Here, we discuss the modulation of inflammation upon pathogen invasion, including the new pathway triggered by lipoxin involved in the repression of immune response during infection, as well as this mechanism from the perspective of the pathogen, which pirates the host's lipoxygenase machinery to its own advantage as a probable immune-escape mechanism.

INNATE IMMUNITY AND PATHOGENS

It is well known that a series of pattern-recognition receptors is involved in the recognition of different microbial pathogens and induction of the innate response. Such receptors recognize distinct biochemical patterns of molecules displayed by the invading pathogen. The repertoire of innate immune receptors is very broad and includes several classes of germ-line–encoded proteins such as Toll-like receptors (TLRs), scavenger receptors, and C-type lectins. This wide array of recognition molecules allows the host to detect a variety of microbial molecules including carbohydrates, lipids, nucleic acids, and proteins [1, 2]. Distinct TLR ligands provide distinct activation status and cytokine production patterns for antigen-presenting cells (APCs), resulting in the induction of differential immune responses. Thus, TLRs are critical molecules to induce not only inflammatory responses but also fine-tune adaptive immune responses depending on invading pathogens [3]. TLRs activation can upregulate costimulatory molecules on APC, thus enhancing the activation of adaptive T-cell responses.

THE INNATE AND ADAPTIVE IMMUNE SYSTEMS: DEFINITIONS, CONTEXT, AND CONTRASTS

Standard accounts of the immune system emphasize the antigen-specific immunity and memory afforded by the adaptive immune system, contrasting it with the “nonspecific” defenses provided by the phylogenetically more ancient innate immune system. While study of the innate immune system has undergone a recent renaissance, most immunology textbooks still present innate immunity as an initial stopgap defense that holds the line until the “real” (efficient, effective, sophisticated) adaptive immune system can take over. There are obvious flaws in such formulations. First, while adaptive immunity may usefully be seen as a single system – with its cells (B and T lymphocytes) and antigen receptors (immunoglobulins [Ig], T-cell receptors) depending directly on the evolution of the recombination-activating gene (RAG) in jawed vertebrates – innate immunity, present in all metazoans, is a congeries of pathways. “Innate immune systems” is a much better term. Second, the innate immune systems are in no way less sophisticated than the adaptive immune system, having been under evolutionary pressure for far longer. Third, the innate immune systems are not of secondary importance; the adaptive immune system is directly dependent on the former for efficient and appropriate activation. Fourth, innate immune effector mechanisms are not less effective than adaptive immune effector mechanisms.

INTRODUCTION

Neutrophils (polymorphonuclear leukocytes, PMN) have a clearly defined role in inflammation. In response to injury or infection, PMN migration across vascular endothelial cells is a first line of defense against infectious agents, and defects in such PMN–endothelial interactions contributes to fulminate microbial infections, mucosal ulcerations, and delayed tissue healing. The protective aspects of PMN in disease are objectively exemplified by the clinical observation that patients with primary defects in PMN function, including neutropenia and genetic PMN immunopathologies (e.g., leukocyte adhesion deficiencies, chronic granulomatous disease, Chediak–Higashi syndrome, myeloperoxidase deficiency, etc.), exhibit ongoing mucosal infections.

This chapter focuses on our current understanding of how PMN interact with vascular endothelial cells under physiologic and pathophysiologic conditions (Figure 11.1).

MOLECULAR MECHANISMS OF PMN ADHESION AND TRANSMIGRATION

PMN migration across the endothelial surface is a result of an orchestrated series of events, ultimately resulting in PMN accumulation at sites of tissue injury. The recruitment signals, the cell–cell interaction steps, and the regulatory pathways for these events have been an area of extensive exploration in the past two decades. A number of recent reviews have addressed these steps in detail [1 –4]. Here, we will summarize some of the major steps and guide the reader to the primary literature for more insight into this dynamic process.

INTRODUCTION

The oral cavity is a complex organ system composed of salivary glands, tongue, tonsils, and teeth. The tissues of the oral cavity are either mineralized-hard (e.g., enamel, dentin, cementum, and bone) or soft tissues (e.g., mucosa, periodontal ligament, and gingiva), which altogether maintain a complex system of function and esthetics. The oral cavity is the entrance to and a major component of the gastrointestinal tract as the first site in the body to break down the food due to its masticatory function; it is also the gateway for respiration. Oral systems are crucial for proper phonation; the alignment of the teeth affects how words are pronounced. Facial esthetics is also directly associated with the shapes of the teeth and soft tissues surrounding them. With this unique blend of components and functions, the health and the disease of the oral cavity, therefore, present an important area of research as well as a challenge to the maintenance of general health. As in many diseases common to humankind, oral pathologies are associated with alterations in tissue homeostasis. Oral pathological conditions and diseases have been recognized as important health problems since the dawn of the early civilizations. For example, golden toothpicks found in Mesopotamia have indicated that Sumerians were practicing oral hygiene as early as 3000 B.C. Various herbal medications were used by Babylonians and Assyrians to “treat” periodontal problems. Egyptians, Chinese, and Indians all have written documentation of treating dental and periodontal inflammation, ulcerations, and abscesses.

Metabolic stress, hypoxia, and cell damage cause adenosine to accumulate in the extracellular space, and increases in extracellular adenosine levels are observed in hypoxia, ischemia, inflammation, and trauma [1, 2]. Extracellular adenosine levels accumulate following the release of adenosine from cells or as a consequence of extracellular degradation of released ATP and ADP. Intracellular adenosine, which can originate from increased intracellular metabolism of ATP during cellular stress or S-adenosyl homocysteine, is released through equilibrative nucleoside transporters ENT1 and ENT2. Extracellular ATP and ADP are catabolized by a cascade of ectoenzymes which consists of CD39 (ENTPD1 [ectonucleoside triphosphate diphosphohydrolase-1]), an enzyme that hydrolyzes ATP and ADP to AMP, and CD73 (ecto-5'nucleotidase), which in turn, rapidly dephosphorylates AMP to adenosine [3]. Owing to the widespread expression of equilibrative nucleoside transporters, adenosine derived from extracellular ATP is rapidly recycled from the extracellular space by uptake into cells. Adenosine in the cytosol is then either phosphorylated by adenosine kinase to AMP or metabolized by adenosine deaminase to inosine [4, 5]. As a net result of these various metabolic processes, adenosine levels in the extracellular space are maintained in a range of 10–200 nM in normal, healthy tissues. In contrast, under pathophysiological conditions adenosine is generated at a rate that is higher than the rate of degradation leading to markedly increased extracellular adenosine levels that can range between 10 and 100 μM.

IMPORTANCE OF STUDYING CELL TRAFFICKING IN VIVO

The innate response has long been compartmentalized into several facets traditionally termed redness, heat, pain, and edema. Inflammatory insults induce release of a plethora of tightly regulated intra- and extracellular mediators, rapidly modulating the local microenvironment. The initial “humoral” response is largely a nongenomic reaction conducted by constitutive proteins and metabolic products released by resident cells (depending on the site of insult), for example, histamine, tumor necrosis factor alpha (TNF-α), and metabolites of the arachidonic acid cascade. These nonspecific or “classical” signals concurrently increasing vascular dilation, permeability, and blood flow to allow the exudation of fluid and protein. Consequentially, a variety of systemic mediators, cytokines, chemokine, and centrally acting molecules are produced to orchestrate cellular infiltration, local activation of blood-borne cells, and dispose of the inflammogen; ultimately, resolution of inflammation occurs in a time-dependent and space-regulated fashion, resulting in restoration of tissue integrity. When these symptoms persist, through deregulation or repeated insult, chronic inflammatory conditions (such as rheumatoid arthritis [RA]) can occur resulting in loss of function locally as well as effecting systemic pathology.

Among this multitude of molecular and cellular processes, migration of blood white cells to the site of inflammation is central to the overall response orchestrated by the host.

Lymphocytes are a type of white blood cell or leukocyte and are critical for the defense of the body against invaders such as infectious pathogens and foreign materials. There are approximately 1012 lymphocytes in the average human body, though this fluctuates considerably during illness. Indeed, fluctuation from a normal range is used as an indicator of disease. For example, immune deficiency leads to reduced lymphocyte numbers in the blood whereas infection or allergy leads to an increase. Several different types of lymphocyte exist, and though they display highly specialized and diverse functions, they all derive from a common hematopoietic stem cell in the bone marrow (Figure 9.1). Mature lymphocytes are found throughout the body: in the blood and lymphatic system; concentrated in immune specialized regions (lymph nodes, thymus, spleen, and Peyer's patches); and scattered in most other tissues.

Lymphocytes can be divided on the basis of size and granularity. Natural killer (NK) cells are large and highly granular, and there are two main types of small lymphocyte: B lymphocytes (or B cells) and T lymphocytes (or T cells). As we will see in this chapter, these are further subdivided based on their expression of different surface molecules, their secretion of different products important for immunity, and their ultimate effector function. B cells (so-called because they were originally identified in birds in the Bursa of Fabricius) are not only produced in the bone marrow but also mature there. However, the precursors of T cells leave the bone marrow and mature in the thymus (which explains the notation “T”).

The term atheroma, derived from Greek and meaning “porridge,” was first proposed by Albrecht von Haller in 1755 to label the degenerative process observed in the intima of arteries. London surgeon Joseph Hodgson (1788–1869) published in 1815 his Treatise on the Diseases of Arteries and Veins in which he claimed that inflammation was the underlying cause of atheromatous arteries. Atherosclerosis is now widely appreciated as an inflammatory disease involving the vascular wall. Histologically, the lipid-laden foam cells of the fatty streak, which characterize the plaque at an early stage, are derived from macrophages. In time, the lipid/necrotic core is covered with fibrous tissue composed mainly of α-actin positive smooth muscle cells, and thus forms the fibrolipid plaque. Large amounts of T lymphocytes are found surrounding the plaque and in the fibrous cap, pointing to a role for the body's immune system in atherosclerosis.

Advanced complex atheromata that set the stage for overt clinical events in atherosclerosis are preceded by less complex lesions. The factors that enable some lesions to progress while others regress remain unclear. It is clear, however, that lack of regression is associated with persistent inflammation in the vascular wall. Most studies to date rely heavily on animal models to define mechanistic pathways [1, 2].