CHAPTER 4 Innate Immunity

A macrophage (yellow) binds and phagocytoses E. coli bacteria (red).

Learning Objectives

After reading this chapter, you should be able to:

1. Identify and describe the components and characteristics of the two lines of defense that comprise the innate immune system.
2. Categorize the pattern recognition receptors in terms of the types of pathogen components that they bind, the basic mechanisms by which they stimulate responses, and the types of protective responses that result.
3. Describe effector mechanisms used by the innate immune system, the cells and molecules involved in each mechanism, and the type of pathogen destroyed by each mechanism.
4. Explain why the innate immune system is so highly regulated, with many types of both positive and negative regulation of responses.
5. Connect elements of the innate and adaptive immune systems and describe how innate responses help to ensure that an effective adaptive immune response is generated for a specific pathogen.

Key Terms

• Physical barriers
• Chemical barriers
• Cellular innate immune responses
• Phagocytosis
• Inflammation
• Antimicrobial proteins and peptides
• Defensins
• Cathelicidin
• Pattern recognition receptors (PRRs)
• Pathogen-associated molecular patterns (PAMPs)
• Damage-associated molecular patterns (DAMPs)
• Toll-like receptors (TLRs)
• C-type lectin receptors (CLRs)
• NOD-like receptors (NLRs)
• Autophagy
• Inflammasomes
• Pyroptosis
• AIM2-like receptors (ALRs)
• RIG-I-like receptors (RLRs)
• cGAS
• STING
• Type I interferons
• Opsonins
• Reactive oxygen species (ROS) and reactive nitrogen species (RNS)
• Regulated cell death
• Innate lymphoid cells (ILCs)
• Sepsis
• Adjuvants

Vertebrates are protected by both innate immunity and adaptive immunity. In contrast to adaptive immune responses, which take days to arise following exposure to antigens, innate immunity consists of the defenses against infection that are ready for immediate action or are quickly induced when a host is attacked by a pathogen (viruses, bacteria, fungi, or parasites; see Table 1-3). The innate immune system includes anatomical barriers against infection—both physical and chemical—as well as cellular responses (Overview Figure 4-1). The main physical barriers—the body’s first line of defense—are the epithelial layers of the skin and of the mucosal and glandular tissue surfaces connected to the body’s openings; these epithelial barriers prevent infection by blocking pathogens from entering the body. Chemical barriers at these surfaces include specialized soluble substances that possess antimicrobial activity as well as acid pH.

OVERVIEW FIGURE 4-1

Innate Immunity

Key elements of innate immunity include the physical and chemical barriers that prevent infection, provided by the epithelial cell layers of the skin, mucosal tissues (e.g., gastrointestinal, respiratory, and urogenital tracts), and glandular tissues (e.g., salivary, lacrimal, and mammary glands). These barriers constitute the innate immune system’s first line of defense. Once pathogens enter the body, such as through a breach in an epithelial layer, they are confronted by the second line of defense, an array of cells with cell surface and intracellular receptors that recognize pathogen components and trigger a variety of cellular responses. Pathogen recognition by these receptors activates some cells to phagocytose and degrade the pathogen, and many cells are activated through their receptors to produce a variety of antimicrobial substances that kill pathogens, as well as cytokine and chemokine proteins that recruit cells, molecules, and fluid to the site of infection, leading to swelling and other symptoms collectively known as inflammation. Innate lymphoid cells (ILCs) are activated by soluble mediators from nearby cells to also produce cytokines and chemokines. One type of ILC, the natural killer (NK) cell, recognizes and kills some virus-infected cells. Cytokines and chemokines can cause systemic effects that help to eliminate an infection, and also contribute—along with dendritic cells that carry and present pathogens to lymphocytes—to the activation of adaptive immune responses, the third line of defense in vertebrates. See Figure 1-7 for how these processes are integrated within the entire immune system.

The events in innate immunity are enlarged from the immune response scheme diagram. It shows a sequence of three defense mechanisms: physical and chemical barriers to infection, cellular responses to infection, and activation of adaptive immune responses. The first line of defense shows the epithelial layers of skin, mucosal tissues, and glandular tissues as a vertical arrangement of cells. A layer of acidic pH and antimicrobial proteins and peptides, represented by red and green dots and H superscript plus ions, cover the epithelial layers. Pathogens enter the body through a break in the epithelial layer cells and encounter the cells that form the second line of innate immunity defense. Once the pathogen binds to these cells, pathogen elimination occurs is several ways. In some cells, phagocytosis and degradation leads to pathogen elimination. In some cells, cell activation produces antimicrobial substances that eliminate pathogens. In some cells, cell activation produces cytokines and chemokines that cause inflammation which eliminates pathogens. If the pathogen infects a cell, the infected cell is killed by a natural killer cell, leading to pathogen elimination. Macrophage and dendritic cells engulf the pathogens and carry them to the lymph nodes (kidney-shaped). These cells along with cytokines and chemokines activate adaptive immunity which forms the third line of defense. The T-cell responses and the antibodies in the lymph nodes eliminate pathogens.

If an infectious agent overcomes the initial epithelial physical and chemical barriers, cellular innate immune responses are rapidly activated, typically beginning within minutes of invasion. These responses, which constitute the innate immune system’s second line of defense, are triggered by cell surface or intracellular receptors that recognize conserved molecular components of pathogens. Some white blood cell types are activated to rapidly engulf and destroy extracellular microbes through the process of phagocytosis. Other receptors induce the production of proteins and other substances that have a variety of beneficial effects, including direct antimicrobial activity, as well as the recruitment of fluid, cells, and molecules to sites of infection. This influx causes swelling and other physiological changes that collectively are called Inflammation. Such local innate and inflammatory responses usually are beneficial in that they eliminate pathogens and damaged or dead cells, promote healing, and help to activate adaptive immune responses.

As members of the innate lymphoid cell (ILC) lineage, natural killer (NK) cells recruited to the site can recognize and kill virus-infected, altered, or stressed cells. However, in some situations these innate and inflammatory responses can be harmful, leading to local or systemic consequences that can cause tissue damage and occasionally death. To prevent these potentially harmful responses, regulatory mechanisms have evolved that usually limit such adverse effects.

Despite the multiple layers of the innate immune system, some pathogens may evade the innate immunity effect or mechanisms, the various chemical and cellular mechanisms by which the innate immune system eliminates pathogens. On call in vertebrates is the adaptive immune system, which counters infection with tailor-made responses specific for the attacking pathogen. These powerful responses, to be described in detail later in this text, consist of B cell–derived antibodies and effector T cells that specifically recognize and neutralize or eliminate the invaders but take longer to develop.

In many ways, innate and adaptive immunity are complementary systems (Table 4-1). Innate immunity is the most ancient form of defense, found in all multicellular plants and animals, while adaptive immunity is a much more recent evolutionary invention, having arisen in vertebrates. In these animals, adaptive immunity complements a well-developed system of innate immune mechanisms that share important features with those of our invertebrate ancestors. A growing body of research has revealed that as innate and adaptive immunity have co-evolved in vertebrates, a high degree of interaction and interdependence has arisen between the two systems. Recognition by the innate immune system not only kicks off the adaptive immune response but also helps to ensure that the type of adaptive response generated will be effective for the invading pathogen.

TABLE 4-1 Innate and adaptive immunity

Attribute	Innate immunity	Adaptive immunity
Response time	Minutes/hours	Days
Specificity	Specific for molecules and molecular patterns associated with pathogens and molecules produced by dead/damaged cells	Highly specific; discriminates between even minor differences in molecular structure of microbial or nonmicrobial molecules
Diversity	A limited number of conserved, germ line–encoded receptors	Highly diverse; a very large number of receptors arising from genetic recombination of receptor genes in each individual
Memory responses	Some (observed in invertebrate innate responses and mouse/human NK cells)	Persistent memory, with faster response of greater magnitude on subsequent exposure
Self/nonself discrimination	Very good; no microbe-specific self/nonself patterns in host	Very good; occasional failures of discrimination result in autoimmune disease
Soluble components of blood	Many antimicrobial peptides, proteins, and other mediators, including cytokines	Antibodies and cytokines
Major cell types	Phagocytes (monocytes, macrophages, neutrophils, dendritic cells), natural killer (NK) cells, other leukocytes, epithelial and endothelial cells	T cells, B cells, antigen-presenting cells

This chapter describes the components of the innate immune system—physical and chemical barriers, a battery of protective cellular responses carried out by numerous cell types, and inflammatory responses—and illustrates how they act together to defend against infection. We conclude with an overview of innate immunity in plants and invertebrates.