Current Pharmaceutical Design, Volume 10, No. 2, 2004
Contents
Autoimmunity
Executive
Editors: D. Stahl and W. Sibrowski
Functional Consequences of Immune Cell
Adhesion to Endothelial Cells
Pp.109-120
M.
Rosemblatt and Maria Rosa Bono
Control of Autoimmune Diseases by the B7-CD28
Family Molecules Pp.121-128
Sudarshan
Anand and Lieping Chen
Endothelial Expression of MHC Class II
Molecules in Autoimmune Disease
Pp.129-143
Carl
Turesson
Endothelial Chemokines in Autoimmune Disease Pp.145-154
Kent W. Christopherson II and Robert A. Hromas
Regulation of B Cell Activation by PECAM-1:
Implications for the Development of Autoimmune Disorders Pp.155-161
Mae-Xhum Wong and Denise E. Jackson
Modulation of PMN-Endothelial Cells
Interactions by Cyclic Nucleotides Pp.163-170
Yukio
Sato
Dendritic Cell Endothelium Interaction in
Autoimmunity Pp.171-181
C.L.
Schlichting, W.D. Schareck and M. Weis
Erythropoietin Withdrawal Leads to the
Destruction of Young Red Cells at the Endothelial-Macrophage Interface Pp.183-190
J.
Trial and L. Rice
Red Blood Cells as Modulators of T Cell
Growth and Survival
Pp.191-201
Fernando
A. Arosa, Carlos F. Pereira and Ana M.
Fonseca
Complement and Complement Regulatory Proteins
as Potential Molecular Targets for Vascular Diseases Pp.203-211
Juan Acosta, Xuebin Qin and Jose Halperin
Antibody-Mediated Endothelial Cell Damage Via
Nitric Oxide Pp.213-221
Y.S. Lin, C.F. Lin, H.Y. Lei, H.S. Liu, T.M. Yeh, S.H. Chen and C.C. Liu
Abstracts
[Back to top] Functional Consequences of Immune Cell Adhesion
to Endothelial Cells
M.
Rosemblatt and Maria Rosa Bono
Research regarding the interactions between the endothelium and immune
cells has undergone a significant expansion during the past decade. Major
shifts of emphasis have been the norm, from the production of a detail catalog
of the cell surface receptors and counter-receptors acting at the interface
between the vascular endothelium and circulating cells to a more mechanistic
account of leukocyte/endothelium interactions. The past five years has seen
new, groundbreaking developments in the field, with exiting studies aimed at
understanding the functional consequences of the direct contact of endothelial
cells and leukocytes. Based on early work to be discussed below, new data on
local chemokine production and cell-to-cell contacts, attempt to clarify the
physiopathological significance of these events. The exceptional anatomical
arrangement of endothelial cells insures a permanent contact of the endothelium
with leukocytes, an event likely to result in cellular signals originating from
direct cell contact or through the action of soluble factors produced by
endothelial cells or immune cells. As we will discuss, current evidence
supports the idea that endothelial cells present at vascular endothelium as
well as at specialized high endothelial venules, play not only a critical role
in the homing and recruitment of immune cells but that it can also influence
the outcome of the immune response. Additionally, new evidence clearly
corroborates the idea that B and T lymphocytes as well as NK cells can modulate
endothelial cell function.
[Back to top] Control of Autoimmune Diseases by the B7-CD28
Family Molecules
Sudarshan
Anand and Lieping Chen
The roles of B7-CD28 family molecules in the regulation of immune
responses have been intensively studied over the past decade. The findings
resulting from these studies not only broaden our understanding in the control
of immune responses at the molecular level, but also lead to identification of
molecular targets for future manipulation and potential treatment of human
diseases. There is convincing evidence that the B7-CD28 family molecules play
critical roles in the control of initiation, progression and pathogenesis of
autoimmune diseases, which is the focus of this review. Currently, five
molecular pathways within this family have been identified and each of them
appears to overlap but have distinct functions in the control of priming,
activation, maturation and amplification of cellular and humoral immune
responses. Rationale-based design of intervention, targeting on multiple
pathways should lead to new methods and approaches for management of autoimmune
diseases.
[Back to top] Endothelial Expression of MHC Class II
Molecules in Autoimmune Disease
Carl
Turesson
Major histocompatibility complex (MHC) class II molecules are
up-regulated on endothelial cells in human allografts, and are thought to be
involved in graft rejection. The MHC class II subtypes HLA-DR, DQ and DP
regulate T cell dependent immune responses, and aberrant expression could be
important in autoimmunity. Increased endothelial MHC class II expression has
been demonstrated in several autoimmune diseases, including myocarditis with dilated
cardiomyopathy, rheumatoid arthritis (RA) and systemic lupus erythematosus
(SLE). Recent data suggest that there is an association between endothelial
expression of MHC class II molecules and diffuse endothelial dysfunction, which
may be part of the explanation of the increased risk of cardiovascular disease
in patients with RA, SLE and other chronic inflammatory conditions. MHC class
II transcription is in part genetically determined. Cytokine induced
up-regulation of MHC class II molecules can be inhibited in vitro by
antioxidants and different drugs, such as cyclosporin and statins. Research on
the development of new treatments for systemic autoimmune diseases and
cardiovascular disease should include evaluation of effects on endothelial
activation, including MHC class II expression.
This review also discusses the genetic basis of MHC class II expression
and its implications for understanding MHC genotype associations with
autoimmune diseases. Recent studies of interactions between endothelial cells
and T cells are reviewed. Such interactions could be of major importance in the
pathogenesis of autoimmune and vascular diseases.
[Back to top] Endothelial Chemokines in Autoimmune Disease
Kent W. Christopherson II and Robert A. Hromas
Compelling evidence now exists supporting the involvement of chemokines
in the pathogenesis of autoimmune diseases. Examples of chemokines and
chemokine receptors being involved in mediating autoimmune disease exist for
rheumatoid arthritis, multiple sclerosis, allograft rejection, systemic lupus
erythematosus, psoriasis, atopic dermatitis, lichen planus, and
graft-versus-host-disease. Expression of chemokines by endothelial cells
appears to be an important step in the development of these diseases. Since
chemokines are small molecular weight molecules that act through Gprotein
coupled receptors, they make attractive drug targets. Several antagonists of
chemokine – chemokine receptor interactions have been used to successfully
alleviate some or all of the symptoms associated with many of these diseases in
animal models. Further investigation of the involvement of chemokines in the
pathogenesis or progression of autoimmune diseases may lead to practical
clinical advances in diagnosis, prognosis, and therapy of such diseases.
[Back to top] Regulation of B Cell Activation by PECAM-1:
Implications for the Development of Autoimmune Disorders
Mae-Xhum Wong and
Denise E. Jackson
Regulation of B-cell development and activation is imperative to the
myriad of activities that perpetuate humoral immunity. This T-cell dependent
immune mechanism often relies upon the maintenance of T-cell tolerance, such
that the maturity of the antigen-presentating cell, its function and molecular
mimicry are contributing factors. Recent findings have implicated the
involvement of the B-cell and their corresponding surface co-receptors in
regulating autoimmune disease. One candidate receptor, PECAM-1, has
demonstrated the ability to downregulate both B and T-cell signalling pathways.
The deletion of PECAM-1 in mice has led to a hyper-responsive B-cell phenotype
with abnormal Bcell development. Additionally, in vivo functional studies have
found that absence of PECAM-1 results in an increased susceptibility to
autoimmune disorders of encephalomyelitis and Type I hypersensitivity
reactions. Taken together, these findings indicate that PECAM-1 may have an
important role in maintaining B-cell tolerance and regulatory function in
preventing the onset of autoimmune disease. Elucidating the mechanisms of
PECAM-1 function in autoimmune disorders could facilitate development of novel
therapeutics.
[Back to top] Modulation of PMN-Endothelial Cells
Interactions by Cyclic Nucleotides
Yukio Sato
Polymorphonuclear leukocytes (PMN) interact with endothelial cells (EC)
under normal and diseased conditions. Common mechanisms exist regulating PMN-EC
interactions in the systemic and pulmonary circulations and adhesion molecules
play significant roles in both circulations, however there are important
differences. Alterations in PMN deformability appear to be important in the
pulmonary circulation because of the unique geometric and hydrodynamic
conditions that exist in the pulmonary microvasculature. PMN work as the host’s
first line of defense against invading pathogens. Under certain circumstances,
however, dysregulation of PMN-EC interactions may contribute to local or global
tissue injury in diseases such as acute respiratory syndrome and multiple organ
failure syndrome. Therefore, a thorough understanding of the regulation of
PMN-EC interactions is important to understand the pathogenesis of this type of
tissue injury, and modulation of PMN-EC interactions could be applicable to prevent
or treat injury. cGMP and cAMP are cyclic nucleotides that work as second
messengers and control numerous functions in PMN. This review covers the
modulation of PMN-EC interactions with cGMP and cAMP. Recent studies have shown
that both cGMP and cAMP have inhibitory effects on events such as rolling,
adhesion, migration and deformability change of PMN that are essential to
PMN-EC interactions. Therefore, it is expected that the modulation of cyclic
nucleotides is applicable for the treatment not only of local inflammatory
diseases such as asthma but also of global tissue injury such as acute
respiratory distress syndrome.
[Back to top] Dendritic Cell Endothelium Interaction in Autoimmunity
C.L. Schlichting, W.D. Schareck and M. Weis
Monocyte derived dendritic cells play a central role in controlling
immunity by activating naïve T lymphocytes. Monocytes can leave the blood
stream by endothelial cell transmigration and differentiation into dendritic
cells. A fundamental aspect of dendritic cell biology is their capacity to
engulf tissue antigens and revers-migrate into lymph nodes. In lymph nodes
dendritic cells can traffic to T-cell areas where they activate naïve T-cells.
Throughout this review we are developing a model of in vivo activation of
auto-reactive T-cells by activated dendritic cells.
[Back to top] Erythropoietin Withdrawal Leads to the Destruction of Young Red Cells
at the Endothelial-Macrophage Interface
J. Trial and L.
Rice
Erythropoietin is a growth factor for endothelial cells as well as for
erythroid cells. In contrast to their proliferative response to physiological
levels of erythropoietin, endothelial cells may respond to decreased levels by
triggering a process called neocytolysis. Neocytolysis is the selective
destruction of the youngest circulating red cells, which may be prompted by
endothelial cells communicating with macrophages to stimulate phagocytosis of
this unusual cell subset. We speculate that this is due to decreased production
by endothelial cells of the macrophage-deactivating transforming growth
factor-ß. The resulting proinflammatory phenotype may include macrophage
production of thrombospondin, which forms bridges between adhesion molecules
selectively expressed on young red cells (CD36) and the CD36/avß3 complex on
macrophages that triggers phagocytosis. Alternatively, inflammatory mediators
secreted by endothelial cells and macrophages during erythropoietin withdrawal
may signal young red cells to expose phosphatidylserine, which would mark them
for elimination via the normal pathway for aged red cell destruction.
Neocytolysis has been demonstrated in returning astronauts and in polycythemic
individuals at high altitude on descent to sea level. It contributes to the
anemia of renal disease, is triggered by the rapidly falling levels of
erythropoietin seen after intravenous administration, and may be the normal
mechanism for reduction of red cell mass in newborns. It may play a role in
chronic diseases including malaria and sickle cell anemia. New erythropoietin
products and methods of administration avoid the intermittent rapid decreases
associated with the stimulus for neocytolysis, but study of this phenomenon may
yield further improvements in drug design.
[Back to top] Red Blood Cells as Modulators of T Cell Growth and Survival
Fernando A. Arosa, Carlos F. Pereira and Ana M. Fonseca
T cell homeostasis is largely controlled by a balance between cell
death and survival and anomalies in either process account for a number of
diseases linked to excessive or faulty T cell growth. Yet, the influence that
cells outside the immunological system have on these processes has only
recently received attention. Accumulated evidence indicate that homeostasis of
the CD4+ and CD8+ T cell pools is highly dynamic and regulated by signals
delivered by cells and molecules present in the different internal
microenvironments. The major function of red blood cells (RBC) is generally
considered to be oxygen and carbon dioxide transport. In recent years, however,
RBC have been implicated in the regulation of basic physiological processes,
from vascular contraction and platelet aggregation to T cell growth and
survival. Regulation of T cell survival by RBC may influence the response of
selected subsets of T cells to internal or external stimuli and may help
explaining the immunomodulatory activities of red blood cells. By interfering
in the balance between death and survival RBC become potential tools that can
be manipulated to improve or reverse pathological situations characterized by
anomalies in the control of T cell growth.
[Back to top] Complement and Complement Regulatory Proteins as Potential Molecular
Targets for Vascular Diseases
Juan Acosta, Xuebin Qin
and Jose Halperin
By-products of complement activation and complement regulatory proteins
are increasingly recognized to play an important pathogenic role in a variety
of vascular diseases including atherosclerosis, ischemia and reperfusion
injury, hyperacute graft rejection, vasculitis, and the vascular complications
of human diabetes. “Self” damage by autologous complement is mediated by
activation products of the complement cascades or by direct insertion of the
membrane attack complex (MAC) into cell membranes. Specifically, insertion of
MAC complexes into endothelial cells results in the release of an array of
growth factors and cytokines that induces proliferation, inflammation and
thrombosis in the vascular wall. This paper reviews complement and complement
regulatory proteins with specific focus on the vasculature and vascular
diseases; it highlights complement and its regulators as potential targets for
the rational design of mechanismspecific drugs for the treatment of some of the
most prevalent human diseases.
[Back to top] Antibody-Mediated Endothelial Cell Damage Via Nitric Oxide
Y.S. Lin, C.F. Lin, H.Y. Lei, H.S. Liu, T.M. Yeh, S.H.
Chen and C.C. Liu
Vascular disorders, resulting from endothelial cell dysfunction, may be
caused by various stimuli, including infectious pathogens, cytotoxic reagents,
and pathophysiological mechanisms mediated by immune responses. Endothelial
cell dysfunction characterized by apoptosis and abnormal immune activation is,
at least in part, induced by antiendothelial cell antibody (AECA) in some cases
of autoimmune disease. However, the molecular mechanisms of AECAmediated
pathogenetic damage to host vascular system remain unclear. The dual role of
nitric oxide (NO) both in endothelial cell apoptosis and survival has been
described. In this paper, endothelial cell apoptosis caused by the presence of
cross-reactive AECA via a NO-mediated mechanism is demonstrated in dengue virus
infection. Endothelial cells undergo apoptosis via the mitochondria-dependent
pathway that is regulated by NO production. NO-regulated endothelial cell
injury thus may play a role in the disruption of vessel endothelium and
contribute to the AECA-induced pathogenesis of vasculopathy. The modulation of
NO may provide the therapeutic strategies for autoimmune diseases by preventing
the AECA-mediated endothelial cell damage.