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C H A P T E R 19

OVERVIEW AND COMPARTMENTALIZATION OF THE

IMMUNE SYSTEM

Dinesh S. Rao

The immune system is critical to the survival of humans and other pattern of hydrophobic or charged molecules. Common PAMPs
mammals, keeping at bay a seemingly endless variety of pathogenic include lipopolysaccharide (LPS, or endotoxin of gram-negative bac-
organisms that are encountered continuously in the course of life. It teria), peptidoglycans and teichoic acids (gram-positive and negative
is a complex, multilayered system that has evolved over millions of bacteria), mannans (fungi), single-stranded (ss) or double-stranded
years. From its earliest evolutionary incarnation in invertebrate (ds) RNA (viruses), dsDNA (viruses or necrotic/apoptotic cells),
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species as a system of cells that ingests and destroys pathogens, the and as most recently discovered, bacterial pigments. PAMPs are
human immune system has evolved a variety of functions, including thus integral structural motifs within various pathogens, and these
the ability to discriminate between highly related biochemical struc- common motifs are recognized by the PRRs (Table 19.2). PRRs
tures that differentiate harmful pathogens from harmless antigens. It are germline encoded and constitutively expressed, key features that
also plays an increasingly recognized role in the clearance of dead cells distinguish them from the receptors expressed by cells of the adaptive
and tissues, promotion of wound healing, and recognition of trans- immune system. PRRs may be transmembrane proteins expressed on
formed cells. Disorders that are the consequence of immune under- or the surface of bone marrow (BM)-derived effector cells, while others
overactivity are found in all areas of medicine. Methods of manipulat- are soluble receptors found both intra- and extracellularly. They are
ing the immune system in the areas of infectious disease, transplanta- also produced by epithelial cells in the gut, bronchial airways, renal
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tion biology, autoimmunity, and tumor immunology are active tubules, uterus, skin, and endothelial cells in the liver. As such, they
frontiers of medical research and drug development. are poised to act at the four major portals of pathogen entry.
Conceptually, the immune response may be divided into innate Pathogen recognition molecules or receptors encompass several
and adaptive systems (Table 19.1). The innate system is evolutionarily different structural families (see Table 19.2). Two PRR families—
the oldest, with many components found in invertebrate species. peptidoglycan receptor proteins (PGRPs) and the Toll-like receptors
Activated early in an immune response, the innate immune system (TLRs)—were first identified in Drosophila and only later demon-
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is responsible for a rapid response mediated by cells with invariant strated in vertebrate organisms. In humans, four PGRPs have been
pathogen recognition receptors. Pathogen–receptor binding results in identified and are secreted by neutrophils, hepatocytes, and epithelial
the immediate activation of specific protective humoral and cellular cells on mucous membranes and defend against gram-positive and
responses. In contrast, cells of the adaptive system are responsible for gram-negative organisms. Ten TLRs have been identified; their
development of long-term immunity against specific pathogens. In ligands include bacterial lipopeptides (TLR1, TLR2, TLR6), pepti-
general, recurrent infections or infections by pathogens that escape doglycans (TLR2), LPS (TLR2, TLR4), fungal saccharides (TLR2,
the innate immune system result in the expansion of populations of TLR6), ds- and ssRNA (TLR3, TLR7, TLR8), flagellin (TLR5), and
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pathogen-specific lymphocytes and the formation of immunologic dsDNA and CpG DNA fragments (TLR9). The TLRs are type I
memory. Although superficially separate, there is extensive cross-talk transmembrane proteins that contain leucine repeats extracellularly
between the innate and adaptive immune systems, such that patho- that bind to their cognate PAMPs and intracellular domains that
gens that activate one lead to the recruitment and activation of mediate signaling. Other PRR families include the C-type lectins
the other. (including the mannose-binding lectin [MBL] and pulmonary sur-
The innate and adaptive immune systems have been characterized factant proteins), dectin-1, macrophage scavenger receptors, RIGI-
in depth at the cellular and molecular levels. The principal goal of like receptors (RLRs), NOD-like receptors (NLRs), and the aryl
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these systems is defense against pathogens seeking entry through one hydrocarbon receptor (AhR). These families include extracellular
of four anatomic sites: the respiratory, gastrointestinal, and genito- PRRs, transmembrane and intracellular (cytosolic) PRRs. The cyto-
urinary tracts and the skin. Consequently, immune function has to solic PRRs are thought to be important in recognition of intracellular
be understood in terms of the anatomy of these four entry points and pathogens such as viruses and bacteria. The RLRs recognize RNA
their relation to lymphatics, blood vessels, and lymphoid organs. This viruses via their RNA helicase enzymatic activity; the twenty different
chapter provides an introduction to the molecular and cellular NLRs recognize a variety of PAMPs, non-PAMP particles, and cel-
components of innate and adaptive immunity with an overview of lular stresses, and the AhR binds to bacterial pigments. Hence the
their anatomic relationships. innate immune system has evolved a number of strategies to recognize
common structural motifs and thereby initiate the immune response.
THE INNATE IMMUNE SYSTEM
Consequences of PRR–PAMP Engagement:
Pathogen Recognition Receptors and Pathogen- Phagocytosis, the Cytokine Response, and Priming the
Associated Molecular Patterns Adaptive Immune Response

As the first responders to a pathogenic insult, the cells of the PRR–PAMP ligation triggers immune and inflammatory responses
innate immune system use surface receptors, known as pathogen in three stages. In the first stage, the “professional” innate immune
(or pattern) recognition receptors (PRRs), that recognize common cells, including monocytes, macrophages, and neutrophils, facili-
molecular motifs, known as pathogen-associated molecular patterns tate clearance of pathogens. This process is initiated by pathogen
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(PAMPs), on various types of pathogens. PAMPs are molecular binding directly to PRRs on the surfaces of these cells followed
motifs common to bacteria, fungi, and some viruses but not viable by internalization, or the opsonization of pathogens bound by a
mammalian cells. They frequently are characterized by a repeating soluble PRR, which are subsequently recognized by receptors on a

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