CARDIOVASCULAR disease remains the chief cause of death in the United States and Western Europe, and atherosclerosis, the principal cause of myocardial and cerebral infarction, accounts for the majority of these deaths.1 This review, like its predecessor,2 will not attempt to cover all literature on atherosclerosis. In a previous review of the pathogenesis of atherosclerosis,2 Glomset and I discussed various hypotheses of atherogenesis2 3 4 5 6 7 and emphasized the importance of intimal smooth-muscle proliferation as the key event in the development of the advanced lesions of atherosclerosis. The response-to-injury hypothesis of atherogenesis2 3 4 5 6 proposes that "injury" to the endothelium is the initiating event in . . .

The Pathogenesis of Atherosclerosis — An Update

The class I histocompatibility antigen from human cell membranes has two structural motifs: the membrane-proximal end of the glycoprotein contains two domains with immunoglobulin-folds that are paired in a novel manner, and the region distal from the membrane is a platform of eight antiparallel beta-strands topped by alpha-helices. A large groove between the alpha-helices provides a binding site for processed foreign antigens. An unknown 'antigen' is found in this site in crystals of purified HLA-A2.

Structure of the human class I histocompatibility antigen, HLA-A2.

Chemokines constitute a family of chemoattractant cytokines and are subdivided into four families on the basis of the number and spacing of the conserved cysteine residues in the N-terminus of the protein. Chemokines play a major role in selectively recruiting monocytes, neutrophils, and lymphocytes, as well as in inducing chemotaxis through the activation of G-protein-coupled receptors. Monocyte chemoattractant protein-1 (MCP-1/CCL2) is one of the key chemokines that regulate migration and infiltration of monocytes/macrophages. Both CCL2 and its receptor CCR2 have been demonstrated to be induced and involved in various diseases. Migration of monocytes from the blood stream across the vascular endothelium is required for routine immunological surveillance of tissues, as well as in response to inflammation. This review will discuss these biological processes and the structure and function of CCL2.

Monocyte chemoattractant protein-1 (MCP-1): an overview.

The four distinct T-cell antigen receptor polypeptides (alpha, beta, gamma, delta) form two different heterodimers (alpha:beta and gamma:delta) that are very similar to immunoglobulins in primary sequence, gene organization and modes of rearrangement. Whereas antibodies have both soluble and membrane forms that can bind to antigens alone, T-cell receptors exist only on cell surfaces and recognize antigen fragments only when they are embedded in major histocompatibility complex (MHC) molecules. Patterns of diversity in T-cell receptor genes together with structural features of immunoglobulin and MHC molecules suggest a model for how this recognition might occur. This view of T-cell recognition has implications for how the receptors might be selected in the thymus and how they (and immunoglobulins) may have arisen during evolution.

T-cell antigen receptor genes and T-cell recognition.

Infusion of different hematopoietic stem cell populations and ex vivo expanded endothelial progenitor cells augments neovascularization of tissue after ischemia and contributes to reendothelialization after endothelial injury, thereby, providing a novel therapeutic option. However, controversy exists with respect to the identification and the origin of endothelial progenitor cells. Overall, there is consensus that endothelial progenitor cells can derive from the bone marrow and that CD133/VEGFR2 cells represent a population with endothelial progenitor capacity. However, increasing evidence suggests that there are additional bone marrow-derived cell populations (eg, myeloid cells, “side population” cells, and mesenchymal cells) and non-bone marrow-derived cells, which also can give rise to endothelial cells. The characterization of the different progenitor cell populations and their functional properties are discussed. Mobilization and endothelial progenitor cell-mediated neovascularization is critically regulated. Stimulatory (eg, statins and exercise) or inhibitory factors (risk factors for coronary artery disease) modulate progenitor cell levels and, thereby, affect the vascular repair capacity. Moreover, recruitment and incorporation of endothelial progenitor cells requires a coordinated sequence of multistep adhesive and signaling events including adhesion and migration (eg, by integrins), chemoattraction (eg, by SDF-1/CXCR4), and finally the differentiation to endothelial cells. This review summarizes the mechanisms regulating endothelial progenitor cell-mediated neovascularization and reendothelialization.

This Review is part of a thematic series on Angiogenesis, which includes the following articles: Endothelial Progenitor Cells: Characterization and Role in Vascular Biology Bone Marrow–Derived Cells for Enhancing Collateral Development: Mechanisms, Animal Data, and Initial Clinical Experiences Arteriogenesis Innate Immunity and Angiogenesis Syndecans Growth Factors and Blood Vessels: Differentiation and Maturation Ralph Kelly Guest Editor

Endothelial Progenitor Cells: Characterization and Role in Vascular Biology

Most cellular interactions essential for the development of an immune response involve the membrane glycoproteins encoded in the major histocompatibility gene complex. The products of the I region, the class II histocompatibility molecules (Ia molecules), are essential for accessory cells such as macrophages to present polypeptide antigens to helper T cells. This interaction, antigen presentation, is needed for T-cell recognition of the antigen and its consequent activation. How the Ia molecules regulate the immune response during antigen presentation is not known, although it is commonly thought to result from their association with the presented antigen. Recent studies, including the elucidation of the structure of the T-cell receptor, favour recognition of a single structure, an antigen-Ia complex. Here we report attempts to determine whether purified Ia glycoproteins have an affinity for polypeptide antigens presented by intact cells in an Ia-restricted manner. We first identified the epitope of a peptide antigen involved in presentation. Several laboratories have shown that globular proteins are altered (processed) in intracellular vesicles of the antigen-presenting cell before antigen presentation. A major component of the T-cell response is directed toward determinants found in the unfolded or denatured molecule, and our laboratory has shown that the determinant of the hen-egg lysozyme protein (HEL), presented in H-2k mice to T cells, is a sequence of only 10 amino acids. This portion resides in an area of the native molecule partially buried inside the molecule, in a beta-sheet conformation. To be presented, intact or native HEL must first be processed in acidic intracellular vesicles. Having isolated the peptide responsible for T-cell recognition of HEL, we sought a physical association of this peptide with purified, detergent-solubilized I-Ak molecules from B-hybridoma cells. We have found such an association, which may explain the role of the Ia glycoproteins in cellular interactions.

Binding of immunogenic peptides to Ia histocompatibility molecules

MICROVASCULAR proliferation is essential to many biological processes, such as wound healing, but the mechanisms underlying this vascular response are poorly understood1. Neovascularisation can be induced by extracts from various cell types, including malignant solid tumour cells2, normal and viral-transformed (SV40) BALB/c 3T3 cells, and diploid human embryonic lung fibroblasts3, and neutrophils4. Extracts of mouse salivary gland5 and skin6 have been reported to induce vascular growth, but the relevance of these observations to the vascular proliferation that occurs in wound healing and chronic inflammation is unclear. Neovascularisation is also an important component of immunological reactions. Sidky and Auerbach reported increased vessel density in the skin during graft-versus-host reactions and attributed it to the lymphocyte7. Herman and associates8 and Anderson et al.9 found an increase in capillary density, and extensive proliferation of postcapillary venular endothelium, respectively, in lymph nodes undergoing strong immunological reactions. We have shown significant endothelial proliferation in delayed hypersensitivity reactions in the skin of guinea pigs at the time of maximal mononuclear cell infiltration10 and so we have investigated whether macrophages, an important component of immunological and non-immunological inflammatory reactions, might be involved in this vascular response. We report here that macrophages activated in vivo and in vitro, and media conditioned by these cells, induce vascular proliferation in the guinea pig cornea.

Activated macrophages induce vascular proliferation

Publisher Summary This chapter focuses on the role of the macrophage in removing antigen from extracellular fluids, degrading the larger part of this antigen while presenting a small part of it in persisting immunogenic form. This handling of antigen is done without contributing to the specificity of the immune response, which is determined by the antigenreactive T and B lymphocytes. During the process of uptake of antigen, macrophages appear to retain a few molecules of antigen, undegraded or with few chemical changes. Macrophage-associated antigen becomes an effective immunogenic stimulus mainly in conditions that require two types of lymphocytes to meet with antigen molecules. These lymphocytes are specifically antigen-committed and few in number. The positive immunogenic role of macrophages is related to their capacity to (1) remove extracellular antigen, which might be capable of interacting with and eliminating isolated T or B lymphocytes and (2) retain antigen in lymphoid tissues and promote its necessary meeting with both T and B cells.

The regulatory role of macrophages in antigenic stimulation.

Prostaglandins are important modulators of inflammation and of humoral and cellular immune responses1–8. In order to evaluate a possible mechanism for the regulation of immune responses we have studied the effects of prostaglandins on the expression of I-region-associated (Ia) antigens by macrophages. The expression of these glycoproteins is essential for macrophages to function as antigen-presenting cells during the induction of immune responses9. The synthesis and membrane expression of Ia, however, is not a constitutive property of the phagocyte10 but is under regulation and a positive regulation of this process is exhibited by activated T cells11. In contrast, a negative regulation is conspicuously found in the neonate where a product from a young replicating macrophage inhibits the expression of Ia by the mature macrophages12. We show here that prostaglandins of the E series (PGE) are potent inhibitors of the expression of Ia-antigens on macrophages and that thromboxane B2 (TXB2) antagonizes the effect of PGE.

Prostaglandins modulate macrophage ia expression.

Publisher Summary Changes in antigen molecules that resulted in enhanced or decreased uptake by the phagocytes resulted in higher or lower immune responses, respectively. After the development of methodologies for obtaining live exudate cells rich in phagocytes and for pulsing these with antigen, the immune response to macrophage-associated antigens was possible to assay, using combinations of in vivo and in vitro methods. The presentation of antigen bound to live macrophages to the lymphocytes was a highly efficient mode of generating an immune response. In the marine system, the requirement for phagocytes or other acc|essory cells was such that as little as 1% contamination with phagocytes still enabled a T-cell proliferative response to develop. Thus, depletion procedures had to be extremely efficient. Macrophages are definitely involved in some response to many of the conventional polyclonal stimuli. Involvement of the macrophage may be by way of secreted active molecule. Fc fragments of Ig act as a polyclonal stimulant only after a processing of the fragment by the macrophages. The developments in macrophage biology over the past few years were not predicted till 1972.

Emil R. Unanue

Papers

Binding of immunogenic peptides to Ia histocompatibility molecules

Activated macrophages induce vascular proliferation

The regulatory role of macrophages in antigenic stimulation.

Prostaglandins modulate macrophage ia expression.

The regulatory role of macrophages in antigenic stimulation. Part Two: symbiotic relationship between lymphocytes and macrophages.