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Chapter 19 Overview and Compartmentalization of the Immune System 203

specificity, γδ T cells respond to bacterial and viral infections and being more predominant in tissues and basophils in circulation. Both
possibly malignant transformation. cell types express FcεR, which induces rapid degranulation when
triggered by aggregated IgE, and have granules containing histamine,
platelet-activating factor, and bioactive proteoglycans. Degranulation
NK Cells can be rapid, producing anaphylaxis, or sustained, inducing a more
sustained inflammatory response. Mast cells and diseases related to
Natural killer cells are a distinct lymphocyte subset and comprise mast cells are discussed in Chapter 72.
approximately 10% of the circulating lymphocyte population. NK Eosinophils are found predominantly in tissues, with a smaller
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cells are identifiable by their CD3 CD56 phenotype. They function fraction found in circulation. The eosinophilic granules of this subset
in defense against virally infected cells and transformed cells through contain hydrolytic enzymes that may be damaging to invading
the generation of cytotoxic cytokines, direct cytolytic activity, and pathogens and host tissues. Eosinophil activation also triggers leuko-
antibody-dependent cellular cytotoxicity. Although traditionally triene production and the release of an array of cytokines. A role in
included as a subset of lymphocytes, like B1 B cells and γδ T cells, allergic responses and defense against helminth pathogens has long
NK cells seem to bridge the adaptive and innate immune systems. been presumed consequent to the eosinophilia characteristic of these
These cells carry invariant receptors, including both activating and conditions; however, the true physiologic function of eosinophils
inhibitory receptors. The activating receptors such as CD94/NKG2s, remains elusive. Although traditionally thought of as part of the
and natural cytotoxicity receptors (NCRs), lead to the generation of innate immune system, eosinophils may be viewed as effector cells of
cytotoxic cytokines and direct cytolytic activity. NK cells also have the adaptive immune system because they can be acutely triggered by
inhibitory receptors, including the killer cell Ig-like receptors (KIRs), a B-cell product (IgE) and their development in part depends on T
which allow for suppression of NK cell activity, generally through cells. Disorders of eosinophils are discussed in Chapter 71.
ligation of a self-molecule (classical major histocompatibility class I
molecules). Hence the balance between activating and inhibitory
signals allows NK cells to function in clearance of infected, damaged, Non–Bone Marrow–Derived Cells Involved in
or cancerous cells, and to function in immune system surveillance. Immune Function

Populations of non-BM–derived cells function in innate immunity.
Monocytes, Macrophages, and Dendritic Cells Renal tubular cells and epithelial cells in the gut, bronchial airways,
reproductive organs, and dermis express PRRs. In these cells, the
Monocytes develop in the BM and then circulate through the blood receptors function in pathogen clearance or by triggering pathogen-
and lymphatics with an average half-life of 1 to 3 days before migrat- dependent inflammatory responses. Bronchial airway cells secrete
15
ing into tissues and maturing into macrophages. Macrophages can pulmonary surfactants and antimicrobial peptides, creating a local-
be found in all tissues, particularly at points of entry for pathogens ized antimicrobial barrier. Liver endothelial cells use several PRRs,
such as the skin, respiratory tract, gastrointestinal tract, and genito- including the Fcγ, scavenger, and mannose receptors, to clear particu-
urinary tract. Tissue-specific macrophage populations include Kupffer lar serum proteins and pathogens. The functions of these cells dovetail
cells (liver), alveolar macrophages (lung), osteoclasts (bone), microglia with those of the leukocytes in pathogen defense and tissue
(central nervous system), and type A lining cells (synovia), which can homeostasis.
be identified morphologically and by surface immunophenotype.
Macrophages function at many levels in the immune response, with
their traditional role being in phagocytosis, cytolytic granule release, ANATOMY OF THE IMMUNE SYSTEM
and antigen presentation. More recently, their role as cytokine secret-
ing cells and in coordinating the immune response has been An array of soluble mediators and a repertoire of immune cells
appreciated. mediate the host response to microbial pathogens, to tumors, to
Dendritic cells are specialized antigen-presenting cells (APCs). self-antigens in autoimmunity, and to foreign antigens in graft rejec-
Similar to macrophages, DCs are found at points of pathogen entry, tions. Where do these cells and mediators come from, and where do
including the skin and mucosal surfaces, and locations of lymphocyte these interactions take place?
proliferation, such as germinal centers (GCs). Their main role is to
present processed antigens to T-helper cells, but they are also known
to activate the cytotoxic T-cell response. DC biology is described Immune Cell Development: Primary and Secondary
further in Chapter 23. Lymphoid Organs
The organs and tissues of the immune system are divided into the
Granulocytes primary (or generative) lymphoid organs and secondary (or peripheral )
lymphoid organs. The primary lymphoid organs consist of the BM and
Granulocytes can be further subclassified into neutrophils, basophils, thymus and are the sites where cells of the innate and adaptive
and eosinophils by the types of cytoplasmic granules that they immune system are generated and produced. The secondary lymphoid
contain. Neutrophils mature in the BM, and large pools of neutro- organs include the spleen, LNs, and epithelial- and mucosa-associated
phils are found there, with significant numbers also found in the lung, lymphoid tissues such as Peyer patches in the small intestine. These
spleen, and liver. The recruitment of neutrophils from these reservoirs secondary lymphoid tissues are the anatomic site for coordination of
into the circulation and inflamed tissues can occur within hours of the adaptive immune response.
exposure to bacterial products such as endotoxin. Neutrophils can be Most immune cells arise in the BM (discussed in detail in Chapters
triggered to their effector function via PAMP-PRR ligation. Neutro- 9, 20, 21, and 27). The cellular components of the innate immune
phils have multiple functions, including the direct killing of foreign response—neutrophils, eosinophils, basophils, and monocytes—leave
organisms via phagocytosis or release of toxic enzymes from granules, the BM as mature, functional cells. In contrast, the cellular compo-
release of PRRs, and the formation of neutrophil extracellular nets nents of the adaptive immune response require further development
(webs of degraded nucleic acids and histones), which trap organisms. and refinement of function in specific anatomic sites. T-cell precur-
Neutrophils can also recruit and activate the cells of the adaptive sors leave the BM and migrate to the thymus, where they develop
immune system (lymphocytes and DCs). their antigen receptor, the TCR. Following acquisition of a functional
The basophilic leukocytes—mast cells and basophils—have TCR, the T cells undergo further refinement of function in the
several structural and functional similarities. They are key mediators periphery, where they can adopt various fates. Although B cells leave
of immediate allergic and inflammatory responses, with mast cells the BM with a functional BCR/Ig, they require further maturation