Page 358 - Clinical Immunology_ Principles and Practice ( PDFDrive )

338 ParT TwO Host Defense Mechanisms and Inflammation

including IL-3 and the epithelial cell–derived cytokine TSLP, KEY CONCEPTS
regulate basophil development as well. 3
Ex vivo developmental studies with human progenitor cells Mast Cell and Basophil Mediators
have suggested a common origin for basophils and eosinophils. • Mast cells and basophils produce distinct but overlapping panels of
Denburg et al. showed that a fraction of clonal colonies arising mediators with diverse biological effects.
from human peripheral blood progenitor cells contained both • Some mast cell and basophil mediators are preformed and stored in
eosinophils and basophils, with some cells showing an intermedi- cytoplasmic granules (e.g., histamine, proteoglycans, proteases). These
22
ate phenotype with granules of both lineages. Saito et al. showed can be released rapidly (seconds to minutes) upon cellular activation
and degranulation.
that recombinant IL-3 stimulated the growth of both eosinophils • Mast cells and basophils produce lipid mediators (e.g., PGD 2 , LTC 4 ),
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and basophils from cord blood progenitors. Human basophils which are derived from arachidonic acid and are newly synthesized
express eosinophil cationic protein, major basic protein, Charcot- upon cell activation.
Leyden crystal protein, and eosinophil peroxidase, all of which • Mast cells and basophils can transcribe and secrete many cytokines,
24
are eosinophil granule markers, consistent with a common chemokines, and growth factors (see Table 23.1).
origin of both cell types. A recent transcriptional profiling study
confirmed that mouse blood basophils are more similar to
eosinophils in their gene expression pattern than to any other
5
cell type. The shared lineage pathway for basophils and eosino- are among the oldest antiallergy medications, and their efficacy
phils explains why blood basophil counts are frequently elevated supports the role of histamine in mediating the clinical signs
in conditions associated with increased blood eosinophil counts. and symptoms of rhinitis, allergic conjunctivitis, and urticaria.
Basophil recruitment to the tissues is likely governed by a Proteases, including tryptases, chymase, and CPA3, comprise
combination of protein and lipid chemoattractants. Human the major protein component of mast cell secretory granules.
basophils express CCR1, CCR2, CCR3, CCR5, CXCR1, and CXCR2 Tryptases are the most abundant proteases in the human mast
and respond ex vivo to the corresponding ligands. Basophils cell and are found in basophils as well. Human tryptases are
strongly express chemoattractant receptor homologue expressed encoded by several different alleles, including α, β, γ, and δ. As
by Th2 cells (CRTH2), a specific receptor for prostaglandin D 2 noted previously, only a single mast cell–specific chymase gene
(PGD 2 ). PGD 2 is an abundant product of activated mast cells, exists in humans. CPA3 is expressed strongly by mast cells and
1,16
and CCR3 ligands (CCL11, CCL24, CCL26) are abundantly weakly by basophils. Tryptase β can activate protease-activated
1
expressed by structural cells in allergic inflammation. Thus all receptors, inducing fibroblast proliferation and collagen secretion.
of these are good candidates to account for the accumulation Both human tryptase β and its murine orthologue, mouse mast
of basophils that is frequently observed in rhinitis and asthma, cell protease 6, can induce neutrophil recruitment in models of
and that is characteristic of allergen-induced late-phase responses. bacterial sepsis, suggesting prominent functions in innate
immunity. Human mast cell chymase converts angiotensin 1 to
BIOLOGICAL MEDIATORS PRODUCED BY MAST angiotensin 2, suggesting a potential role in the control of blood
CELLS AND BASOPHILS pressure and cardiovascular homeostasis. CPA3 can neutralize
25
endothelin 1 and the snake venom protein sarafotoxin. These
vasoprotective and antivenom functions are consistent with a
Mast cells and basophils can elaborate a broad array of potent role for resident cutaneous and perivascular mast cells vascular
biologically active mediators (see Table 23.1). Some of these homeostasis and host defense. The functions of the mast cell
products are stored preformed in cytoplasmic granules (e.g., proteases are reviewed comprehensively elsewhere. 16,26
histamine, proteases, proteoglycans, certain cytokines), and others
are synthesized de novo upon activation of the cell (e.g., products Newly Synthesized Mediators
of arachidonic acid oxidation via the cyclooxygenase [COX] or Both mast cells and basophils utilize membrane phospholipid-
lipoxygenase pathways, platelet-activating factor [PAF], cytokines, derived arachidonic acid to synthesize eicosanoid mediators and
19
chemokines, growth factors). These mediators enable mast cells can use the resultant lysophospholipids to generate PAF. These
and basophils to orchestrate various functions in inflammation mediators are released within 15 minutes of activation. Both
and host defense. Some, such as histamine and cysLT, are targets mast cells and basophils express 5-LO and LTC 4 S, permitting
of the best-established drugs for the treatment of allergic diseases, them to generate LTC 4 , the parent cysLT, from endogenous
validating the pathogenetic importance of mast cells, basophils, arachidonic acid. Mast cells, but not basophils, can generate
and their associated effector systems. smaller quantities of the dihydroxy leukotriene, LTB 4 , which is
a potent neutrophil chemoattractant. LTC 4 is converted extracel-
Preformed Mediators lularly to LTD 4 (the most potent known bronchoconstrictor)
Mediators that are stored in secretory granules can be rapidly and then to the stable metabolite LTE 4 . 3,19 CysLTs are abundant
(seconds to minutes) released into the extracellular environment in allergic inflammation, increasing microvascular permeability
upon stimulation. These mediators include histamine, proteo- and causing bronchoconstriction. Mouse models suggest they
glycans, and (in the case of mast cells) proteases. 19 play important roles in amplifying Th2 responses through several
Histamine is stored in the granules of mast cells and, to a cellular targets. There are three cysLT receptors, respectively
27
lesser extent, basophils. Histamine is released within minutes termed CysLT 1 R, CysLT 2 R, and GPR99. Both CysLT 1 R antagonists
of cell activation and mediates increased vascular permeability, and 5-LO inhibitors show efficacy in asthma, supporting the
smooth muscle contraction, mucus production, and increased pathogenic role of the cysLT in this disease.
heart rate and cardiac output, gastric acid secretion, itching, and In contrast to basophils, mast cells generate substantial quanti-
sneezing. These actions are mediated via four types of histamine ties of PGD 2 , a product of successive metabolism of arachidonic
receptors (H1–4) on target cells. 1,3,16 H1 receptor antagonists acid by COX-1 or COX-2 and hematopoietic PGD 2 synthase, an