Current Pharmaceutical Design - Volume 10, Issue 2, 2004

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.

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.

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.

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.

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.

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.

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.

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 / αvß3 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.

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.

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.

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.