Page 359 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPTEr 23 Mast Cells, Basophils, and Mastocytosis 339

enzyme that is expressed more strongly by mast cells than any chains. Human hematopoietic cells other than mast cells and
other cell type. PGD 2 binds to two specific receptors, termed basophils (e.g., eosinophils and dendritic cells [DCs]) express
DP 1 and CRTH2 (also known as DP 2 ). Once released, PGD 2 FcεRI in the absence of the β chain. The β chain amplifies signal-
elicits vasodilation (via DP 1 ) and bronchoconstriction (via the ing through the receptor, and the tetrameric form on mast cells
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actions of a putative metabolite at the T prostanoid receptor). and basophils is thus fully functional. Activation occurs when
Additionally, PGD 2 is potently chemotactic for basophils, adjacent FcεRI receptors, occupied by receptor-bound IgE, are
eosinophils, Th2 cells, and group 2 innate lymphoid cells (ILC2), cross-linked by multivalent antigen, stimulating degranulation
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each of which express CRTH2. PGD 2 induces cytokine generation and release of preformed mediators as well as de novo production
(IL-4, IL-5, IL-13) from both human Th2 cells and ILC2 and and release of additional mediators described above. 1,3,19,29 The
could, therefore, amplify type 2 inflammation in a polyclonal signaling cascades that are initiated by FcεRI cross-linking are
fashion. There are several CRTH2-selective antagonists in clinical reviewed in detail elsewhere. 30
development for the treatment of asthma and other allergic At the ultrastructural level, stimulation of sensitized human
diseases. basophils with specific antigen provokes fusion of the membranes
enveloping individual cytoplasmic granules with the plasma
Cytokines, Chemokines, and Growth Factors membrane (Fig. 23.2). This results in the release of the granules’
Basophils and mast cells produce a wide variety of cytokines contents via multiple narrow communications between single
and chemokines that recruit and activate other cells (see Table granules and the cell surface. IgE-dependent degranulation of
23.1). Mast cells generate tumor necrosis factor-α (TNF-α), IL-6, human lung mast cells results in the fusion of granule membranes
and IL-1β, which is consistent with their sentinel role in innate with the plasma membrane (Fig. 23.3). However, in this cell type
antimicrobial immunity (Chapter 3). Mast cells can generate the first ultrastructural changes detectable in the stimulated cells
the Th2 cytokines IL-5 and IL-13, a functional property that is are granule swelling, followed by fusion of individual granule
induced when the cells are exposed to IL-4. TNF-α can be stored membranes forming interconnecting chains of swollen granules;
in granules constitutively as well as produced de novo in response histamine release is initiated by the opening of these channels
19
to activation. Activated mouse and human mast cells express to the exterior through multiple narrow points of fusion with
a large range of both CC and CXC chemokines, likely reflecting the plasma membrane. 31
their role in facilitating the recruitment of bloodborne effector
cells. A recent study demonstrated that mast cell progenitors in the Non–IgE-Mediated Activation
intestinal mucosa are an important source of IL-9 and IL-13 in a Mast cells and basophils can be activated through a variety of
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model of food allergy. Basophils can secrete large quantities of non–IgE-mediated mechanisms. Both mast cells and basophils
IL-4 (and IL-13) rapidly, contributing to Th2 immune responses express receptors for complement fragments C3a and C5a and
in a variety of settings. These observations suggest that basophils release histamine in response to these complement components.
are more specialized than mast cells for a role in type 2 immunity. The C5a receptor (CD88), in particular, is expressed in human
lung on MC TC s, and elevated C5a concentrations have been
MECHANISMS OF ACTIVATION OF MAST CELLS measured in induced sputum from subjects with asthma. Mast
2,19
AND BASOPHILS cells and basophils can be activated by microbial constituents
via Toll-like receptors (TLRs), many of which are expressed on
their surface and internal membranes. 19,29 Both cell types respond
to the barrier-derived cytokines IL-33 and TSLP, both of which
KEY CONCEPTS drive Th2-type immune responses. Each cytokine can directly
Mechanisms of Mast Cell and Basophil Activation activate mast cells and, in some cases, amplify IgE-mediated
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responses. In contrast to the complement fragment-dependent
• Mast cells and basophils have cell-surface high-affinity immunoglobulin activation, IL-33 and TSLP fail to induce degranulation but are
E (IgE) receptors (FcεRI) that are tetrameric and thus fully functional, powerful inducers of cytokine production, particularly when
unlike the trimeric FcεRI found on other cells (e.g., dendritic cells they are provided together. Thus non–IgE-dependent activation
[DCs] and eosinophils).
• IgE-mediated activation of mast cells and basophils occurs when mechanisms tend to elicit a response from mast cells that is
multivalent antigen cross-links IgE antibodies bound to adjacent FcεRI more compartmentalized than FcεRI-mediated activation.
receptors, resulting in degranulation and de novo mediator production A variety of drugs, such as opiates and muscle relaxants, can
and release. directly activate mast cells. 19,29 Recently, the murine counterpart
• Mast cells and basophils can be activated by non–IgE-mediated of the human G protein-coupled receptor, MAS-related G
mechanisms (anaphylatoxins, Toll-like receptor [TLR] ligands, certain protein-coupled receptor X2 [MRGPRX2], was found to be
cytokines, drugs, venoms, etc.). necessary to trigger mast cell degranulation in vivo response to
• Some types of non–IgE-mediated activation cause a more compart-
mentalized activation (e.g., cytokine production without degranulation a range of basically charged drugs, as well as compound 48/80,
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caused by activation of mast cells or basophils by interleukin-33 [IL-33] a classic secretagogue for mast cells. The potential that certain
and thymic stromal lymphopoietin [TSLP]). drugs possess in their ability to mimic components of innate
immunity to trigger mast cells represents a major conceptual
FcεRI-Mediated Activation (and Inhibition of step forward toward understanding drug-induced pseudoallergic
reactions that do not involve specific IgE.
IgE-Dependent Activation) Basophil activation is promoted by IL-3, and other cytokines,
Both mast cells and basophils express the high-affinity IgE including IL-18 and IL-33, can activate basophils and enhance
3
receptor, FcεRI. The FcεRI expressed on these cells is unique in their effector functions. Basophils can be directly activated by
3
that it has a tetrameric structure consisting of a single IgE-binding protease allergens, including the house dust mite protease Derp1.
αα chain, a single β chain, and two identical disulfide-linked γ Finally, both mast cells and basophils respond to PAF with