expanding field
due to its applicability in cancer therapy, where combined
application of electric pulses and chemotherapeutic drugs
is used for treatment of cutaneous and subcutaneous nodules
of different malignancies. Another application of electropulsation
in vivo is electrogene therapy, where after injection
of naked plasmid DNA and delivery of electric pulses directly
to the tissue the expression of gene of interest can be obtained.
However, the transfection efficiency of this methodology in
vivo is still lower than with viral vectors. Nevertheless,
due to the lack of immuno-genicity of the method, easiness
of the preparation of large quantities of endotoxin free plasmid
DNA, control and reproducibility of the method and the development
of electropulsators approved for the clinical use, electrically-assisted
nucleic-acid delivery holds a great potential for the clinical
application. This aim of this minireview is to critically
discuss the main limitations and obstacles associated with
electrogene therapy and the failures and problems as well
as the successes. Topics on electric field distribution in
the tissue, electrode geometries, construction of plasmid,
modulation of extracellular space, tissue damage, pro-inflammatory
and immune response as well as blood flow modification associated
with application of electric pulses and injection of naked
DNA are presented with possible directions how to overcome
these limitations. Furthermore, for successful electrogene
therapy in clinical setting it is of utmost importance to
elucidate the mechanisms of DNA transfer into the cells of
tissues in vivo. This will enable appropriate selection
of electric pulse parameters and plasmid DNA constructs for
each particular intended use. In the long run, this review
should encourage other scientists to consider electrically
assisted gene delivery for gene therapy as it matures.
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