Page 38 - Clinical Immunology_ Principles and Practice ( PDFDrive )

24 Part one Principles of Immune Response

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antibody-dependent cellular cytotoxicity (ADCC). It is expressed The predominant APCs of the skin are the Langerhans cells
on macrophages, but not on blood monocytes. Monocytes and found in the epidermis and characterized by rocket-shaped
macrophages also express CD89, the Fc receptor for IgA. 12 granules called Birbeck granules. Immature tissue DCs in periph-
Macrophages are more differentiated monocytes that reside eral tissues engulf and process antigen and home to T-cell areas
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in various tissues, including the lungs, liver, and brain. Cells in the draining lymph nodes or spleen. Mature DCs can directly
of the monocyte–macrophage lineage adhere strongly to glass present processed antigens to resting T cells to induce proliferation
or plastic surfaces. This process activates them, and this can and differentiation, and this is a key functional difference between
confound functional studies when they are isolated in this way. mature DCs and macrophages. The effector cells produced after
Many cells of this lineage phagocytose organisms or tumor cells this presentation then home to the site of the antigenic assault.
in vitro. Cell surface receptors, including CD14, Fcγ receptors, TNF-α maintains viability of Langerhans cells in skin and
and CR1 (CD35), are important in opsonization and phagocytosis. stimulates their migration. In Peyer patches (Chapter 20),
This lineage expresses MHC class II, and some express the low- immature DCs occur in the dome region underneath follicle-
affinity receptor for IgE (CD23). Other cell surface molecules associated epithelium (FAE), where they actively endocytose
include myeloid antigens CD13 (aminopeptidase N) and CD15 antigens taken up by M cells. Mature interdigitating DCs are
(Gal (1–4) or [Fuc (1–3)] GlcNAc) and the adhesion molecules found in T-cell regions, where they can induce Th2 immune
CD68 and CD29 or CD49d (VLA-4). Classic blood monocytes responses (Chapter 16).
in humans (85%) express high levels of CD14, but no CD16. Three types of DC are prominent—two types of “conventional”
Nonclassic monocytes express less CD14, but more CD16. This dendritic cells (cDCs) and plasmacytoid dendritic cells (pDCs).
later subset produces more IL-12, TNF-α, and IL-1β. These cells cDC1s derive from bone marrow are found in lymphoid tissues
have receptors for various cytokines (e.g., IL-4 and IFN-γ). and express CD1a and CD11c. About 50% peripheral blood DCs
Activated macrophages are a major source of cytokines, including are cDC1. cDC2s express CD141, are similar to murine CD8
IFN, IL-1, and TNF, as well as complement proteins and α/α DCs in function, and are rare in peripheral blood but are
prostaglandins. common in lymph nodes. pDCs are high producers of IFN-α.
Macrophages, along with dentritic cells (DCs), are much more They express CD123 and low levels of CD11c, along with BDCA
plastic in differentiation and function than previously realized. 2 and 4. DCs can be derived from either myeloid or lymphoid
They can be alternatively activated and thereby become sup- lineages. DCs are largely influenced by stimulation with Toll-like
pressive, developing antiinflammatory properties relevant in ligands found on a variety of stimuli, which then direct the
immune responses to cancer as well in maintaining adipose differentiation and function of innate and acquired immune
integrity. Alternative activation is induced by the T-helper cell cells.
2 (Th2) (Chapter 16) cytokines IL-4 and IL-13. 14
Monocytes and macrophages arise from colony-forming Polymorphonuclear Granulocytes
unit–granulocyte monocyte (CFU-GM) progenitors that dif- Polymorphonuclear (PMN) granulocytes arise and mature in
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ferentiate into monoblasts, promonocytes, and then monocytes. bone marrow. After release from bone marrow, their life span
Mature monocytes leave bone marrow and circulate in the varies from a few to 5 to 6 days and is regulated by environmental
bloodstream until they enter tissues, where they develop into conditions. They constitute 65–75% of the white blood cells in
tissue macrophages (alveolar macrophages, Kupffer cells, intestinal peripheral blood, are 10–20 µm in diameter, and have a multilobed
gut macrophages, and microglial cells). Tissue macrophages pyknotic nucleus characteristic of cells undergoing apoptosis
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appear to originate from fetal macrophages and seed tissues (see Table 2.4). PMNs use diapedesis to gain access to tissues
early in fetal development, where they are maintained by longevity from blood.
and slow self-renewal. 13 Granulocytes are early responders to stress, tissue damage,
Several cytokines participate in the development of monocytes or pathogen invasion. Because of their function in phagocytosis
and granulocytes. SCF, IL-3, IL-6, IL-11, and GM-CSF promote and killing, they possess granules with unique staining charac-
+
development of myeloid lineage cells from CD34 stem cells, teristics that are used to categorize the cells as neutrophils (Chapter
especially at early stages. M-CSF acts at later stages of development 22), basophils (Chapter 23), or eosinophils (Chapter 24).
and is lineage specific, inducing macrophage maturation. 12
Neutrophils
Dendritic Cells Most circulating granulocytes are neutrophils (90%). Their
DCs express high levels of MHC class II molecules and are potent granules are azurophilic and contain acid hydrolase, myeloper-
inducers of primary T-cell responses. Except for bone marrow, oxidase, and lysozymes. These granules fuse with ingested
they are found in virtually all primary and secondary lymphoid organisms to form phagolysosomes, which kill the invading
tissues and in skin, mucosae, and blood. DCs are abundant in organism. In some cases, there is extracellular release of granules
the thymus medulla for selection of thymocytes. after activation via the Fc receptors. Neutrophils express CD13,
+
DCs are derived from CD34 MHC class II-negative precursors CD15, CD16 (FcγRIII), and CD89 (FcαR). In response to bacterial
present in bone marrow, which also give rise to macrophages infection, the number of circulating granulocytes typically
and granulocytes. GM-CSF and TNF-α are involved in DC increases. This often includes the release of immature granulocytes,
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development. DCs residing in peripheral sites, such as skin, called band or stab cells, from bone marrow. In a mild infection,
the intestinal lamina propria, lungs, the genitourinary tract, and both the number and the function of neutrophils are increased.
so on, are typically immature. These cells are more phagocytic This is associated with a delay in apoptosis. With more severe
with less MHC class I, MHC class II, and costimulatory molecules. infection, function may be impaired due to the immaturity of
These immature DCs take up antigens in tissues for subsequent cells.
presentation to T cells, and as they migrate, they mature into A newly described function of some neutrophils is to
efficient APCs. release neutrophil extracellular traps, which can capture