| Inflammation
& Allergy - Drug Targets
ISSN: 1871-5281
Current Drug Targets - Inflammation
& Allergy
Volume 4, Number 1, February 2005
Contents
Antiangiogenesis in Chronic Inflammation
Guest Editor: Domenico Ribatti
Molecular Biology-Pathophysiology of
Inflammation and Autoinflammation
Guest Editor: Kostas Konstantopoulos
Editorial
Domenico Ribatti
[Editorial
In PDF]
Role of Inflammatory Mediators in Angiogenesis
Pp. 3-8
Antonella Naldini and Fabio Carraro
[Abstract]
[Full text article]
Involvement of Mast Cells in Angiogenesis and
Chronic Inflammation Pp. 9-11
Enrico Crivellato and Domenico Ribatti
[Abstract] [Full
text article]
Development of Vasculature Targeting Strategies
for the Treatment of Chronic Inflammatory Diseases Pp.
13-22
Girolamo Ranieri, Roberto Ria, Aldo M. Roccaro, Angelo
Vacca and Domenico Ribatti
[Abstract] [Full
text article]
CXC Chemokines in Angiogenesis Relevant to Chronic
Fibroproliferation Pp. 23-26
Robert M. Strieter, John A. Belperio, Marie D.
Burdick and Michael P. Keane
[Abstract] [Full
text article]
Antiangiogenesis for Rheumatoid Arthritis Pp.
27-30
Aldo M. Roccaro, Francesca Russo, Teresa Cirulli,
Guilia Di Pietro, Angelo Vacca and Franco Dammacco
[Abstract] [Full
text article]
Inhibition of Angiogenesis by Non-Steroidal Anti-Inflammatory
Drugs: From the Bench to the Bedside and Back Pp.
31-38
Yan Monnier, Jelena Zaric and Curzio Rüegg
[Abstract] [Full
text article]
Editorial
Kostas Konstantopoulos
[Editorial
In PDF]
Biological Therapies of Autoimmune Diseases Pp. 41-46
Irene S. Kourbeti and Dimitrios T. Boumpas
[Abstract] [Full
text article]
Genetic Heterogeneity of Hepatitis Viruses and
its Clinical Significance Pp. 47-55
A. Alexopoulou and S.P. Dourakis
[Abstract] [Full
text article]
Amyloidosis and Auto-Inflammatory Syndromes Pp.
57-65
Gilles Grateau, Isabelle Jeru, Saad Rouaghe,
Cecile Cazeneuve, Nathalie Ravet, Philippe Duquesnoy, Laurence
Cuisset, Catherine Dode, Marc Delpech and Serge Amselem
[Abstract] [Full
text article]
Familial Mediterranean Fever in the Post-Genomic
Era: How an Ancient Disease is Providing New Insights into
Inflammatory Pathways Pp. 67-76
Philip E. Schaner and Deborah L. Gumucio
[Abstract] [Full
text article]
Molecular and Genetic Characteristics of Hereditary
Autoinflammatory Diseases Pp. 77-80
Mehmet Tunca, and Huri Ozdogan
[Abstract] [Full
text article]
Behçet’s Disease as an Autoinflammatory
Disorder Pp. 81-83
Ahmet Gul
[Abstract] [Full
text article]
Oxidative Stress in the Molecular Mechanism of
Pathogenesis at Different Diseased States of Organism in Clinics
and Experiment Pp. 85-98
Konstantin G. Karageuzyan
[Abstract] [Full
text article]
The Role of Infections in the Pathogenesis of
Autoimmune Diseases Pp. 99-103
Michael Samarkos, and George Vaiopoulos
[Abstract] [Full
text article]
MEFV Mutation Carriers and Diseases Other than
Familial Mediterranean Fever: Proved and Non-Proved Associations;
Putative Biological Advantage Pp. 105-112
Daniel Cattan
[Abstract] [Full
text article]
Molecular Study of FMF Patients in Armenia Pp.
113-116
T. Sarkisian, H. Ajrapetyan and G. Shahsuvaryan
[Abstract] [Full
text article]
Pharmacological and Clinical Basis of Treatment
of Familial Mediterranean Fever (FMF) with Colchicine or Analogues:
An Update Pp-117-124
C. Cerquaglia, M. Diaco, G. Nucera, M. La Regina, M. Montalto
and R. Manna
[Abstract] [Full
text article]
Complement: An Inflammatory Pathway Fulfilling
Multiple Roles at the Interface of Innate Immunity and Development
Pp-125-127
D. Mastellos, A.E. Germenis, and J.D. Lambris
[Abstract] [Full
text article]
Abstracts
[Back to top]
Editorial
Domenico Ribatti
[Editorial
In PDF]
This issue of “Current Drug Targets – Inflammation
& Allergy” is dedicated to the topic of “Antiangiogenesis
in chronic inflammation”.
Interest in angiogenesis research remains strong in recent
years: many laboratories worldwide are actively involved in
the study of several aspects of this field and the literature
on angiogenesis increases exponentially.
The growth of new microvessels from resting vessels is the
outcome of a fine balance between molecules that are either
positive or negative regulators of angiogenesis (the so called
“angiogenic switch”).
The explosion of clinical research in angiogenesis is a result
of the realization that in many diseases characterized by
persistent, unregulated angiogenesis, as cancer, atherosclerosis,
rheumatoid arthritis and diabetic neuropathy, a common underlying
pathogenetic aspect is a derangement in angiogenesis.
Suppressors of angiogenesis have potential clinical applications
in conditions where abnormal proliferation of blood vessels
is related to the disease progression.
In this issue several leading investigators report new findings
about antiangiogenesis in chronic inflammation. The role of
angiogenesis in chronic inflammation is analyzed and the effect
of inflammatory mediators on angiogenesis is reviewed, where
possible we have tried to indicate the areas of each process
that are poorly understood in order to prvide directions for
future research.
Dr. Naldini and Carraro present an overview on the relevance
of both physiological and pathological inflammatory processes
in angiogenesis, with particular regards to microenvironment.
Dr. Crivellato and myself summarize the most recent acquisition
concerning mast cells involvement in angiogenic processes
and chronic inflammatory processes. Dr. Ranieri and co-workers
review recent studies on the vasculature targeting strategies
for the treatment of chronic inflammatory diseases. Dr. Strieter
and co-workers discuss the biology of the angiogenic and angiostatic
CXC chemokines and their disparate angiogenic activity in
the context of a variety of chronic fibroproliferative disorders.
Dr. Roccaro and co-workers present recent data about the use
of antiangiogenesis as a therapeutic tool in the treatment
of rheumatoid arthritis. Finally, Dr. Monnier and co-workers
review the most recent advances in understanding the mechanisms
by which non-steroidal anti-inflammatory drugs and inhibitors
of cyclooxygenase suppress angiogenesis and discuss their
potential clinical use as antiangiogenic drugs.
[Back to top]
Role of Inflammatory Mediators in Angiogenesis
Antonella Naldini and Fabio Carraro
[Full text
article]
The angiogenic process involves several cell types and mediators,
which interact to establish a specific microenvironment suitable
for the formation of new capillaries from pre-existing vessels.
Angiogenesis occurs in several physiological and pathological
conditions, such as embryo development and wound healing,
diabetic retinopathy and tumours. Inflammatory cells, namely
monocytes/macrophages, T lymphocytes and neutrophils, fully
participate in the angiogenic process by secreting cytokines
that may affect endothelial cell (EC) functions, including
EC proliferation, migration and activation. Angiogenesis is
the result of a net balance between the activities exerted
by positive and negative regulators. With regards to inflammatory
cells and endothelium cross-talk, such balance is conceptually
very similar to that of pro-inflammatory and anti-inflammatory
mediators that modulate an appropriate inflammatory response.
In this review we will mainly discuss the relevance of both
physiological and pathological inflammatory processes in angiogenesis,
with particular regards to microenvironmental contribution.
We will also describe some of the most relevant pro-inflammatory
cytokines in the modulation of the angiogenic process. Furthermore,
we will concentrate on what has been recently reported about
the mechanism by which some of these cytokines are induced
during inflammation to promote a suitable microenvironment
for angiogenesis and tumour progression. Pro-angiogenic cytokines,
such as IL-1 and TNF, and anti-angiogenic cytokines such as
IFN-g and IL-12, will be briefly described. We will try to
provide a rationale for the use of both cytokines and cytokine
blockades as novel potential pharmaceutical targets to modulate
angiogenesis in chronic inflammation as well as in cancer.
[Back to top]
Involvement of Mast Cells in Angiogenesis and Chronic
Inflammation
Enrico Crivellato and Domenico Ribatti
[Full text
article]
Mast cells (MC) are granulated secretory cells that have
long been recognized as a rich source of biologically highly
active mediators such as biogenic amines, prostaglandins,
leukotrienes, proteases, cytokines and chemokines. Most of
their biological functions however has been rather elusive.
There are now emerging data assigning these cells a relevant
role in orchestrating angiogenesis, both in normal and pathological
conditions. MC indeed synthesize and release a large array
of proangiogenic factors upon different stimulation pathways.
In addition, MC have been recognized as key cells in mediating
host innate and adaptive immune responses. This review summarizes
the most recent acquisitions concerning MC involvement in
angiogenic processes and chronic inflammatory reactions.
[Back to top]
Development of Vasculature Targeting Strategies for the Treatment
of Chronic Inflammatory Diseases
Girolamo Ranieri, Roberto Ria, Aldo M. Roccaro,
Angelo Vacca and Domenico Ribatti
[Full text
article]
The pathogenesis of a number of chronic inflammatory processes
can be attributed to prolonged neovascularization. This article
reviews recent studies on the vasculature targeting strategies
for the treatment of chronic inflammatory diseases. Targeting
of the vasculature of inflamed organs could underlie a new
pharmacological approach in the treatment of inflammatory
diseases by taking advantage of formulations that deliver
drugs to blood vessels specifically located at disease sites
and to inflammatory cells.
[Back to top]
CXC Chemokines in Angiogenesis Relevant to Chronic Fibroproliferation
Robert M. Strieter, John A. Belperio, Marie D.
Burdick and Michael P. Keane
[Full text
article]
The CXC chemokines are an unique family of cytokines known
for their ability to behave in a disparate manner in the regulation
of angiogenesis. The mechanisms for the different activity
in regulating angiogenesis by members of this chemokine family
is related to the following: 1) the presence or absence of
the structural/functional motif (Glutamic acid-Leucine-Arginine;
‘ELR’ motif) that immediately precedes the first
cysteine amino acid residue in the primary structure of these
cytokines; 2) interferon-inducible gene expression; and 3)
receptors that these chemokines use to mediate their biological
activity. Members that contain the ‘ELR’ motif
(ELR+) are potent promoters of angiogenesis, and mediate their
angiogenic activity via binding and activating CXCR2 on endothelium.
In contrast, members that are inducible by interferons and
lack the ELR motif (ELR-) are potent inhibitors of angiogenesis,
and bind to the alternatively splice variant of CXCR3, CXCR3B
on endothelium. This review will discuss the biology of these
angiogenic and angiostatic CXC chemokines, and discuss their
disparate angiogenic activity in the context of a variety
of chronic fibroproliferative disorders.
[Back to top]
Antiangiogenesis for Rheumatoid Arthritis
Aldo M. Roccaro, Francesca Russo, Teresa Cirulli,
Guilia Di Pietro, Angelo Vacca and Franco Dammacco
[Full text
article]
Angiogenesis, i.e., the induction of new blood vessels from
existing vasculature, is a crucial event in the formation
and maintenance of the pannus in rheumatoid arthritis (RA).
The arthritis is characterized by destruction of peripheral
joints in which the cartilage and bone are destroyed by proliferative
synovitis. This is characterized by infiltration of inflammatory
cells and formation of new blood vessels. Angiogenesis occurs
since the early stage of the disease, and supports progression
of the arthritis. It has been demonstrated in animal models
of arthritis that inhibition of angiogenesis reduces of the
arthritis. This suggests that pharmacological inhibition of
angiogenesis may play an important role in the treatment of
RA. In particular, disruption of new blood vessels can not
only prevent delivery of nutrients to the inflammatory site,
but can also lead to vessel regression, hence reversal of
disease.
To sum up, since angiogenesis is central in maintaining of
synovitis in RA, antiangiogenesis probably represents a therapeutic
tool. This view is supported by recent studies in animal models
of arthritis where antiangiogenic drugs deliver a therapeutic
benefit.
[Back to top]
Inhibition of Angiogenesis by Non-Steroidal Anti-Inflammatory
Drugs: From the Bench to the Bedside and Back
Yan Monnier, Jelena Zaric and Curzio Rüegg
[Full text
article]
The formation of new blood vessels, a process globally referred
to as angiogenesis, occurs in a number of pathological conditions,
such as cancer and chronic inflammation. Recent findings indicate
that cyclooxygenase-2 (COX-2), the inducible form of the cyclooxygenase
(COX) isoenzymes, acts as a potent inducer of angiogenesis.
Non-steroidal anti-inflammatory drugs (NSAIDs) are classical
inhibitors of COX enzymes, which are widely prescribed for
the treatment of inflammation, pain and fever. Selective COX-2
inhibitors (COXIBs) have been subsequently developed with
the purpose to improve the safety profile of this class of
therapeutics. More recently, substantial preclinical evidence
demonstrated that NSAIDS and COXIBs have anti-angiogenic properties.
This newly recognized activity opens the possibility of using
these drugs for the treatment of angiogenesis-dependent diseases.
In this article we review the most recent advances in understanding
the mechanisms by which NSAIDs and COXIBs suppress angiogenesis,
and we discuss their potential clinical use as anti-angiogenic
drugs.
[Back to top]
Editorial
Kostas Konstantopoulos
[Full text
article]
It is a great pleasure and an honor as well for me to present
to the readers of this Journal a Special Issue dedicated to
a set of topics in the area of molecular biology-pathophysiology
of inflammation and autoinflammation.
Inflammation, a rather cardinal concept in biology and not
only in medicine, representing the most common reaction to
a variety of stimuli has recently been widened as to cover
conditions related to immune mechanisms without any evidence
of involvement of antibodies or antigen specific cells (auto-inflammation)
as well. Although seemingly rare, genetically controlled and
encompassing a variety of diverse entities, it turns to be
an ideal model of tissue reaction with a lot of secrets hiding
behind very primitive concepts. Understanding the pathogenesis
of entities, (=EA=FC=EC=EC=E1) such as Familial Mediterranean
Fever, is essential not only for reliable diagnosis, counseling
and treatment but also as a first step in understanding better
the concept of inflammation and the other so-called auto-inflammatory
conditions.
The pathophysiology of inflammation and autoinflammation
is thoroughly covered in several chapters of this issue. Distinguished
co-authors from several centers around the world have contributed
to detailing these concepts from the clinical, pharmacological,
molecular and developmental view.
Boumpas and Kourbeti (Greece) discuss the concept of biological
treatment strategies in autoimmunity. Dourakis and Alexopoulou
(Greece) unfold the secrets of clinical implications of the
genetic heterogeneity of hepatitis, a very special infection
with a wide impact on public health. Grateau (France) presents
the serious and fascinating problem of amyloidoses that are
currently becoming more and more difficult to understand.
Gumucio (Michigan-US) deals with the emerging molecular details
of inflammatory processes occurring at least in part via the
interaction of several intracellular mediators and pyrin,
the protein involved in pathogenesis of Familial Mediterranean
Fever. Tunca and Ozdogan (Turkey) review the concept of molecular
and genetic characteristics of hereditary autoinflammatory
diseases. Gul (Turkey) reviews the similarities between the
hereditary autoinflammatory diseases and an acquired entity
of auto-inflammatory type, namely Bechet's disease. Karageuzyan
(Armenia) proposes his model on oxidative stress in the pathogenesis
of several disease states, hereditary or acquired. Samarkos
and Vaiopoulos (Greece) discuss the literature data on the
causative role and induction of autoimmunity. Cattan (France)
reviews the relations between vasculitides and Familial Mediterranean
Fever, an as-yet unsolved question; he also deals with the
putative selection advantages, if any, of Mediterranean Fever
gene. Sarkisian (Armenia) is reporting on the genotype-phenotype
correlation(s) of pyrin mutations in Armenia, a hot area for
Mediterranean Fever. Manna (Italy) reviews the pharmacology
of the most popular (and most efficient) agent for treating
Mediterranean Fever, colchicin. Germenis and his group (Greece)
comment on the versatility of complement framework, a strategic
function in innate immunity.
I am much obliged to all authors and their collaborators
for the time and efforts they devoted for this production.
I wish to thank Bentham Publishers for honouring me with their
decision and invitation to act as a Guest Editor in this Special
Issue. I wish to thank people in my Department for allowing
me enough time for the editing duties. I am sure that this
volume will prove valuable contribution to a better understanding
of the complex and diverse field of the pathophysiology of
inflammation and auto-inflammation.
[Back to top]
Biological Therapies of Autoimmune Diseases
Irene S. Kourbeti and Dimitrios T. Boumpas
[Full text
article]
The advances in the understanding of the pathogenesis of
the autoimmune diseases have led to new treatment targets.
Biological agents enhance or replace conventional immunosuppressive
therapies in the treatment of autoimmune diseases. TNF-a has
been validated as a good treatment target but the potential
modalities also include the inhibition of the interaction
between LFA-3 (lymphocyte function-associated antigen 3) and
CD2, the blockade of the IL-1 receptors, the antibodies against
the a4 integrins, the antibodies against B-cell CD20 and the
inhibition of the activation of T-cells. The new treatments
have had a major impact on inflammatory symptoms, the radiological
damage and the anemia of chronic disease in rheumatoid arthritis
and have substantially controlled the signs and symptoms in
the spondylarthropathies group and plaque-type psoriasis.
The efficacy of the biologic agents in systemic lupus erythematosus
warrants further investigation but there have been some promising
results in proliferative lupus nephritis. Several small studies
have explored their use in the treatment of Sjogren’s
syndrome, adult onset Still’s disease and several vasculitides
but the results are still preliminary and warrant confirmation.
The efficacy of the biological agents has been impressive.
Susceptibility to infections has always been a major concern;
a high level of suspicion is necessary and strategies should
be implemented for the prevention, the rapid identification
and pre-emptive therapy of such infections.
[Back to top]
Genetic Heterogeneity of Hepatitis Viruses and its Clinical
Significance
A. Alexopoulou and S.P. Dourakis
[Full text
article]
The genetic heterogeneity of hepatitis B virus (HBV) (8 genotypes
A-H) has been applied for tracing the route of HBV transmission
and the geographical migration of HBV carriers but it also
appeared to have clinical implications. The secondary structure
of e encapsidation signal could explain why the precore mutant
virus prevails in Mediterranean countries, where genotype
D is most prevalent, while the wild type virus is frequent
in Western countries, where genotype A is most prevalent.
There is increasing evidence that patients infected with genotype
C have more severe outcome of chronic liver disease than those
infected with genotype B. Genotype B was associated with fulminant
hepatitis and more severe episodes of acute exacerbation of
chronic HBV infection. Patients infected with genotype B appeared
to seroconvert earlier than those infected with genotype C.
The hepatitis delta virus (HDV) has 3 genotypes (I, II, III)
which are associated with different disease patterns. Genotype
III is the most distantly related HDV genotype and is associated
with the most severe outcome while genotype II with relatively
mild liver disease. The most geographically widespread genotype
is I and is associated with a broad spectrum of chronic liver
disease.
The hepatitis C virus (HCV) displays high genetic heterogeneity
with six genotypes (1-6), multiple subtypes and quasispecies.
This viral diversity has epidemiological and clinical implications
and has been associated with the severity of liver disease,
prognosis, response to treatment and failure to generate an
effective protective vaccine. HCV genotype 1 is the predominant
genotype in Western countries and has been associated with
a low response rate to interferon-alpha (IFN-a) or to the
combination of ribavirin and IFN-a. Consequently the duration
of treatment has been tailored according to HCV genotype.
[Back to top]
Amyloidosis and Auto-Inflammatory Syndromes
Gilles Grateau, Isabelle Jeru, Saad Rouaghe,
Cecile Cazeneuve, Nathalie Ravet, Philippe Duquesnoy, Laurence
Cuisset, Catherine Dode, Marc Delpech and Serge Amselem
[Full text
article]
Amyloidosis remains currently a severe potential complication
of many chronic inflammatory disorders. It is not exactly
know why some patients develop a progressive amyloidosis,
whereas others do not although latent deposits may be present.
A permanent acute phase response, ideally evaluated with serial
measurement of serum protein SAA, the precursor of the AA
protein deposited in tissues, seems to be a prerequisite to
the development of inflammatory (AA) amyloidosis. Genetic
factors have however been recently emphasized. Among persistent
or emerging causes of AA amyloidosis, hereditary periodic
fever syndromes also known as auto-inflammatory syndromes
are a group of diseases characterised by intermittent bouts
of clinical inflammation with focal organ involvement mainly:
abdomen, musculoskeletal system and skin. The most frequent
is familial Mediterranean fever which affects patients of
Mediterranean descent all over the world. Three other types
have been recently clinically as well as genetically characterised.
A thorough diagnosis is warranted, as clinical and therapeutic
management is specific for each of these diseases.
[Back to top]
Familial Mediterranean Fever in the Post-Genomic Era: How
an Ancient Disease is Providing New Insights into Inflammatory
Pathways
Philip E. Schaner and Deborah L. Gumucio
[Full text
article]
Familial Mediterranean fever (FMF, MIM24900), described as
a clinical entity only slightly over a half-century ago, has
ancient roots among populations surrounding the Mediterranean
basin. It is the most prevalent of the hereditary periodic
fever syndromes, a group of disorders characterized by episodic
attacks of fever and inflammation. Seven years ago, it was
discovered that FMF is caused by mutations in MEFV, a gene
that encodes a protein variously called pyrin or marenostrin.
As exciting as that discovery was, physicians and patients
alike were disappointed that the protein sequence of pyrin/marenostrin
did not immediately suggest clues as to the molecular etiology
of FMF. Though we are still far from a complete understanding
of the function of pyrin/marenostrin at the cellular level,
continued study of this intriguing protein is revealing new
molecular details about inflammatory processes; the emerging
information is relevant not only to FMF, but to innate immunity
in general. Data from several laboratories demonstrate that
pyrin/marenostrin is intimately connected to three important
cellular pathways: apoptosis, cytoskeletal signaling and cytokine
secretion. These connections occur, at least in part, through
the direct interaction of the pyrin/marenostrin protein with
two cytosolic protein adaptors: ASC (also called PyCARD or
Tms1) and PSTPIP (also called CD2BP1). Here, we review the
more recent literature regarding the molecular and cellular
biology of pyrin/marenostrin and pinpoint open questions for
future study.
[Back to top]
Molecular and Genetic Characteristics of Hereditary
Autoinflammatory Diseases
Mehmet Tunca, and Huri Ozdogan
[Full text
article]
Autoinflammatory diseases are defined as recurrent "unprovoked"
inflammatory events which do not produce high-titer autoantibodies
or antigen-specific T cells. There are currently eight hereditary
forms of these diseases: Familial Mediterranean fever (FMF),
hyperimmunoglobulinemia D with periodic fever syndrome (HIDS),
tumor necrosis factor receptor–associated periodic syndrome
(TRAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory
syndrome (FCAS), chronic infantile neurologic cutaneous articular
(CINCA) syndrome or neonatal-onset multisystem inflammatory
disease (NOMID), pyogenic sterile arthritis, pyoderma gangrenosum,
acne (PAPA) and Blau syndrome. Apart from FMF (which has a
prevalence of about 0.1 percent among non-Ashkenazi Jews,
Armenians, Turks and Arabs), they are very rare disorders.
FMF and HIDS are autosomal recessive diseases, all the other
members of the family are autosomal and dominantly transmitted.
Their common clinical features are recurrent and usually short
attacks of synovitis and various skin eruptions; abdominal
pain and fever are also frequently observed. The genes of
all of these diseases have been discovered and, with the exception
of HIDS, it was found that the proteins they encode share
certain domains taking part in innate immunity and apoptosis.
Thus it was evident that hereditary autoinflammatory diseases
may help us understand better a number of important and prevalent
pathologic events. We have reviewed the recent and rapidly
accumulating knowledge on the molecular aspects of these disorders.
[Back to top]
Behçet’s Disease as an Autoinflammatory Disorder
Ahmet Gul
[Full text
article]
Autoinflammatory diseases are a group of heritable disorders
that are characterized by seemingly unprovoked episodes of
inflammation at certain locations and and relative lack of
high-titer autoantibodies or antigen-specific T cells. Behcet’s
disease is an inflammatory disorder of unknown aetiology,
and many of its characteristic recurrent manifestations overlap
with those of autoinflammatory diseases. Behcet’s disease
has a complex genetic aetiology, and it is more prevalent
in certain geographic regions and/or in particular ethnic
groups. Enhanced inflammatory response and over-expression
of proinflammatory cytokines are the prominent features of
Behcet’s disease, and they are compatible with the findings
in other autoinflammatory disorders. There are also evidences
of antigen-driven immune response in Behcet’s disease,
but it possibly develops on the background of enhanced innate
immune reactivity. Delineation of the similarities of Behcet’s
disease to other hereditary autoinflammatory diseases may
help to clarify its pathogenesis and also to identify the
missing links in the shared inflammatory pathways.
[Back to top]
Oxidative Stress in the Molecular Mechanism of Pathogenesis
at Different Diseased States of Organism in Clinics and Experiment
Konstantin G. Karageuzyan
[Full text
article]
According to modern images and results of our observations
the oxidative stress (OS) is a non-specific though certain
component of pathogenesis at numerous diseased states of organism
having in the basis the thoroughness of pathogenic disturbances
of phospholipids (PL) metabolism and processes of their free
radical oxidation (FRO), which takes place in the membrane
formations of as the whole cell, as well as the mitochondrial
and microsomal fractions (MCF and MSF) of the white rat brain,
liver mitochondria, lung shadows, at the same time erythrocyte
and lymphocyte shadows at brain acute edema, ischemia, reperfusion
and desympathization, infarction of myocardium, tuberculosis
of lungs, diabetes, Familial Mediterranean Fever (FMF), intoxications
under halothane anaesthesia (HA) and with micotoxin zearalenon.
The regularities observed promote to understand from the point
of view of modern approaches the molecular mechanisms of initiation,
development and generalization of factors for OS formation
under pathologic conditions. It is more obvious at zearalenon
intoxication with intensification of lipids FRO processes
and failures in PL-PL ratio phenomena. The lymphocytes membranes
of the white rats spleen subjected OS induced by zearalenon
intoxication permit us conclude that the general immune status
of the organism decreases. It is generally peculiar to the
states under conditions of generalized intoxication. The observed
increase of phospholipase A2 activity induces the release
of high concentrations of lysophosphatidylcholines (LPC) and
non-etherified fatty acids (NEFA) of polyenic range with prevail
of arachidonic acid as a pathogenic factor, namely, at modelling
brain acute edema by tetraethylolovo to white rats. Formation
of the above mentioned disturbances to some extent depends
on hydrophobic properties of toxins, particularly, zearalenon.
The latter gives certain tropism to dopamine-b-monooxygenase
(DBM), and ability to stimulate functional activity of the
enzyme. Striking haemolytic properties of phospholipase A2
induced by existence of LPC and NEFA high concentrations,
and products of their peroxidation, promote elimination of
separate protein fractions of erythrocyte membranes (EM) responsible
for OS formation and decrease of erythrocytes resistance to
peroxide hemolysis.
Increase of DBM activity under the effect of relatively moderate
doses of zearalenon (1-15 µg/ml) is accompanied with
extra intensification of catecholamine synthesizing function
of the organism with lethal result.
Data of publications represented testify exceptional efficiency
of sodium thiosulfate (STS) as a powerful synergist for endogenous
factors of antioxidant effect, particularly a-tocopherol (a-T),
which is the main component for the system of cell antiradical
defence. Detoxicating effect of STS can be demonstrated indeed
on the example of zearalenon intoxication during the first
two hours with the reduction of metabolism disturbances of
PL and products of its peroxidation [1, 2]. Comparative evaluation
of molecular mechanisms of STS normalizing effect as a supplier
for hydrogen and sulphur ions, as well as an effective synergist
for a-T on the level of various formations of the live cell
in compare with the effects of a-T and ubiquinone [3-11],
allowed to make a special accent on the role of STS in interaction
with energy-dependent enzymatic systems of cell antiradical
defence, as well as accumulation and transformation of energy
on the level of mitochondrial membranes [12, 13]. The results
obtained by us confirm a number of clinical experimental observations,
which demonstrate treatment and prophylactic role of STS at
different pathologic states of the organism [14-25]. STS protectory
role at toxic injuries of the organism is higher at its preliminary
introduction to the organism before modelling of the studied
diseased states, especially at zearalenon and halothane (H)
intoxication (in the last case before HA). These data serve
a sound affirmation for protectory function of STS, detailed
revelation of molecular properties of pathogenesis of the
studied intoxication to which a part of our clinical and experimental
studies at present is devoted.
[Back to top]
The Role of Infections in the Pathogenesis of Autoimmune Diseases
Michael Samarkos and George Vaiopoulos
[Full text article]
The autoimmune diseases result from inappropriate responses
of the immune system to self antigens. The etiology of autoimmune
diseases remains largely unknown but candidate etiologic factors
include genetic abnormalities and infections. Although there
are considerable data supporting the role of infections in
a variety of autoimmune diseases, this role has been unequivocally
established in only a few autoimmune diseases. The difficulty
in establishing the infectious etiology of autoimmune diseases
stems from several factors such as the heterogeneity of clinical
manifestations in individual autoimmune diseases and the time
interval between infection and autoimmune disease. The data
on this association derive from clinical observations, epidemiological
studies and research using laboratory techniques, protein
sequence database screening and animal models.
Infectious agents can cause autoimmune diseases by different
mechanisms, which fall into two categories: antigen specific
in which pathogen products or elements have a central role
e.g. superantigens or epitope (molecular) mimicry, and antigen
non-specific in which the pathogen provides the appropriate
inflammatory setting for "bystander activation".
The most important mechanisms are molecular mimicry and superantigens.
As far as molecular mimicry is concerned the recent data on
the degeneracy of T cell recognition shifted the focus from
searching for linear sequence homology to looking for similarity
of antigenic surfaces. Special mention has to be made to retroviruses
as they have some unique means of inducing autoimmunity.
[Back to top]
MEFV Mutation Carriers and Diseases Other than Familial Mediterranean
Fever: Proved and Non-Proved Associations; Putative Biological
Advantage
Daniel Cattan
[Full text
article]
Vasculitis is definitely associated with familial Mediterranean
fever. This familial Mediterranean fever-associated vasculitis
takes one of three forms: polyarteritis nodosa, with or without
microscopic polyangiitis, and Henoch-Schonlein purpura. Behcet
disease and inflammatory bowel diseases may also be associated
with familial Mediterranean fever, though this is yet to be
formally proven.
The selective biological advantage, if any, for carriers
of simple heterozygotic mutations in the gene responsible
for familial Mediterranean fever, MEFV, is not known. Indirect
arguments are given for a better defense against certain groups
of bacterial pathogens and amongst intra-cellular bacteria,
Mycobacterium tuberculosis.
[Back to top]
Molecular Study of FMF Patients in Armenia
T. Sarkisian, H. Ajrapetyan and G. Shahsuvaryan
[Full text
article]
Familial Mediterranean Fever (FMF, MIM 249100), or Periodic
disease, is a recessively transmitted and ethnically restricted
condition prevalent in population from the Mediterranean decent.
FMF notoriously has been hard to diagnose until mutations
in the MEFV gene have been identified and as a tremendous
help are used for the diagnosis of difficult cases. Since
FMF can be controlled by medication, it is extremely desirable
to have a firm diagnosis. The aim of this study was to establish
the frequency of the most common mutations and genotypes in
Armenian population. Molecular analysis of MEFV gene mutations
in 3000 Armenian patients has demonstrated direct correlation
between the clinical severity and the molecular diagnostic
criteria of the disease, including the development of renal
amyloidosis with MEFV genotypes. MEFV genotyping performed
in the framework of a genetic counseling may reveal and identify
affected individuals in presymptomatic phase, providing the
possibility of a precocious start of the therapy.
[Back to top]
Pharmacological and Clinical Basis of Treatment of Familial
Mediterranean Fever (FMF) with Colchicine or Analogues: An
Update
C. Cerquaglia, M. Diaco, G. Nucera, M. La Regina,
M. Montalto and R. Manna
[Full text
article]
Familial Mediterranean Fever (FMF), an autosomal recessive
disorder, is characterised by recurrent attacks of fever and
serositis, lasting 24-72 hours.
Since 1972 colchicine has become the drug of choice for prophylaxis
against FMF attacks and amyloidosis FMF-associated.
Colchicine, an alkaloid neutral, is absorbed in the jejunum
and ileum. It metabolised by liver and only small amounts
are recovered unchanged in the urine. Really plasma half-life
is prolonged in patients with liver or renal failure.
Colchicine is able to prevent activation of neutrophils,
binding b-tubulin and making b-tubulin-colchicine complexes;
this way inhibits assembly of microtubules and mitotic spindle
formation; moreover its mode of action includes modulation
of chemokines, prostanoids production, inhibition of neutrophil
and endothelial cell adhesion molecules.
The minimal daily dose in adults is 1.0 mg/die, but in children
there is not a definite dose.
Since in vitro high dosages of colchicine stop mitosis, this
drug might interfere with male and female fertility and with
children growth, but, according to current guidelines and
because of rare side effects of the drug, FMF patients are
recommended to take colchicine.
Since colchicine treatment is often complicated by frequent
gastrointestinal side effects, by our experience, in order
to improve colchicine tolerance we recommend: lactose-free
diet and treatment of intestinal bacterial overgrowth and/or
Hp-infection, assessed by breath tests.
Since our data showed that 10-15% of FMF patients seem are
non-responders or intolerant to colchicine, today we are working
in the design of colchicine analogues which may have lesser
toxicities and a larger therapeutic window.
[Back to top]
Complement: An Inflammatory Pathway Fulfilling Multiple
Roles at the Interface of Innate Immunity and Development
D. Mastellos, A.E. Germenis, and J.D. Lambris
[Full text
article]
Complement has been long perceived as an innate immune system
that plays a pivotal role in the maintenance of host defense
against infectious agents and the propagation of pro-inflammatory
responses in the context of human disease. Complement activation
has been associated with the onset of acute inflammatory reactions
leading to complications such as acute graft rejection, local
tissue injury and multi-organ failure. However, recent studies
have indicated that various complement activation products
may exert a beneficial effect by contributing to critical
developmental and regenerative processes. Appreciating this
extraordinary ‘versatility’ of complement proteins
provides a framework for revisiting the design of effective
complement therapeutics. A balanced strategy will have to
consider limiting the detrimental proinflammatory effects
of complement while preserving those activities that promote
tissue repair and regeneration, cell survival and early development.
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