NCR-
ILC3
IFNγ
IL-17IL-22
IL-5IL-9
IL-13
IFNγ
IL-22
IL-17
α4β7?
IL-12
IL-18
IL-25
IL-33
TSLP
GATA3
RORα
RORγt
IL-12
IL-18
IL-23IL-1β
IL-23
IL-1β
IL-12
IL-18
RORγt
T-bet
Gfi1
Figure 1 Ontogeny of innate lymphoid cells (ILCs). A committed ILC precursor (ILCP) having a high level of transcriptional factor PLZF (2) can give rise to ILC1s, ILC2s and ILC3s, but not to LTi cells and NK cells, which originate from a α4β7+ common progenitor shared with the three ILC lineages. Development of ILC2s depends on the transcription
factors Gfi1, GATA3 and RORα. ILC3s require the transcription factor RORγt for their development and function. Although NCR+ ILC3s can give rise to ILC1s if stimulated with IL-12 and IL-18, the differentiation pathway of ILC1s is not
fully understood yet.
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ILC2
ILC3
Protease
Allergen
IL-17
IL-1β
IL-25
IL-33
TSLP
Macrophage
Neutrophilic
Inflammation
PAMPs
DAMPs
IL-22
IL-5
Eosinophilic
Inflammation
IL-13
Goblet cell
hyperplasia
Figure 2 The role of ILCs in allergy. Epithelial tissues can release IL-25, IL-33 and TSLP in response to protease allergens such as house dust mites or papain, DAMPs, PAMPs and TH2 cytokines. In response to the epithelium-derived cytokines ILC2s can release IL-13, which induces inflammation and remodeling (such as goblet cell hyperplasia) in the tissue, and IL- 5, which can induce eosinophilic inflammation. ILC3s release IL-17, which can induce neutrophilic inflammation, and IL-22,
which inhibits the release of ILC2-activating cytokines.
ated molecular patterns (DAMPs) and/or pathogen-associated mo- lecular patterns (PAMPs). The expression of the IL-10 family cytokine IL-22, which is capable of being released from ILC3s, LTi cells or Th17 cells, is increased in chronic allergic inflammation in the lung and skin. IL-22 inhibits the production of ILC2-activating cytokines, IL-25 and IL-33.
KEY REFERENCES
1. Spits H, Artis D, Colonna M, Diefen- bach A, Di Santo JP, Eberl G, et al. Innate lymphoid cells-a proposal for uniform nomenclature. Nat Rev
Immunol 2013;13:145-149.
2. Constantinides MG, McDonald BD, Verhoef PA, Bendelac A. A commit- ted precursor to innate lymphoid cells. Nature 2014 [Epub ahead of print Feb 9] doi: 10.1038/na- ture13047.
3. Walker JA, Barlow JL, McKenzie AN. Innate lymphoid cells--how did we miss them? Nat Rev Immunol 2013;13:75-87.
4. Kim HY, Lee HJ, Chang YJ, Picha- vant M, Shore SA, Fitzgerald KA, et al. Interleukin-17-producing innate lymphoid cells and the NLRP3 in- flammasome facilitate obesity-as- sociated airway hyperreactivity.
Nat Med 2014;20:54-61.
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• Mast cells develop in essentially all tissues from precursors that circulate in the blood
• Mast cells are major sources of histamine and other products (mediators) that contribute to anaphylaxis and other allergic disorders
• Mast cells can be rapidly activated (within minutes) to release mediators when allergens are recognized by IgE antibodies bound to IgE receptors (FcεRI) on the cells’ surface
• Mast cells also can be activated to release mediators by many agents that act independently of IgE
• Mast cells can have beneficial roles in enhancing resistance to animal venoms and in host defense against certain parasites
WHAT ARE MAST CELLS?
In humans and other vertebrates, mast cells reside in virtually all tissues, often close to epithelial surfaces (e.g., the skin, respira- tory system, and gastrointesti- nal tract) and near blood vessels, nerves, smooth muscle cells and fibroblasts. Mast cell precursors are generated in the bone mar- row, circulate in the blood, and then enter the tissues where they complete their maturation, be- coming cells with many prominent cytoplasmic granules (Figure 1A & C). These granules are storage sites for mast cell products (often called “mediators”) that, when re- leased by the cell, have powerful effects on other cell types. Mast cell granules contain most of the body’s histamine and virtually all of its heparin, as well as a variety of proteases (Table 1). When mast cells are “activated” (i.e., stimulat- ed to release their products), they release histamine, heparin and proteases by “degranulation” (Fig- ure 1B & D), and they also secrete many other mediators that are not stored, but are synthesized by the activated cells, including leukot- rienes, prostaglandins, cytokines, chemokines and peptide growth factors (Table 1). Mast cell num- bers can increase in tissues at sites
Stephen J. Galli
Stanford University
Stanford, USA
MAST CELLS
9
Key messages
Mast cellsof allergic diseases or parasite in- fections, and in other settings.
HOW CAN MAST CELLS BE ACTIVATED TO RELEASE THEIR PRODUCTS?
Mast cells express on their sur- face hundreds of thousands of high affinity receptors (FcεRI) that strongly bind the Fc portion of IgE antibodies. Individual mast cells can bind IgEs which recognize any of a variety of different aller- gens derived from pollens, foods, dust mites, medicines, etc. Such mast cells can be activated when they encounter any antigens that cross-link two adjacent IgE mole- cules, which results in aggregation
of the IgE-bound FcεRIs, signaling the cells to release their products (Figure 1B & D). Mast cells also can be activated independently of IgE, e.g., by products of microorgan- isms, certain neuropeptides, and compounds present in animal ven- oms (Table 2).
When large numbers of mast cells are rapidly activated by the sys- temic distribution of an allergen in subjects who have IgE recog- nizing that allergen, anaphylaxis can occur within minutes. Such IgE-dependent anaphylaxis is ab- sent or markedly diminished in mice genetically lacking mast cells (even though they have basophils, another bone marrow-derived cell
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Figure 1 (A, C) A resting mast cell (shown in a transmission electron micrograph in A and as a cartoon in C)
contains many cytoplasmic granules (indicated by arrows in A) and has allergen-specific IgE (yellow symbols in C) bound to FcεRI receptors (green symbols in C) on its surface (B, D). When allergen (red symbols in D) is recognized by adjacent IgE antibodies
bound to the mast cell’s FcεRI receptors, this aggregates the FcεRIs on the cell’s surface, activating the mast
cell to release its granule contents at points where the granules fuse with the plasma membrane (indicated by arrows in a transmission electron micrograph in B and as a cartoon in D).
Such activated mast cells also secrete newly synthesized products that are not stored in the granules. (Modified from Fig. 9.44 in Parham P. The Immune
System. 3rd edition, Copyright 2009 from The Immune System by Parham. Reproduced by permission of Garland Science/Taylor & Francis LLC. The electron micrographs in A & B are
courtesy of Ann M. Dvorak.) TABLE 1
Mast Cell Products
Products Biological effects*
Stored preformed in granules and secreted upon activation (in minutes)
Histamine
• Increases vascular permeability and blood vessel dilatation • Contracts airway smooth muscle
• Causes itching and pain
• Influences immune responses and the function of some nerves Heparin • Anticoagulant • Required for storage of other products in granules
Proteases (e.g., tryptase, chymase, carboxypeptidase A3)
• Degrade certain proteins and peptides, including components of animal venoms
• Regulate tissue remodeling
• Converts angiotensin I to angiotensin II (chymase) Synthesized and se-
creted upon activation (beginning in minutes for lipid mediators, extending over hours for peptide products†)
Lipid mediators (e.g., leukotrienes, prostaglandins)
• Regulate migration and function of leukocytes • Increase vascular permeability
• Induce constriction or dilatation of blood vessels (depending on the type of mediator)
• Contract or relax smooth muscle (airways, gastrointestinal tract) • Enhance mucus secretion
Cytokines, chemok- ines, peptide growth factors
• Many effects on other cells (both leukocytes and tissue structural cells) that can promote or suppress inflammation and/or tissue re- modeling
* Only some of the many biological effects of these products are listed.
† Some of these can be present in granules and therefore also can be released rapidly upon mast cell activation.
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TABLE 2
Mechanisms of mast cell activation*
Activation mechanisms† Settings in which this occurs Comments
Cross-linking of IgE bound to mast cell surface FcεRI by multivalent antigen recognized by the IgE
Anaphylaxis, allergic rhinitis, atopic dermatitis, allergic asthma, some types of urti- caria
The site of mast cell activation depends on the site of exposure to the antigen; in anaphylaxis, there is systemic distribution of the offending antigen throughout the body.
Reaction of microbial products or products of damaged or dead cells with receptors (Toll-like receptors or other pattern recognition receptors) on the mast cell surface or inside the mast cell
Various types of viral or bac- terial infections; diverse set- tings in which cell damage or cell death occurs
Exposure of mast cells to some of these prod- ucts cells can influence how the mast cells re- spond to other activation signals, such as IgE and antigen.
Reaction of endogenous peptides with receptors for those peptides on the mast cell surface
Various disease processes or mechanisms of host defense that maintain health
Endogenous peptides that can activate some types of mast cells include certain neuropep- tides, endothelin-1, and products of comple- ment activation (C3a, C5a).
Reaction of exogenous peptides with receptors on the mast cell surface that recognize such peptides
Envenomation by venomous reptiles
Some of these venom peptides are structur- ally similar to endogenous peptides that can also activate mast cells; mast cell proteases released when the activated mast cells de- granulate can degrade and thereby reduce the toxicity of some components of the venoms.
* In addition to mechanisms that activate mast cells, certain stimuli can diminish the extent of mast cell activation.
† Mast cells activated by IgE and specific antigen can release many or all of the products listed in Table 1. By contrast, other acti-
vation mechanisms can result in the relatively selective release of granule-stored products (e.g., in response to certain peptides) or cytokines, chemokines and growth factors (e.g., in response to certain microbial products).
type that can bind IgE), showing that mast cells importantly con- tribute to this acute, catastroph- ic and potentially fatal reaction. Through effects of released mast cell products on inflammation and structural cells in the affected tissues (Table 1), IgE-dependent mast cell activation can contribute to late phase reactions (that devel- op hours after allergen exposure) and to the features of chronic al- lergic inflammation (e.g., in allergic asthma).
DO MAST CELLS CONTRIBUTE TO HEALTH, OR ONLY TO DISEASE?
From an evolutionary perspective,
mast cells did not develop in order to cause disease. Likely beneficial roles of mast cells include enhanc- ing host resistance to some par- asites and other pathogens and enhancing innate and acquired re- sistance to certain animal venoms. Mast cells also have the potential to limit the pathology associated with certain innate or acquired immune responses through the production of mediators with an- ti-inflammatory or immunosup- pressive effects.
KEY REFERENCES
1. Galli SJ, Metcalfe DD, Arber DA, Dvorak AM. Basophils and mast cells and their disorders. In: Kau-
shansky K, Lichtman MA, Beutler E, Kipps TJ, Seligsohn U, Prchal JT, eds. Williams Hematology, 8th ed. New York: McGraw-Hill Medical, 2010;63:915-932.
2. Galli SJ, Tsai M. IgE and mast cells in allergic disease. Nat Med 2012;18:693-704.
3. Reber L, Marichal T, Galli SJ. New models for analyzing mast cell functions in vivo. Trends Immunol 2012;33:613-625.
4. Marichal T, Starkl P, Reber LL, Kale- snikoff J, Oettgen HC, Tsai M, Metz M, Galli SJ. A beneficial role for Immunoglobulin E in host defense against honeybee venom. Immunity 2013;39:963-975.
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• Basophils have long been neglected in immunological studies, owing to their small numbers and phenotypic similarity to mast cells
• The finding that basophils secrete large quantities of Th2 cytokines (IL-4 and IL-13) ended the long-held view of basophils as minor relatives of mast cells with little function
• Basophils normally circulate in the blood, and are recruited to affected tissues in various allergic disorders, including allergic rhinitis, chronic urticaria, atopic dermatitis, and asthma
• Recent development of analytical tools in mouse models has identified pivotal and nonredundant roles for basophils in a variety of immune responses, including allergy
Basophils are the least abundant granulocytes, and represent less than 1% of peripheral blood leuko- cytes. They were first document- ed by Paul Ehrlich more than 100 years ago, but their functional sig- nificance remained enigmatic for a long time. Basophils share certain features with tissue-resident mast cells, including the presence of ba- sophilic granules in the cytoplasm, the surface expression of IgE re- ceptor (FcεRI), and the release of chemical mediators in response to various stimuli (Table 1). There- fore, they have often erroneously been considered as minor and re- dundant relatives or precursors of tissue-resident mast cells. Indeed, in clinical settings, basophils have been used, as surrogates of less accessible tissue mast cells, for the in vitro quantification of immedi- ate-type response to allergens in allergic patients.
Basophils circulate in the periph- eral blood, and are rarely present in peripheral tissues under home- ostatic conditions, in contrast to mast cells. The half-life of circu- lating basophils is estimated at approximately 2 days, while mast cells survive for months in periph- eral tissues. Although these differ- ences suggest that basophils and