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1 discuss innate and acquired immunity and

In innate immunity, signaling is through germ-line receptors of limited repertoires that respond by pattern recognition of exogenous agents and antigens. The promptness of the response is a consequence of the availability of innate or natural immune cells that express their responding receptors before exposure to the stimulants. These receptors include the scavenger receptors discussed in this series by Greaves and Gordon 1 and the Toll-like receptors TLRs reviewed by Tobias and Curtiss 2.

They may also be present on natural killer NK cells, endothelial cells, and cells of the adaptive immune system. On the other hand, the adaptive immune system is composed of cells bearing rearranged cell surface receptors, generating an almost unlimited diversity of recognition response elements.

  • An enzyme secreted by macrophages that attacks the cell wall of some bacteria;
  • As its name suggests, the innate immune system consists of cells and proteins that are always present and ready to mobilize and fight microbes at the site of infection;
  • Oxidized LDL is regarded as a major neoantigen in atherogenesis and is probably the major source of the lipids that are stored in the macrophage foam cells;
  • Unit 5 dealt with innate immunity.

Bridging these two branches of the immune response are a number of cell types that have functional characteristics of both systems. These cells express immunoglobulins or T-cell receptors that have much more limited diversity than traditional B- and T-cells of the adaptive immune system. These cells are present at birth, having been selected during ontogeny, perhaps in response to apoptotic cells.

This characteristic allows them to respond promptly like an innate immune cell, for example to a mimic molecule such as the phosphatidylcholine of Streptococcus pneumoniae 3. B1 cells and the natural antibodies that they secrete will be discussed in detail in a forthcoming review by Binder and colleagues.

  1. The third major cell of the innate immune system that should be discussed is the NK cell. Similar to macrophages, there are several subclasses of dendritic cells that are differentiated by their TLR profiles.
  2. Let's first again briefly compare acquired and innate immunity.
  3. Glossary The innate and adaptive immune systems The immune system is the collection of cells, tissues and molecules that protects the body from numerous pathogenic microbes and toxins in our environment. An immunogen is an antigen that is recognized by the body as nonself and stimulates an adaptive immune response.

The former does so in some cases without the necessary involvement of major histocompatibility complex MHC molecules, whereas the invariant T cell receptor on NKT cells recognizes lipid antigens in the context of CD1, a MHC class I-related protein. Recent work has implicated these cells in atherosclerosis, which will be discussed in more detail in a forthcoming review by VanderLaan and Reardon.

The immune system as a whole represents a very complex interacting network that includes within it proinflammatory and anti-inflammatory mediators. The communication between the innate and adaptive immune systems involves cell-cell interactions in relation to antigen presentation or soluble molecules such as cytokines or chemokines.

  • Heterogeneity among innate immune cells is worthy of further consideration;
  • Several studies have suggested the reciprocal regulation of the lipid efflux pathway in macrophages and the inflammatory phenotype of these cells;
  • As you will see, each aspect differs with respect to how quickly it responds and for how long it responds to pathogens, its central effector cell types and its specificity for different classes of microbes;
  • There is much more heterogeneity among cells of both the innate and adaptive immune systems than was previously supposed;
  • In all, the innate immune system is thought to recognize approximately 103 of these microbial molecular patterns;
  • Much of the communication between the innate immune system and its adaptive immune partner relies on the presentation of an antigen.

These are not necessarily mutually exclusive interactions. The response to presented antigens is often a major basis for the stimulation of adaptive immune cells to produce cytokines. These interactions can result in either target cell activation or suppression.

Such networks of communication are likely at play between innate and adaptive immune systems or between components within each of these systems themselves.

  1. T-cell receptors TCRs of most T4-lymphocytes and T8-lymphocytes can only recognize peptide epitopes from protein antigens presented by the body's own cells by way of special molecules called MHC molecules Figure 4. Adaptive immunity thus harnesses innate immunity to destroy many microorganisms.
  2. The major cytokines implicated in atherosclerosis are produced by cells of both the adaptive and innate immune systems, acting upon one another in both a paracrine and an autocrine manner. Because all microbes, not just pathogenic microbes, possess PAMPs, pathogen-associated molecular patterns are sometimes referred to as microbe-associated molecular patterns or MAMPs.
  3. Finally, macrophages that express large numbers of scavenger receptors and become cholesteryl ester-loaded foam cells, and hence are highly involved in atherosclerosis, may no longer function as effective antigen-presenting cells.

For example, NK cells can lyse immature dendritic cells as well as positively regulate dendritic cell maturation 45. Furthermore, cross-talk between the innate and adaptive systems may be bidirectional.

The major cytokines implicated in atherosclerosis are produced by cells of both the adaptive and innate immune systems, acting upon one another in both a paracrine and an autocrine manner. IL-5 in particular mediates a link between adaptive and natural immunity 6and this will be discussed in detail in a forthcoming review by Binder et al. IL-10, which can be produced by T-cells, dendritic cells, and macrophages, inhibits IL-12 production and Th1-mediated inflammation.

The effects of cytokines on various target cells will be addressed in more detail in two forthcoming reviews in this series. Elaine Raines will discuss the smooth muscle and endothelial cell targets, and Alan Daugherty will focus on monocytes and other leukocytes.

Acknowledgments

Much of the communication between the innate immune system and its adaptive immune partner relies on the presentation of an antigen. Yet, the adaptive immune system is not required for the development of pronounced atherosclerosis 9. This places heavy emphasis on the role of the innate system in atherosclerosis.

  • There is much more heterogeneity among cells of both the innate and adaptive immune systems than was previously supposed;
  • There is also a complexity of communications between the elements of this network;
  • Among human NK cells, two distinct phenotypes can be distinguished on the basis of their cytotoxicity and cytokine production;
  • A phenomenon whereby antibodies bind to the surface of bacteria, viruses or other parasites, and increase their adherence and phagocytosis;
  • The innate immune response is activated by chemical properties of the antigen.

The innate immune system is generally thought to yield prompt, blunt responses to stimuli. However, the innate immune response may not be as blunt as once supposed, and within each major class of innate cells there is considerable specificity and heterogeneity. Heterogeneity among innate immune cells is worthy of further consideration. Because monocyte recruitment is central to the pathogenesis of this disease, the innate immune system is at the core of atherogenesis.

Not widely recognized is the difference between the resident macrophage, of which the Kupffer cell is an example, and the inflammatory macrophage, which is presumably the macrophage subtype involved in atherosclerosis 10.

Activation of macrophages in response to microbial stimuli, mediated by unique microbial plasma membrane molecules through TLRs or scavenger receptors, results in the production of type I interferons and the upregulation of costimulatory molecules. Although microbial infection may modulate atherogenesis, it is most likely that endogenous altered self ligands such as oxidized LDL play a more significant role in atherosclerosis.

Engagement of the TLR facilitates the antigen-presenting capability of the innately activated macrophages.

Introduction

Of interest is the recent observation that TLR2 is regulated by hemodynamic forces 11. A second class of activating molecules influencing the macrophage response are complement and antibodies via Fc receptorswhich also result in the secretion of a variety 1 discuss innate and acquired immunity and cytokine mediators 1 discuss innate and acquired immunity and inflammation. In this case, this is accompanied by an increased capacity for tissue repair, including collagen production.

Finally, macrophages that express large numbers of scavenger receptors and become cholesteryl ester-loaded foam cells, and hence are highly involved in atherosclerosis, may no longer function as effective antigen-presenting cells.

Each of these macrophage subsets can also be distinguished on the basis of its chemokine secretory profile 12. Whether these are separate macrophage lineages or represent a continuum of plastic cell lines is not clear.

This differential activation and polarization of the macrophage would be of interest not only with respect to early lesion development but also with respect to the evolution of the macrophage phenotype as the lesion progresses. For example, it has been suggested that the Th2 cytokines IL-4 and IL-13 and chemokines are more abundant in late atherosclerotic lesions 13. Such a cytokine profile may induce a macrophage that improves the stability of the plaque, although this interaction remains to be clearly demonstrated experimentally.

Given the important role of the macrophage in lesion formation, the possibility that its phenotype may evolve during lesion progression and thus have different roles at different stages of the lesion is an important area of future atherosclerosis research. In recent years, a new understanding has developed of the relationship between lipid metabolism in the artery wall, especially in macrophages, and inflammation. Oxidized LDL is regarded as a major neoantigen in atherogenesis and is probably the major source of the lipids that are stored in the macrophage foam cells.

Although the bulk of the lipid stored in foam cells is cholesteryl ester, it is likely that increased concentrations of lipid signaling molecules, such as unsaturated fatty acid and oxysterol, are also present.

These serve as ligands for the peroxisome proliferator-activated receptor PPAR and liver X receptor LXR families of nuclear hormone receptors, respectively 1415.

12.1: An Overview of Innate and Adaptive Immunity

Several studies have suggested the reciprocal regulation of the lipid efflux pathway in macrophages and the inflammatory phenotype of these cells.

Furthermore, LXR-dependent genes have been implicated in macrophage cell survival 20. This cross-talk does not require the participation of the adaptive immune system. Similar to macrophages, there are several subclasses of dendritic cells that are differentiated by their TLR profiles. The major subsets are the myeloid or classical dendritic cells and the plasmacytoid dendritic cells.

In responding to various microorganisms, dendritic cells produce different cytokine profiles: Classical dendritic cells are highly efficient antigen-presenting cells.

The origin of these dendritic cell subsets is not clear 23although each may have the capacity to program Th1 or Th2 development depending upon its TLR profile and the antigen dose to which it is exposed 24.

Like the subsets of macrophages, the dendritic cell subsets produce different profiles of chemokines. The dendritic cell has received relatively little attention in atherosclerosis research, although this is bound to change soon 2526 ; see VanderLaan and Reardon in this series. Recent studies also are notable for the interaction between lipid mediators and the behavior of dendritic cells in the atherosclerotic plaque 2526. The third major cell of the innate immune system that should be discussed is the NK cell.

It effect on atherosclerosis is modest see VanderLaan and Reardon in this series.

Bridging the innate and adaptive immune systems

The NK cells express some diversity in receptors, and their biological activity is probably the result of the repertoire of stimulatory and inhibitory cell surface receptors 4.

Among human NK cells, two distinct phenotypes can be distinguished on the basis of their cytotoxicity and cytokine production. The reported modest influence of NK cells on atherosclerosis may be related to the fact that the cytokine producers have the major effect on atherosclerosis but are only a small proportion of the total NK cell population 28.

In conclusion, this review has drawn attention to a limited aspect of the complexity of the immune network. There is much more heterogeneity among cells of both the innate and adaptive immune systems than was previously supposed.

There is also a complexity of communications between the elements of this network. This indicates that many opportunities remain for research to improve our understanding of these systems as they operate in the context of atherosclerosis.

Immunology Module >> Prologue

A more system-based approach may prove rewarding. The improved understanding will present many possibilities for therapeutic intervention in the process of atherosclerosis.

The author is grateful to Irena Dopter for her help in the preparation of the manuscript.