S450 Prussin and Metcalfe
patients can have superimposed polymyalgia rheumatica.
Therapy with high-dose steroid should be started promptly
if GCA is suspected. Many patients require steroidsparing agents.
Takayasu’s arteritis.11 Takayasu’s arteritis is a granulomatous vasculitis of unknown cause affecting predominantly young women, especially Asians The presence of
3 or more of the following ACR criteria yields a 91%
sensitivity and 98% specificity for diagnosis: age less than
40 years, claudication of extremities, decreased brachial
artery pulse, blood pressure difference between the extremities of greater than 10 mm Hg, bruit over subclavian
artery or aorta, and/or arteriographic narrowing-occlusion
of the aorta and its primary branches. Patients are treated
similarly to those with GCA.
Kawasaki’s syndrome (mucocutaneous lymph node
syndrome). Kawasaki’s syndrome is the most common
vasculitis of childhood, with a peak incidence at the age
of 1 year. It is a self-limited, immune-mediated vasculitis
of unknown cause with a predilection for Asians. Classically, children present with fever, bilateral conjunctivitis,
mucositis, polymorphous rash, lymphadenopathy, and
desquamation of palms-soles. Children treated with highdose aspirin and intravenous immunoglobulin (2 g/kg)
within the first 10 days of fever are less likely to have
potentially life-threatening coronary artery aneurysm.
Unlike other types of vasculitis, steroids are contraindicated because of an association with the development
of coronary aneurysm.12
CONCLUSION
Autoimmune diseases encompass a wide spectrum of
diseases, but all are characterized by alterations in normal immune responsiveness, such that there is a loss of
tolerance to particular host constituents reflected by the
production of autoantibodies (Table II).13,14 Recent research has identified several key changes in components
of the immune response (eg, upregulation in proinflammatory cytokines) relevant to the propagation and sustenance of many autoimmune conditions. With this
greater understanding of pathogenesis, several novel
J ALLERGY CLIN IMMUNOL
FEBRUARY 2006
immunomodulatory therapies targeting specific components of the inflammatory and immune systems have
been introduced into the clinic. This has resulted in
improved disease outcomes for patients with a number
of autoimmune conditions.
REFERENCES
1. De Rycke L, Peene I, Hoffman IE, et al. Rheumatoid factor and anticitrullinated protein antibodies in rheumatoid arthritis: diagnostic value,
associations with radiological progression rate, and extra-articular manifestations. Ann Rheum Dis 2004;63:1587-93.
2. Van Gaalen FA, Linn-Rasker SP, van Venrooij WJ, et al. Autoantibodies
to cyclic citrullinated peptides predict progression to rheumatoid arthritis
in patients with undifferentiated arthritis. Arthritis Rheum 2004;50:
709-15.
3. Wener MH, Hutchinson K, Morishima C, Gretch DR. Absence of
antibodies to cyclic citrullinated peptide in sera of patients with hepatitis C virus infection and cryoglobulinemia. Arthritis Rheum 2004;50:
2305-8.
4. Lopez-Hoyos M, Ruiz de Alegria C, Blanco R, et al. Clinical utility
of anti-CCP antibodies in the differential diagnosis of elderly-onset rheumatoid arthritis and polymyalgia rheumatica. Rheumatology 2004;43:
655-7.
5. Forslind K, Ahlmen M, Eberhardt K, et al. Prediction of radiological
outcome in early rheumatoid arthritis in clinical practice: role of antibodies to citrullinated peptides (anti-CCP). Ann Rheum Dis 2004;63:
1090-5.
6. Sheldon J. Laboratory testing in autoimmune rheumatic disease. Best
Pract Res Clin Rheumatol 2004;18:249-69.
7. Ng B, Yang F, Huston DP, et al. Increased noncanonical splicing of
autoantigen transcripts provides the structural basis for expression of
untolerized epitopes. J Allergy Clin Immunol 2004;114:1463-70.
8. Ballinger S. Henoch-Schonlein purpura. Curr Opin Rheumatol 2003;15:
591-4.
9. Davis MD, Brewer JD. Urticarial vasculitis and hypocomplementemic
urticarial vasculitis syndrome. Immunol Allergy Clin North Am 2004;
24:183-213.
10. Wegener’s Granulomatosis Etanercept Trial (WGET) Research Group.
Etanercept plus standard therapy for Wegener’s granulomatosis. N
Engl J Med 2005;352:351-61.
11. Weyland CM, Goronzy JJ. Medium and large vessel vasculitis. N Engl
J Med 2003;349:160-9.
12. Burns JC, Glode MP. Kawasaki syndrome. Lancet 2004;364:533-44.
13. Ramos-Casals M, Tzioufas AG, Font J. Primary Sjögren’s syndrome:
new clinical and therapeutic concepts. Ann Rheum Dis 2005;64:347-54.
14. Galie N, Seeger W, Naeije R, et al. Comparative analysis of clinical trials
and evidence-based treatment algorithm in pulmonary arterial hypertension. J Am Coll Cardiol 2004;43:81S-8S.
5. IgE, mast cells, basophils, and eosinophils
Calman Prussin, MD, and Dean D. Metcalfe, MD Bethesda, Md
This activity is available for CME credit. See page 5A for important information.
IgE, mast cells, basophils, and eosinophils constitute essential
elements in allergic inflammation. Allergen-specific IgE,
synthesized in response to allergens in the environment,
becomes fixed to FceRI on the membranes of mast cells and
basophils. Aggregation of receptor-bound IgE molecules on
re-exposure to specific allergen results in the production of
mediators that produce the allergic response. Principal among
the cells drawn to sites of mediator release is the eosinophil.
(J Allergy Clin Immunol 2006;117:S450-6.)
Key words: IgE, IgE receptor, mast cell, basophil, eosinophil
IgE
IgE (reagenic) antibody shows no transplacental transfer, does not activate complement by the classical pathway, is thermolabile, and will not sensitize after it has been
heated to 56°C for several hours. IgE binds with high
J ALLERGY CLIN IMMUNOL
VOLUME 117, NUMBER 2
Abbreviations used
APC: Antigen-presenting cell
ITAM: Immunoreceptor tyrosine-based activation motif
LT: Leukotriene
MBP: Major basic protein
PG: Prostaglandin
SCF: Stem cell factor
STAT: Signal transducer and activator of transcription
TLR: Toll-like receptor
affinity to FceRI found in its complete form (abg2) on
mast cells and basophils.1-3
The concentration of IgE in serum is the lowest of the
5 human immunoglobulin isotypes and is age dependent;
cord blood IgE levels are low (<2 kIU/L; <4.8 mg/L) and
then increase up to 10 to 15 years of age. Those with
an allergic predisposition show an earlier and steeper
increase. Levels decrease from the second to the eighth
decade of life. Approximately 50% of total body IgE is
intravascular, with a half-life of 1 to 5 days.1,4
IgE synthesis
Two signals are required for IgE synthesis. Signal 1 is
provided by IL-4 or IL-13, which activate transcription at
a specific immunoglobulin locus. The second signal is
provided by ligation of CD40 on B cells, which activates
DNA switch recombination. T cells are the principal
source of these signals.2,4,5
The process is initiated when an allergen is taken up by
an antigen-presenting cell (APCs), such as a dendritic cell
or B cell, which then processes and presents the allergen
to the TH2 cell. The peptide-MHC complex is recognized
by the T-cell receptor, resulting in activation of the T cell
and its expression of IL-4, IL-13, and CD154 (CD40
ligand). CD154 engages CD40 expressed on the APC,
resulting in activation of the APC, which, in the case of
the B cell, results in isotype class switching to IgE, followed by secretion of allergen-specific IgE.
IL-4 activation of e-germline transcription is initiated
when it binds to B-cell IL-4 receptor (IL-4R). Liganddependent dimerization of the IL-4R leads to Janus
kinase–signal transducer and activator of transcription
(STAT) signaling, resulting in STAT6 homodimerization
and consequent STAT6 translocation to the nucleus, where
it binds to IL-4–responsive promoter elements and activates transcription.4 In addition to STAT6, nuclear factor
From the Laboratory of Allergic Diseases, National Institutes of Allergy and
Infectious Disease, National Institutes of Health.
The findings and conclusions in this report are those of the authors and do not
necessarily represent the views of the National Institutes of Health.
Reprint requests: Dean D. Metcalfe, MD, NIH/NIAID/LAD, Building 10,
Room 11C205, 10 Center Dr, MSC 1881, Bethesda, MD 20892-1881.
E-mail: [email protected].
0091-6749
doi:10.1016/j.jaci.2005.11.016
Prussin and Metcalfe S451
kB-responsive element proteins play an essential role in
IL-4–dependent responses, as does B-cell lineage–specific
activator protein.
A critical role for CD40-CD154 interactions in IgE
synthesis and in isotype switching in general is shown by
patients with the X-linked hyper-IgM syndrome.4 These
patients have mutations in CD154 and do not undergo
class switching, and thus their B cells are unable to produce IgA, IgG, or IgE in response to thymus-dependent
antigens.
IgE receptors
There are 2 receptors for IgE: the low-affinity IgE
receptor (FceRII; CD23) present on B cells and the highaffinity IgE receptor (FceRI). FceRI on mast cells and
basophils is a tetramer (aßg2). It is expressed in a trimeric
form (ag2) on APCs.3,6,7 Expression of the b-chain results
in increased FceRI surface expression and enhances signaling. The density of human basophil FceRI a expression
correlates with serum levels of IgE,8 where binding of IgE
to FceRI stabilizes the receptor at the cell surface.
The Fc fragment of IgE binds to the a-chain of FceRI.
The b-chain is associated with lyn. Two disulfide-linked
g-chains contain immunoreceptor tyrosine-based activation motifs (ITAMs), which are phosphorylated after
aggregation of receptor-bound IgE. Syk kinase then
binds to the g-chain ITAM, leading to its activation.
Protein levels of syk are undetectable in nonreleaser
basophils that do not degranulate in response to FceRI
cross-linking.9 Lyn bound to the b ITAM is also phosphorylated after FceRI aggregation.
The lyn-syk–dependent signaling cascade involves
phosphorylation of adaptor molecules, such as Src homology 2 domain-containing (SHC), vav, non–T-cell activation linker (NTAL), and linker for activation of T cells
(LAT); phospholipases, such as PLCg1, and PLCg2; tyrosine kinases, such as focal adhesion kinase and Bruton’s
tyrosine kinase; and protein and/or inositol phosphatases,
such as SHP1, SHP2, and Src homology 2 domain-containing inositol phosphatase (SHIP). Coligation of inhibitory receptors, such as FcgRIIb, with FceRI results in
downregulation of secretory responses.
Measurements of total and specific IgE
Total IgE levels are influenced by age, genetic makeup
and race, immune status, environmental factors (eg, season
of the year), and disease process. Increased IgE levels
are found in parasitic diseases, such as schistosomiasis;
infections, such as EBV mononucleosis; cutaneous diseases, such as bullous pemphigoid; neoplastic diseases,
such as Hodgkin’s disease; immunodeficiency diseases (eg,
Wiskott-Aldrich syndrome); hyperimmunoglobulinemia E
syndrome; thymic hypoplasia (Di George’s syndrome);
Nezelof syndrome; Omenn syndrome; and several other
diseases, including nephrotic syndrome, cystic fibrosis,
Kawasaki’s disease, and infantile polyarteritis nodosa.
Total IgE is measured with a 2-site, noncompetitive
immunometric assay. Here a solid-phase anti-IgE is used
to capture IgE and a different anti-human IgE labeled with
S452 Prussin and Metcalfe
enzyme, fluorophor, or radionuclide is added to detect
bound IgE. The minimum amount of IgE detectable in
serum with such assays is usually 0.5 to 1 mg/L, where
1 kIU/L equals 2.4 mg/L of IgE.1
The presence of antigen-specific IgE is determined by
means of skin testing or through the measurement of
allergen-specific IgE in serum. Assays to detect allergenspecific IgE antibody are particularly useful when skin
testing cannot be used due to extensive skin disease or
current medical therapy, significant dermatographism, or
use of an extract believed to have a high probability of
inducing a systemic reaction in the subject to be tested. The
general principle used in such assays is to detect IgE that
will bind to allergen fixed on a surface. The assays are
influenced by the amount and quality of allergen coupled
to the solid support, the degree of nonspecific IgE binding,
the affinity of the anti-IgE antibody, and the degree of
blocking of allergen-specific IgE binding by allergenspecific IgG.
Allergen-specific IgE levels depend on the degree and
duration of exposure to both allergen and cross-reactive allergens. Allergen-specific IgE levels generally peak 4 weeks
into seasonal pollen exposure and gradually decrease until
the next pollen season. IgE levels usually decrease during
immunotherapy. Many individuals have positive test results
to allergens but show no clinical reactivity to these allergens.
However, as a general rule, the more strongly positive
the test result, the more likely the risk of symptoms.
MAST CELLS
The mast cell is a tissue-based inflammatory cell of
bone marrow origin that responds to signals of innate and
acquired immunity with immediate and delayed release
of inflammatory mediators. Mast cells are implicated in
the pathogenesis of allergic diseases by their ability to be
activated through FceRI-bound antigen-specific IgE.
The human mast cell is ovoid or irregularly elongate
with an oval nucleus and contains metachromatic cytoplasmic granules. In the lungs mast cells are found in
bronchial airway connective tissues and in peripheral intraalveolar spaces. In the skin mast cells appear in greatest
numbers near blood vessels, hair follicles, sebaceous
glands, and sweat glands.
Human mast cells are divided into 2 major subtypes
termed MCT or MCTC on the basis of the presence of tryptase, chymase, or both. Tryptase staining identifies all
mast cells in tissues and has become the principal method
to visualize mast cells. MCTC cells predominate in skin
and small bowel submucosa. MCT cells predominate in
normal airway and small bowel mucosa.10 MCT cells
appear selectively attenuated in the small bowel of patients
with end-stage immunodeficiency diseases. Mast cells are
Kit1 (receptor for stem cell factor [SCF]) and FceRI1 and
express a variety of membrane receptors depending on the
state of differentiation and location. Human resting mast
cells express FceRI and FcgRIIb (CD32) and express
FcgRI (CD64) in the presence of IFN-g. Mast cells might
J ALLERGY CLIN IMMUNOL
FEBRUARY 2006
also express C3a and C5a receptors, IL-3R, IL-4R, IL-5R,
IL-9R, IL-10R, GM-CSFR, IFN-gR, CCR3, CCR5,
CXCR2, CXCR4, and nerve growth factor receptor,
among others.
Development
Human mast cells arise from CD341 pluripotent stem
cells. Mast cell precursors circulate in the blood and
home to tissues, where they mature under the influence
of SCF produced by stromal cells, including fibroblasts
and endothelial cells.11 Mast cell phenotype and behavior
is altered by cytokines, such as IL-4, IL-5, and IFN-g.
For example, IL-4 upregulates expression of FceRI, IL-5
promotes proliferation in the presence of SCF, and
IFN-g decreases mast cell numbers.
Mast cells increase in number several-fold in association with IgE-dependent immediate hypersensitivity
reactions, including rhinitis, urticaria, and asthma; connective tissue disorders, such as rheumatoid arthritis and
scleroderma; infectious diseases, such as tuberculosis
and syphilis; neoplastic diseases, such as lymphoma and
leukemias; and osteoporosis, chronic liver disease, and
chronic renal disease.11 The most striking increase in mast
cells occurs with parasitic disorders and in mastocytosis.
Activation
In addition to aggregation of FceRI (abg2), mast cells
are also activated by C3a and C5a through C3aR and
C5aR (CD88), nerve growth factor through TRKA, and
IgG through FcgRI.12 Mast cells might also be activated
through Toll-like receptors (TLRs). For example, activation through TLR-3 with double-stranded RNA induces
human mast cells to produce type 1 interferons.13 The
extent and pattern of mediators released depends on the
signal, its intensity, and the cytokine milieu. For instance,
mediator release is enhanced in the presence of SCF.
Mediators
Mediators produced by mast cells are divided into
preformed mediators, newly synthesized lipid mediators,
and cytokines. These categories are not absolutely exclusive because at least one cytokine, TNF-a, occurs both
preformed and as a newly synthesized molecule.11
Preformed mediators are packaged within secretory
granules and, on activation, are released into the extracellular environment within minutes. Principal granule
constituents include histamine, serine proteases, carboxypeptidase A, and proteoglycans (heparin and chondroitin
sulfate E). Histamine in granules is found in ionic association with acidic residues of the glycosaminoglycan side
chains of heparin and chondroitin sulfate E and dissociates
in extracellular fluids by exchanging with sodium ions.
Histamine has effects on smooth muscle (contraction),
endothelial cells, nerve endings, and mucous secretion.
It is degraded to N-methyl histamine, methylimidazole
acetic acid, and imidazole acetic acid.
The majority of the protein in granules is made up of
neutral proteases: tryptase, chymase, and carboxypeptidase.
Prussin and Metcalfe S453
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VOLUME 117, NUMBER 2
Tryptase is a tetramer with a molecular weight of 110 to
130 kd with subunits of 31 to 36 kd that is stabilized by its
association with proteoglycans. The function of tryptase
in vivo is unknown, but in vitro it can cleave C3 and C3a,
activate fibroblasts, and promote accumulation of inflammatory cells.
Lipid mediators include prostaglandin (PG) D2, the
major cyclooxygenase product, and lipoxgenase products,
including leukotriene (LT) C4 and the peptidolytic products LTD4 and LTE4. Skin mast cells produce more
PGD2 than LTC4, whereas the opposite is true of mast
cells from the lung. PDG2 and LTC4, LTD4, and LTE4
are all bronchoconstrictors. LTC4, LTD4, and LTE4
enhance vascular permeability.11 PGD2 is a neutrophil
chemoattractant.
TNF-a is a major cytokine produced by mast cells; it
upregulates endothelial and epithelial adhesion molecules, increases bronchial responsiveness, and has antitumor
effects. Other cytokines produced by mast cells include
IL-4, which is associated with TH2 cell differentiation
and IgE synthesis; IL-3, GM-CSF, and IL-5, which are
critical for eosinophil development and survival; and
IL-6, IL-8, and IL-16. Human mast cells also produce
chemokines, such as CCL3 (macrophage inflammatory
protein 1a).
Role in health and disease
Mast cell activation through FceRI initiates an immediate hypersensitivity reaction, as well as a late-phase
reaction. The immediate reaction in the skin presents
as erythema, edema, and itch; in the upper airways as
sneezing, rhinorrhea, and mucous secretion; in the lungs
as cough, bronchospasm, edema, and mucous secretion;
and in the gastrointestinal tract as nausea, vomiting,
diarrhea, and cramping. Such reactions might be followed 6 to 24 hours later by persistent edema and a
leukocytic influx, termed a late-phase reaction. In the
lungs the late-phase reaction is believed to play a major
role in the genesis of persistent asthma. Mast cells might
contribute to the downregulation of the allergic response
in that they produce and release IL-1 receptor antagonist,
heparin, and other molecules with anti-inflammatory
properties.
Mast cells are also implicated in innate immunity.14
Mast cells are capable of phagocytosis and are activated
through pattern-recognition receptors to produce inflammatory mediators.
Pathologic excess of mast cells, usually caused by
activating mutations in Kit, leads to mastocytosis. This
disease can occur in any age group, and in the majority of
situations is first identified because of the appearance of
fixed pigmented skin lesions termed urticaria pigmentosa.
The clinical presentation might also include episodes of
unexplained flushing and hypotension. Mastocytosis varies
from benign or indolent forms to mastocytosis associated
with bone marrow pathology, including myelodysplasia.
This disease is diagnosed on the basis of characteristic skin
findings, an increased serum tryptase level, and specific
bone marrow findings.15
BASOPHILS
Basophils are granulocytes that comprise a separate
lineage from mast cells, although both cells share common
features, such as FceRI expression, metachromatic staining, TH2 cytokine expression, and histamine release. After
activation, basophils rapidly produce IL-4 and IL-13, supporting their contribution to allergic inflammation.16,17
Morphology and phenotype
Basophils exhibit a segmented nucleus and are identified by means of metachromatic staining with basic dyes,
such as toluidine blue. Basophils express a variety of cytokine (IL-3R, IL-5R, and GM-CSFR), chemokine (CCR2
and CCR3), complement (CD11b, CD11c, CD35, and
CD88), prostaglandin (CRTH2), and immunoglobulin Fc
(FceRI and FcgRII) receptors.18
Development
Basophils develop from CD341 pluripotent stem cells,
differentiate and mature in the bone marrow, and circulate
in the periphery. IL-3 is the dominant cytokine driving
basophil differentiation and is sufficient to differentiate
stem cells into basophils. Basophils comprise less than
1% of peripheral blood leukocytes.
Activation
Basophils express a complete and functional FceRI
receptor (abg2), cross-linking of which leads to basophil
activation, granule exocytosis, and mediator release.3 C3a
and C5a also activate basophils through specific receptors.
Activation through any of the above receptors leads to histamine release, eicosanoid synthesis, and IL-4/IL-13 gene
expression. Additional mediators, such as CC chemokines
(eotaxins [CCL11, CCL24, and CCL26], monocyte
chemoattractant protein 3 [CCL7], monocyte chemoattractant protein 4 [CCL13], and RANTES [CCL5]), formylmethionine-leucine-phenylalanine, IL-3, IL-5, GM-CSF,
and histamine-releasing factor,18 do not directly cause
basophil mediator release-production but potentiate FceRI
effects.16
Mediators
Basophils produce a spectrum of mediators, including
histamine, leukotrienes, IL-4, and IL-13.16 Basophils are a
dominant and rapid source of IL-4 in both allergen- and
helminth-specific responses in both human and mouse
systems.19,20 Conversely, the mast cell mediators PGD2
and IL-5 are not produced by basophils.
Role in health and disease
The physiologic role of basophils is not known,
although presumably they fulfill a host defense function.14
A role for basophils in innate immunity is suggested by
their expression of a functional TLR-2 receptor,21 as well
as their non–IgE-dependent activation by proteases from
Der p 1 and hookworm.22 Basophils are known to play a
role in rejection of ticks and are a component of the inflammatory response to many parasites. Basophils produce
S454 Prussin and Metcalfe
IL-4 in response to parasites through both IgE-dependent
and IgE-independent mechanisms. Basophils are the
predominant source of IL-4 in allergen- and helminth
parasite–activated human PBMCs,19,20 as well as in corresponding mouse models. Basophils have been identified in
cutaneous and pulmonary late-phase allergic responses
and are found in increased numbers in the lungs of patients
who die of asthma.17
EOSINOPHILS
Eosinophils are granulocytes that were first described
to stain with acid aniline dyes, such as eosin. Blood
and tissue eosinophilia are hallmark signs of helminth
infection, allergy, and asthma.
Morphology and phenotype
Eosinophils exhibit a bilobed nucleus, with highly
condensed chromatin and cytoplasm containing 2 major
types of granules, specific and primary. Specific granules
have a distinctive ultrastructural appearance consisting of
an electron-dense crystalloid core and contain cationic
proteins that give eosinophils their unique staining properties. Primary granules are similar to those found in other
granulocyte lineages and are formed early in eosinophil
development. Eosinophils also contain lipid bodies, which
play a role in the generation of eicosanoid mediators.
Eosinophils express an array of cell-surface molecules,
including bc family cytokine receptors (IL-3R, IL-5R, and
GM-CSFR), chemokine receptors (CCR1 and CCR3),
FcgRII (CD32), FcaRI (secretory IgA), complement
receptors (C3aR, CD88 and CD35), and adhesion molecules (very late antigen 4 and a4b7 integrin). Eosinophil
expression of FceRI is minimal and is of unclear functional significance (see below).
Development and trafficking
Eosinophils develop and mature in the bone marrow
from CD341 progenitor cells and are released to the
peripheral blood as mature cells. IL-5, the major eosinophil-active cytokine, increases the differentiation and
proliferation of eosinophil precursors in the bone marrow.
In this manner IL-5 produced at sites of allergic inflammation or helminth infection acts distally on the bone
marrow.23-25 Additionally, allergen challenge or the experimental administration of CCL11 (eotaxin) causes bone
marrow release of mature eosinophils and eosinophil
precursors.26
Once released from the bone marrow, eosinophils
circulate in the blood and traffic to tissue. The peripheral
blood half-life is 8 to 18 hours. Although eosinophils
are best known as peripheral blood leukocytes, the vast
majority of eosinophils are located in the gut and lungs.
The steps required for eosinophil trafficking from the
peripheral circulation to tissue have been characterized,
and there is an emphasis on exploiting these mechanisms
to treat asthma.18,23 IL-4 and IL-13 play a central role in
promoting eosinophil trafficking by upregulating CCL11
J ALLERGY CLIN IMMUNOL
FEBRUARY 2006
expression by bronchial epithelial cells and fibroblasts
and increasing endothelial cell vascular cell adhesion
molecule 1 expression. In contrast to CCL11, IL-5 does
not have a major role in promoting eosinophil entry into
tissues. Platelet-activating factor and LTB4 are also potent
eosinophil chemotactic factors.
Activation
There is no consensus on the major signaling mechanism for eosinophil activation. Eosinophils are activated
by cross-linking of agarose beads coated with either IgG,
IgA, or secretory IgA, the latter being the most potent.
Most reports have not demonstrated expression of functional FceRI by eosinophils.2,27 Eosinophils express a
number of TLRs. Their function on eosinophils has not
been clearly defined.
Eosinophils can be primed by a number of mediators,
including IL-3, IL-5, GM-CSF, CC chemokines, and
platelet-activating factor.23,27 Eosinophils obtained from
bronchoalveolar lavage fluid after allergen challenge
demonstrate a primed phenotype, supporting the in vivo
relevance of this priming phenomenon. In contrast to the
importance of IL-5 on eosinophil differentiation and
bone marrow release, GM-CSF might play a greater role
in promoting eosinophil survival in the tissue.23
Mediators and effector function
Eosinophils release proinflammatory mediators, including granule-stored cationic proteins, newly synthesized eicosanoids, and cytokines.27 Highly cationic
(isoelectric point pH 9-11) granule proteins play a role
in host defense and in the pathogenesis of eosinophilmediated diseases.
Major basic protein (MBP) accounts for more than
50% of the eosinophil granule protein mass. MBP has
in vitro toxicity against parasites, including helminths and
schistosomula.24 In patients with asthma, serum and
bronchoalveolar lavage fluid MBP correlate with bronchial hyperresponsiveness.
Additional eosinophil granule proteins include eosinophil-derived neurotoxin and eosinophil cationic protein,
both of which have RNAse activity and demonstrate
in vitro toxicity to parasites,24 as well as single-stranded
RNA pneumoviruses, such as respiratory syncytial virus.
Both the eosinophil-derived neurotoxin and eosinophil
cationic protein genes show exceedingly high rates of
molecular evolution, suggesting the molecules are under
extraordinary selective pressure, as might be expected of
genes responding to the rapid evolution of microbial
pathogens.28
Eosinophils are also a major source of cysteinyl leukotrienes, particularly LTC4, and are the principal LTC4synthase producing cells in asthmatic bronchial mucosa.
Eosinophils are capable of producing a number of cytokines, including IL-1, TGF-b, IL-3, IL-4, IL-5, IL-8, and
TNF-a.29 However, eosinophils generally produce lower
amounts of cytokines than other inflammatory cells, such
as T cells. Eosinophils demonstrate immunomodulatory
J ALLERGY CLIN IMMUNOL
VOLUME 117, NUMBER 2
activity through multiple mechanisms, including secretion
of cytokines, antigen presentation,30 or expression of indolamine 2,3 dioxygenase, leading to kynurenine production, which has anti-TH1 activity.23,31
Role in health and disease
Peripheral blood eosinophil counts are increased in
allergic disease, asthma, and helminth infections, and
tissue eosinophilia is often found at inflammatory sites
associated with these diseases. Despite their in vitro activity against parasites, in vivo studies in IL-5 gene knockout
mice have generally not supported an essential role for
eosinophils in clearing parasitic infections.24
In allergic disease and asthma eosinophils play a proinflammatory role, in which eosinophil mediators, such
as MBP, are thought to cause mucosal inflammation and
consequent bronchial hyperresponsiveness.23 Anti-IL-5
has been used as an investigational asthma therapy and
decreases peripheral blood eosinophil counts by more
than 90%, but only decreased lung eosinophil counts by
approximately 50%. These findings suggest that antiIL-5 alone might not be sufficient to abrogate pulmonary
eosinophilia in asthma.25 Results from both a clinical trial
of anti-IL-5 in asthma and from an eosinophil knockout
mouse asthma model suggest that eosinophils contribute
to airway remodeling, possibly through the elaboration
of TGF-b.
A subset of patients with hypereosinophilic syndrome
has a translocation resulting in a FIP1L1-PDGF-R fusion
protein that acts like an oncogene, resulting in increased
numbers of eosinophils. The resulting fusion protein
receptor kinase is sensitive to the drug imatinib.32
Eosinophil knockout mice have been used in asthma
models, with results supporting a role for eosinophils in
airway remodeling and in mucus production and hyperreactivity.33,34 Further studies with these eosinophildeficient mice, as well as antieosinophil pharmacologic
strategies in human asthma, will ultimately result in a
clearer picture of eosinophil contributions to human
disease.
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6. Asthma: Factors underlying inception,
exacerbation, and disease progression
Robert F. Lemanske, Jr, MD,a,b and William W. Busse, MDb Madison, Wis
This activity is available for CME credit. See page 5A for important information.
Asthma is a heterogeneous disorder that is characterized by
variable airflow obstruction, airway inflammation and
hyperresponsiveness, and reversibility either spontaneously or
as a result of treatment. Multiple causes no doubt exist for both
its inception and symptom exacerbation once the disease is
established. Factors underlying inception can range from viral
respiratory tract infections in infancy to occupational
exposures in adults. Factors underlying asthma exacerbations
include allergen exposure in sensitized individuals, viral
infections, exercise, irritants, and ingestion of nonsteroidal antiinflammatory agents among others. Exacerbating factors might
include one or all of these exposures and vary both among and
within patients. Asthma treatment is determined to a large
extent after an assessment of severity, which can be variable
over time and assessed in 2 domains: impairment (current) and
risk (long-term consequences). Unfortunately, despite the
availability of effective therapies, suboptimal asthma control
exists in many patients on a worldwide basis. The future
development of novel therapies and treatment paradigms
should address these disparities. (J Allergy Clin Immunol
2006;117:S456-61.)
Key words: Asthma, respiratory syncytial virus, rhinovirus, allergen, prevention, exacerbation, inception, treatment
NATURAL HISTORY (INCEPTION AND
PROGRESSION)
For many asthmatic patients, the disease has its roots
during infancy and early childhood. Viral respiratory tract
infections produce wheezing episodes during the first 3
years of life in about 50% of children.1 Some of these children will stop wheezing (transient wheezers), whereas
From the Departments of aPediatrics and bMedicine, University of Wisconsin
Medical School, Madison.
Supported by National Institutes of Health grants 1P01HL70831-01,
HL56396, and AI50500.
Disclosure of potential conflict of interest: R. F. Lemanske has consultant
arrangements with Aventis, AstraZeneca, and GlaxoSmithKline. W.
Busse—none disclosed.
Reprint requests: Robert F. Lemanske, Jr, MD, Departments of Pediatrics and
Medicine, University of Wisconsin Hospital, 600 Highland Ave K4-916,
Madison, WI 53792. E-mail: [email protected].
0091-6749/$32.00
Ó 2006 American Academy of Allergy, Asthma and Immunology
doi:10.1016/j.jaci.2005.07.006
others will go on to have persistent symptoms that will
either dissipate before adolescence (primarily nonatopic
individuals) or continue into adolescence (atopic wheezers).1 Once in remission, the disease process might remain
quiescent or the individual could relapse in later life.2-4
The pattern and rate of loss of lung function in
asthmatic subjects has been of interest and concern to
many investigators. A number of groups have reported
that the greatest absolute loss of lung function appears to
occur very early in childhood.1,4,5 Some have reported that
the peak in lung function that is achieved at about 20 years
of age in patients with asthma might be decreased6 and
that the rate of further loss during adulthood might be
increased in asthmatic subjects.7 About one fourth of
children with asthma could experience greater rates of
loss of lung function, and these children have certain phenotypic characteristics: younger age, male sex, higher
postbronchodilator FEV1 percent predicted, and greater
airway eosinophilic inflammation.8
The precise timing for the inception of the inflammatory
response characteristic of asthma is unknown. Although
recent biopsy studies in wheezing infants who have
documented reversible airflow obstruction do not show
any consistent inflammatory or structural changes (ie,
remodeling),9 other groups have demonstrated increased
numbers of inflammatory cells and mediators in wheezing
preschool children.10 Despite these advances in our understanding of factors contributing to mild persistent asthma
in children and their potential for long-term consequences,
much still needs to be learned.11
Risk factors
Risk factors in relationship to asthma have been evaluated in the context of disease inception (eg, viral infections,12 environmental exposures [eg, aeroallergens,13
pollution,14 and tobacco smoke15-17], lifestyle [eg, living
on a farm,18 diet,19,20 and antibiotic use21], comorbid conditions [eg, atopic dermatitis22 and obesity23], and occupational exposures24 among others), as well as disease
severity (as defined by the risk domain, which is discussed
subsequently: hospitalizations,25 frequency and severity
of exacerbations,14,26,27 and loss of lung function7,17).
Genetic factors also contribute significantly to disease
expression and severity. Asthma is genetically classified