Parasite Immunology, 2010, 32, 1–19
Review Article
Granulocytes: effector cells or immunomodulators in the immune
response to helminth infection?
E. T. CADMAN & R. A. LAWRENCE
Royal Veterinary College, Royal College Street, London, UK
SUMMARY
Granulocytes are effector cells in defence against helminth
infections. We review the current evidence for the role of
granulocytes in protective immunity against different hel-
minth infections and note that for each parasite species the
role of granulocytes as effector cells can vary. Emerging evi-
dence also points to granulocytes as immunomodulatory
cells able to produce many cytokines, chemokines and modu-
latory factors which can bias the immune response in a
particular direction. Thus, the role of granulocytes in an
immunomodulatory context is discussed including the most
recent data that points to an important role for basophils
under this guise.
Keywords animal model, basophils, eosinophil, innate immu-
nity, mast cell, neutrophil
Correspondence: Rachel A. Lawrence, Royal Veterinary College,
Royal College Street, London NW1 0TU, UK (e-mail:
rlawrence@rvc.ac.uk).
Disclosures: None
Received: 5 June 2009
Accepted for publication: 22 June 2009
 2010 Blackwell Publishing Ltd
DOI: 10.1111/j.1365-3024.2009.01147.
Granulocytes are activated during helminth infection and
have long been known to act as immune effector cells.
In vitro granulocyte-mediated immunity against helminths
can be achieved by antibody-dependent cell-mediated
cytotoxicity (ADCC): antibody binds Fc receptor (FcR)
on the cell surface and this initiates cell degranulation
and extrusion of toxic granule contents onto the parasite.
In vivo alterations in gut physiology and mucus produc-
tion are also important granulocyte-mediated effector
mechanisms against gut-dwelling helminths. Neutrophils
are the only granulocytes efficient at phagocytosis and
they can engulf and kill micro-organisms by generation
of reactive oxygen intermediates in phagolysosomes.
However, helminths are too large for phagocytosis and
as a consequence the role of neutrophils in helminth-
driven effector mechanisms has been overlooked until
recently.
Over the last decade a more complex picture of the
role of granulocytes has begun to emerge. These cells
are now known to act both as initiators of particular
immune response pathways and as regulators of ongoing
responses (Table 1). Eosinophils, mast cells and most
recently basophils have been mooted as innate cells
responsible for initiation of Th2 generation. Indeed
these granulocytes can be rapidly recruited to sites of
infection and draining lymph nodes (dLN) where they
produce IL-4 and ⁄ or IL-13. Furthermore, basophils can
produce thymic stromal lymphopoietin (TSLP), which
is known to bias the response to Th2. Granulocytes can
also produce ‘alarmins’ which are structurally diverse
proteins that are rapidly released following pathogen
challenge and ⁄ or cell death. Alarmins act as chemo-
attractants and provide maturation signals for antigen
presenting cells such as DC. They include defensins
(neutrophils), cathelicidins (neutrophils and mast cells),
high-mobility group box protein 1 and the RNAse
eosinophil-derived neurotoxin (EDN) (eosinophils)
[reviewed in Ref. (1)].
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E. T. Cadman & R. A. Lawrence
EOSINOPHILS
In healthy individuals, eosinophils make up only 2–5% of
peripheral white blood cells. However, during active
parasitic helminth infection the proportion of eosinophils
in the blood can reach 40% (2). Together with high IgE
levels and mastocytosis, eosinophilia is considered to be
one of the cardinal features of parasitic helminth infection.
Eosinophils are also well-known for their role in asthma
and other allergic diseases of the respiratory system, and
they play a prominent role in gastrointestinal (GI) disor-
ders such as eosinophilic oesophagitis (EE), eosinophilic
gastritis, inflammatory bowel disease and gastro-oesopha-
geal reflux disease [reviewed in Ref. (3)].
Eosinophils have bi-lobed nuclei and three distinct cyto-
plasmic granules: eosinophil-specific granules, which have a
crystalloid electron-dense core; primary granules, which
have no crystalloid core and develop early in maturation;
and smaller granules, which contain enzymes such as
arylsulfatase. Eosinophils also contain lipid bodies, which
contribute to the formation of eicanosoid mediators. Four
eosinophil-specific toxic proteins are stored in granules,
major basic protein-1 (MBP-1), eosinophil peroxidase
(EPO), EDN and eosinophil cationic protein (ECP). MBP,
EPO and ECP are potent helminth toxins, MBP can induce
histamine release from mast cells, while both EDN and
ECP can act as ribonucleases (4,5). Granules also contain a
number of cytokines and chemokines as preformed proteins,
such as IL-4 and IL-13, which can be rapidly and selectively
released. Primary granules contain Charcot-Leyden crystals
(CLC) protein also known as galectin-10 (6).
Eosinophils are capable of piecemeal degranulation, allow-
ing selective release of granule proteins in a process mediated
by eosinophil sombrero vesicles (4,7). Degranulation is trig-
gered by FcRs recognizing antibody-bound antigen; several
cytokines including IL-3, IL-5, granulocyte macrophage col-
ony stimulating factor (GM-CSF), TNF, IFN-b, and platelet
activating factor (PAF) can both enhance, or directly trigger
this process. Human eosinophils express FccRI, FccRIIa,
FccRIIb, FccRIII, FceRII and FcaR. Interestingly, mouse
eosinophils are fundamentally different from human eosin-
ophils in that they do not express the high-affinity IgE FcR,
FceRI, and therefore do not degranulate as readily. This has
resulted in some debate as to the suitability of the mouse as a
model for the study of human eosinophil biology. The recent
development of an IL-5 ⁄ eotaxin-2 transgenic mouse in which
extensive eosinophil degranulation accompanies an asthma
model of pathology should help to clarify this aspect of
eosinophil function (8).
Eosinophils develop in the bone marrow, and their
growth is promoted by IL-5, IL-3 and GM-CSF (9). These
cytokines induce the transcription factor, GATA-1, which
2  2010 Blackwell Publishing Ltd, Parasite Immunology, 32, 1–19
Parasite Immunology
is essential for eosinophil development (10). PU.1 and
members of the C ⁄ EBP family are also involved in eosino-
phil development (11). Release of eosinophils from the
bone marrow into the peripheral blood circulation is medi-
ated by IL-5 (12) and eosinophils are then recruited to the
tissues by the chemokines eotaxin-1 (CCL11), eotaxin-2
(CCL24) and eotaxin-3 (CCL26), which bind to the recep-
tor CCR3 [reviewed in (13)]. Eotaxin-1, IL-5 and RAN-
TES are the primary molecules involved in recruitment of
eosinophils to the lung (14,15). Eotaxin-3 is upregulated
in GI-tract disorders such as EE (16) and eotaxin-1 is also
important in homing to the GI tract (17). Some helminths,
for example, Necator americanus are able to specifically
cleave eotaxin to inhibit the recruitment of eosinophils to
the infection site (18).
Eosinophils as effector cells in helminth infections
The role of eosinophils as effector cells has been difficult
to study during human helminthic infection, and conse-
quently, the majority of studies to date, have dissected the
role of eosinophils in animal models of disease.
In human filariasis, a rare clinical manifestation is tropi-
cal pulmonary eosinophilia (TPE), where asthma-like
symptoms are caused by filarial infection of Brugia malayi
or Wuchereria bancrofti. Microfilariae die in the lungs and
induce an inflammatory response. The pathology of TPE
has been associated with heightened levels of EDN in both
broncho-alveolar lavage fluid and serum, which damages
the lung epithelium through its RNase activity (19).
In vitro the eosinophil granule proteins, MBP, EPO, EDN
and ECP have all been shown to kill Brugia spp. microfila-
riae (20). However, in in vivo filarial-mouse models, the
requirement for eosinophils and the eosinophil granule
proteins EPO and MBP in clearance of parasites depends
upon the parasite species, the parasite stage and whether
the response is an innate response to primary infection or
an adaptive response to secondary infection. Additionally,
the results come from multiple different model systems
which may not always be directly comparable, for example,
studies have used Onchocerca sp. L3 in a chamber model,
Brugia sp. in a nonnatural intra-peritoneal site or Litomos-
oides sigmodontis which invades the thoracic cavity unlike
human infections.
In models of brugian filariasis, the presence of eosin-
ophils is necessary for killing of primary, but not second-
ary infections for both B. pahangi L3 and B. malayi
microfilariae (21,22). Interestingly the eosinophil-mediated
clearance of primary B. pahangi L3 infection was not
dependent on the presence of either EPO or MBP (23).
However, the clearance of primary but not secondary
B. malayi microfilarial infections, was associated with high
Volume 32, Number 1, January 2010
levels of serum EPO. This suggests that during primary,
but not secondary, infection eosinophils degranulate in the
blood (22). In secondary B. malayi microfilariae infections
degranulation does occur in the lung and MBP can be
seen on the surface of the airway epithelial cells. This
degranulation is associated with airway hyper-responsive-
ness (24) reminiscent of the eosinophil-associated remodel-
ling of the lung that occurs in asthma models (25,26).
In contrast to work with Brugia sp., eosinophils increase
clearance of both primary and secondary infections of
Onchocerca volvulus L3. Eosinophils and serum IgE are
required for the induction of immunity to a challenge L3
infection although in both primary and secondary infec-
tion eosinophil-mediated killing is independent of EPO
(27). Death of onchocercal microfilariae following amocar-
zine treatment is, however, associated with eosinophil
degranulation and ECP deposition (28).
In the closely related filarial mouse model, L. sigmodontis,
eosinophils can play a protective role in both primary and
secondary infection. However, their role varies according
to the mouse strain used. Over-expression of IL-5 in
susceptible BALB ⁄ c mice, greatly reduced adult worm
recovery from a primary L3 infection and the worms
become surrounded by deposits of MBP. In nonpermissive
mouse strains (C57Bl ⁄ 6), IL-5 is not necessary for control
of parasite recovery during primary infection, but does
play an important role in protective immunity following
immunization (29). In contrast in another nonpermissive
strain, deficiency in either EPO or MBP enhanced
L. sigmodontis L3 establishment although the nematodes
still do not survive long enough to reach patency. This
study also revealed an interaction between eosinophil gran-
ule proteins and the cytokine responses of macrophages
and CD4+ T cells, which could play a role in worm estab-
lishment (30). For example IL-10 production is elevated in
the absence of EPO or MBP, while IL-5 production is
elevated in the absence of EPO alone. IL-4 production is
reduced in both infected and noninfected EPO or MBP) ⁄ )
mice. Indeed the role of eosinophils in primary infection in
BALB ⁄ c mice is unlikely to be in ADCC as absence of B
cells does not alter worm recovery. In secondary infections
B cells are necessary for eosinophil degranulation and
therefore likely play a role in ADCC (31,32).
Purified eosinophil granule proteins can kill Schistosoma
mansoni schistosomulae (33), and Trichinella spiralis new-
born larvae in vitro (34). However, although eosinophilia
is induced during infection with S. mansoni, eosinophil-
deficient (dblGATA) mice exhibit no obvious defects in
the immune response to this parasite in vivo (35). Indeed,
the lack of eosinophils had no effect on worm burden, egg
deposition, granuloma number, granuloma size or fibrosis
detected at weeks 8 or 12 of infection (35). Thus, the main
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Granulocytes in helminth infection
function of eosinophils in this infection maybe in tissue
remodelling and debris clearance following injury (35).
Similarly although Nippostrongylus brasiliensis infected
animals develop IL-5-dependent eosinophilia, mast-cell
hyperplasia and polyclonal IgE, none of these factors plays
a role in expulsion of a primary infection (36). Eosinophil-
deficient mice (dblGATA) mice exhibit normal expulsion
of a primary N. brasiliensis infection. In addition these
eosinophil-less mice have unaltered Th2 responses, basophil
accumulation and IgE production showing that eosinophils
play little role in these responses during N. brasiliensis
infection (37). In contrast, eosinophils do contribute to
expulsion of secondary N. brasiliensis infections as
dblGATA mice depleted of CD4+ T cells have significantly
greater worm burdens than WT mice depleted of CD4+ T
cells (38). Similarly studies with T. spiralis in IL-5) ⁄ ) mice
showed larger worm burdens and slower expulsion in
secondary but not primary infections (39).
Eosinophils as modulators of the immune response
In detailed studies of the role of eosinophils during
Strongyloides stercoralis infection, eosinophils emerge as
effectors during primary infection when they degranulate
and are directly involved in killing (40,41). In secondary
infection they play a more immunomodulatory role and
their presence is required for the initiation of a protective
IgM-mediated response (40).
The ways in which eosinophils modulate immune
responses are only beginning to be discovered. Eosinophils
cultured in vitro are able to function as antigen-presenting
cells and present S. stercoralis antigen to nave CD4+ T cells
(42). If this also occurs in vivo, eosinophils could amplify
antigen-specific T-cell responses and potentially modulate
the adaptive immune response by expressing either Th1 or
Th2 cytokines (42,43). Furthermore, eosinophil granule
proteins themselves have been shown to modify immune
responses in L. sigmodontis infection (30). MBP-1 and EPO
deficient mice showed increased IL-10 production and
EPO) ⁄ ) mice had increased IL-5 production during
L. sigmodontis infection, additionally both knockout strains
had reduced IL-4 production with or without infection (30).
Interestingly EDN secretion by eosinophils has recently
been shown to induce migration and maturation of DCs, as
well as enhancing Th2 responses via Toll-like receptor
(TLR) 2 activation (44). EDN-stimulated splenocytes
produced enhanced levels of IL-5, IL-6, IL-10 and IL-13
cytokines, as well as higher levels of IgG1 than IgG2a
suggesting that EDN acts as an alarmin that alerts the
immune system for preferential Th2 immune responses.
Eosinophils can also recruit T cells into sites such as the
lung through the expression of CCL17 and CCL22 (45).
3
E. T. Cadman & R. A. Lawrence
Indeed eosinophils indirectly affect the development of
respiratory symptoms through their effects on nerves in
the lung. Eosinophils adhere to parasympathetic nerves
via vascular cell adhesion molecule (VCAM)-1 and inter-
cellular adhesion molecule (ICAM)-1 (46), and release
their granule proteins including EPO, MBP-1 and leukotri-
enes (46,47). MBP-1 blocks inhibitory receptors on nerves,
thereby increasing stimulation of airway smooth muscle
(48). Substance P, a neuropeptide, can also stimulate
eosinophil degranulation (49), providing the potential for
a positive feedback loop of nerve activation. Anti-cholin-
ergic drugs, which would be expected to decrease nerve
excitation, can in fact increase eosinophil activation and
degranulation, thereby exacerbating asthma-like symptoms
(50). Eosinophils can even influence the morphology of
nerves by inducing neurite retraction (51).
Thus, although the role of eosinophils as secretors of
helminthotoxic molecules has been known for some time,
the advent of mouse strains deficient in particular eosino-
phil granule proteins has advanced our understanding of
the function of eosinophils and their associated granule
proteins. In the next few years, the role of eosinophils as
immunological modulators will become more apparent.
MAST CELLS
Mastocytosis is intimately associated with helminth infec-
tions particularly those that live in the intestinal tract.
Mast cells are distributed throughout the connective tis-
sues and lie adjacent to blood and lymphatic vessels,
nerves and epithelial surfaces. Mast cells are most closely
related to basophils, with which they share a common pro-
genitor (52). They are derived from CD34+ progenitor
cells in the bone marrow, and unlike other granulocytes,
mast cells mature in the periphery following interaction
with stem cell factor ⁄ c-kit ligand (SCF) (53). In fact, SCF
is an absolute requirement for mast cell development and
mice lacking c-kit function (W ⁄ Wv) do not produce these
cells (54,55). Despite upregulation in many helminth dis-
eases they are not always necessary for clearance (see
below). However, the protective response to T. spiralis
infection is notably highly dependent on mast cells.
The classical function of mast cells is as end-stage effector
cells, releasing proteases and inflammatory proteins such as
histamine during degranulation. Their granules also contain
preformed cytokines e.g. IL-4 and IL-13 (5). Mast cells
express the high affinity IgE receptor, FceRI, which when
cross-linked by antigen, triggers degranulation (56). They
are generally divided into two types, mucosal mast cells
(MMC) and connective tissue mast cells (CTMC), defined
by anatomic location, granule contents, and function (57).
MMC in mice express MMC protease-1 (mMCP-1) (rMCP-
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Parasite Immunology
II in rats) and tryptase, they are dependent on T cells and
are located predominantly in the lung and nasal cavity and
intestinal epithelia (58–60). MMC are shorter lived than
CTMC (<40 days), have more FceR and also have cytoplas-
mic IgE. CTMC produce tryptase, chymotryptase, heparin
and histamine, are T-cell-independent and are predomi-
nantly in the skin and sub-epithelial mucosa of the respira-
tory and intestinal tracts (57,61). Both cells produce
arachadonic acid metabolites although the amount and type
varies between the two types of mast cells.
Mast cells are recruited to the small intestine by the in-
tegrin a4b7 (62) and to the lungs by both a4b7 and a4b1
(63). For small intestinal homing, a4b7 binds the ligand
MAdCAM-1, however for homing to the lung the a4 inte-
grins bind VCAM-1. Because of the importance of a4b7
for small intestine mast cell responses, protection against
T. spiralis, but not T. muris (which colonizes the large
intestine) is delayed in b7-integrin deficient mice (62,64).
Other chemotactic factors for mast cells include SCF,
which in addition to its role as a growth factor can act as
a chemotactic factor for mast cell exit from the bone mar-
row (65). Cytokines such as TNFa, IL-8 and IL-4, chemo-
kine receptors such as CCR3 and CXCR3 and antigen
cross-linking IgE are also chemotactic for mast cells (66–
68). Monomeric IgE in the absence of antigen can pro-
mote both mast cell survival and the release of mast cell
cytokines (69–72).
Mast cell products
IgE and antigen triggers degranulation of mast cells, and
in mice this is also achieved by IgG1 binding to FccRIII
[reviewed in Ref. (73)]. It was previously thought that
helminths suppress allergic responses by stimulating large
quantities of polyclonal IgE which saturate the high affin-
ity receptor on mast cells [reviewed in Ref. (74)], however
no correlation between levels of serum IgE and histamine
production has been demonstrated in helminth-infected
patients (75). Indeed even small quantities of antigen-spe-
cific IgE are sufficient to trigger mast cell degranulation,
despite the simultaneous presence of nonspecific IgE (76).
Histamine itself further induces mast cell degranulation
indirectly by affecting nonmast cell function and both IL-
10 and SCF will enhance histamine secretion (77,78).
Mast cells produce a wide array of cytokines, the pro-
duction of which can be stimulated by IL-3 and IL-18, in
the absence of IgE cross-linking (79). TLR ligand activa-
tion by LPS or peptidoglycan (PGN) leads to differential
cytokine secretion; LPS stimulates TNFa, IL-6, IL-1b and
IL-13 while PGN stimulates, IL-4, IL-5, IL-6 and IL-13
respectively (80,81). TLR2 and TLR4 ligation also
enhance degranulation mediated by FceRI (82).
Volume 32, Number 1, January 2010
Mast cells also secrete a number of chemoattractants
including chemokines and mast cell proteases (83). Indeed,
mMCP-6) ⁄ ) mice have defective eosinophil recruitment to
the site of T. spiralis larval infection and this results in
reduced larval necrosis (84). Injection of recombinant
mMCP-6 (but not the closely related mMCP-7) can induce
migration of neutrophils into the peritoneal cavity of unin-
fected mice (85,86). Other secreted proteases such as trans-
membrane tryptase (TMT) may increase pathology
following degranulation; TMT can amplify IL-13 produc-
tion from T cells and induce tracheal airway hyperrespon-
siveness (87). Thus mast cells can influence the activity of
other cells of the immune system by the release of granule
products, including cytokines, chemokines and proteases
[reviewed in (88)].
Necessity for cytokines in development and effector
activity of mast cells
Mast cells are important in the immune response to many
helminth infections, particularly T. spiralis, S. ratti, Heligmo-
somoides polygyrus, S. mansoni and Haemonchus contortus
(89–94). However, despite upregulation in a number of
helminth infections, as mentioned above, the role of mast
cells in parasite clearance is less critical. Mast cells play an
important role in expulsion of T. spiralis, however, mast cells
are not critical for expulsion of GI parasites such as T. muris
or N. brasiliensis (95,96) or for the development of vaccine-
induced immunity to S. mansoni in mice (93,97,98).
Much of what is known about mast cells has been dis-
covered in humans or mice with particular cytokine defi-
ciencies. Indeed the T-cell dependency of some mast cell
populations is demonstrated by the absence of intraepithe-
lial intestinal MMC from humans and mice that have T-
cell deficiencies. IL-3, IL-4, IL-9 and IL-10 are all Th2 cell
cytokines that are known to influence mast cell develop-
ment and phenotype (99,100). The necessity for these cyto-
kines in mast cell development has largely been analysed
using mouse models of helminth infection (see below).
A useful tool in analysis of mast cell function has been
the dependence on mast cells for expulsion of the hel-
minth, T. spiralis. Thus, mast-cell deficient W ⁄ Wv mice or
mice treated with anti-SCF are unable to expel T. spiralis
(68). Mast cell protease-1 is known to be critical in T. spi-
ralis clearance, as mMCP-1) ⁄ ) mice have delayed expul-
sion and increased deposition of larvae in the muscles
(101). The importance of IL-10 in mast cell development
is demonstrated by a reduction in mast cells and mMCP-1
production in the gut leading to delayed expulsion of
T. spiralis in IL-10-deficient mice while muscle larval death
is increased due to increased production of IFN-c (102).
Interestingly, the fecundity of N. brasiliensis is increased
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Granulocytes in helminth infection
SCF presence, although MCP-1 has no effect on N. brasili-
ensis infection (103).
IL-3 is necessary for jejunal mast cell hyperplasia during
infection with Strongyloides venezuelensis (104). In con-
junction with SCF, IL-3 also promotes cytoplasmic gran-
ule formation in immature mast cells and IL-3 is often
used to culture mast cells in vitro (105) (despite this how-
ever, IL-3) ⁄ ) mice can still expel T. spiralis as efficiently as
wild-type mice (68)]. Wild-type mice, but not W ⁄ Wv mice,
treated with IL-18 and IL-2, mediate rapid expulsion of
adult S. venezuelensis (as do IL-18 ⁄ IL-2 treated Stat6) ⁄ )
mice) while IL-18) ⁄ ), IL-18Ra) ⁄ ) or Stat6) ⁄ ) mice have
delayed S. venezuelensis expulsion (106). The data suggest
an innate IL-18-dependent MMC activation and a Th2
cell-dependent (acquired type 2) MMC activation is neces-
sary for S. venezuelensis expulsion (106).
The importance of other cytokines for generation of
mastocytosis has also been shown in helminth model sys-
tems. Together, IL-9 and SCF promote differentiation
towards the MMC phenotype. IL-9 transgenic mice gener-
ate a huge mastocytosis and rapidly expel both T. spiralis
and T. muris (107–109). In addition, IL-9) ⁄ ) mice do not
develop jejunal or large intestinal mastocytosis during
N. brasiliensis or T. muris infection respectively which
delays expulsion of T. muris. In another system, IL-4
and IL-10 together can promote mast cell differentiation
in vitro and these cells can rescue impaired immunity to
S. venezuelensis in phosphatidylinositol-3 kinase deficient
mice, which lack GI mast cells (110).
Some cytokines may have slightly differing roles in
human and mouse mast cell development, for example, IL-4
is a mast cell growth factor in mice (99), while in humans
the evidence is conflicting, although in combination with
SCF, IL-4 is now thought to enhance mast cell proliferation
and Th2 cytokine expression (111–113). In the absence of
IL-4, mast cells produce TNFa and IL-18. Recently, it has
been shown that the source of this IL-4 for mast cell devel-
opment may be basophils (see ‘Basophils’ section).
In contrast to the Th2 cytokines, IFN-c suppresses
mouse mast cell differentiation and induces apoptosis
(114) but promotes survival of human mast cells (115).
TNFa (116), IL-6 (111) and nerve growth factor (117) can
all promote mast cell development in concert with IL-3.
The transcription factors GATA-1 and GATA-2 are
involved in mast cell development (118,119), as is PU.1
(120), which is essential for mast cell generation in the
presence of GATA-2.
Pathology
Although mast cells are important in immune responses to
many helminth parasites, they may also be the cause of
5
E. T. Cadman & R. A. Lawrence
excess pathology during helminth infection. Mice which
lack either mast cells or MCP-1 have reduced intestinal
pathology during T. spiralis infection (121). MCP-1
degrades occludin, causing impairment of the epithelial-
cell barriers and increased mucosal leakiness (122). Other
mast cell products such as histamine and prostaglandins
have similar effects on epithelial cell barrier disruption.
Interestingly mast cells can prevent establishment of
S. venezuelensis by secreting glycosaminoglycans that
inhibit the adhesion of worms to the epithelial cells (123).
Mast cells and antigen presentation
There is a growing body of evidence linking mast cells to
the function of antigen-presenting cells. Histamine has
been shown to improve the uptake of soluble antigens by
DCs and the cross-presentation of these antigens on MHC
class I molecules (124). Indeed mast cell histamine, prosta-
glandin E2 and TNFa, can act on DC chemokine expres-
sion to favour the recruitment of Th2 cells (125).
Histamine and IL-3 can also influence the production of
Th1 and Th2 responses through the histamine receptors,
H1 and H2, on T cells (126). Indeed mast cells themselves
are able to act as antigen-presenting cells to T cells
in vitro; they can express MHC Class I and II, as well as
CD28, CD80 and CD86 (127–130). However, whether
mast cells play a role as APC during helminth infection
in vivo is not known.
Stimulation of mast cells by parasite antigens
Relatively few parasite antigens that bind IgE and induce
mast cell degranulation have been identified. In N. brasili-
ensis, Nb-Ag1, a pharyngeal antigen, (possibly a digestive
enzyme) is known to bind IgE and cause mast cell degran-
ulation during primary, secondary and tertiary infection.
This response does not occur in IgE) ⁄ ) mice. The IgE is
likely to be antigen-specific, as although no anti-Nb-Ag1
IgE was detected by ELISA during primary infection,
when infected with H. polygyrus there is no degranulation
of basophils in response to N. brasiliensis antigen (76).
Inhibition of mast cells by parasite products
The importance of mast cells in immunity to some para-
sitic infections is demonstrated by the evolution of para-
sitic molecules that combat mast cell products. A. viteae
secretes a protein, ES-62, which can inhibit mast cell
degranulation by complexing with TLR4 and PKCa and
inducing degradation of PKCa (a regulator of mast cell
responses). The initial peak of calcium mobilization nor-
mally triggered by the high affinity Fce receptor is pre-
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vented by ES-62, which also selectively inhibits mast cell
TNFa, IL-3 and IL-6 but not IL-5 or IL-13 (131).
Another nematode, T. suis, expresses a chymotrypsin
inhibitor which can inhibit chymase (mouse mast cell pro-
tease-1, mMCP-1), as well as neutrophil elastase and
cathepsin G (132). In contrast, some parasite products,
such as the body fluid of the nematode parasite Ascaris
suum, appear to promote histamine release (133).
Given the wide array of cytokines, chemokines and
other immunomodulatory factors that are produced by
mast cells, the classic view of mast cells as simple effector
cells is rapidly changing. We can expect that in the near
future more will be learnt of their role in directing anti-
helminth immunity either by secretion of stimulatory fac-
tors or indeed by playing a part in antigen presentation.
NEUTROPHILS
Neutrophils develop in the bone marrow. They rapidly
accumulate at the site of an infection, kill invading bacte-
ria and regulate the inflammatory response in wound heal-
ing and tissue repair. Neutrophils are often the first cells
to be recruited to a site of inflammation, where they
engulf microorganisms by phagocytosis. Once in the
phagolysosome, the respiratory burst and formation of
oxidative (reactive oxygen species) and nonoxidative mech-
anisms kill and degrade pathogens. Appelberg (134) also
recently suggested that neutrophils may play a nonphago-
cytic role in the transfer of pathogen to local lymph nodes,
in Ag presentation and in early T-cell recruitment. Because
of their predominant function in phagocytosis of micror-
ganisms, until recently the role of neutrophils in combat-
ing helminth infection has been largely ignored.
Neutrophils highly express Ly-6G (Gr-1), as do a subset
of monocytes (Gr1+ F4 ⁄ 80+ alternately activated macro-
phages), DCs and eosinophils. They contain four types of
granule: azurophil (primary), specific (secondary), gelati-
nase (tertiary) and secretory. The primary granules contain
myeloperoxidase acid hydrolases, lysozyme, bacterial per-
meability-increasing protein, defensins and serine proteases
(cathepsin G, neutrophil elastase and proteinase 3). The
secondary granules contain lactoferrin and lysozyme [see
Ref. (135) for a review of neutrophil serine protease biol-
ogy].
In 2004, Tsuda et al. (136), proposed three distinct sub-
sets of neutrophils (PMN-I, PMN-II and PMN-N) distin-
guished as follows: (1) cytokine and chemokine
production (PMN-I, IL-12 ⁄ CCL3; PMN-II, IL-10 ⁄ CCL2;
PMN-N, no cytokine ⁄ chemokine production), (2) macro-
phage activation (PMN-I, classically activated macrophag-
es; PMN-II, alternatively activated macrophages; PMN-N,
no effect on macrophage activation), (3) TLR expression
Volume 32, Number 1, January 2010
(PMN-I, TLR2 ⁄ TLR4 ⁄ TLR5 ⁄ TLR8; PMN-II, TLR2 ⁄
TLR4 ⁄ TLR7 ⁄ TLR9; PMN-N, TLR2 ⁄ TLR4 ⁄ TLR9) and
(4) surface antigen expression (PMN-I, CD49d+CD11b);
PMN-II, CD49d) CD11b+; PMN-N, CD49d) CD11b).
This is useful as an illustration of the plasticity of neu-
trophils, however general use of these terms has not (yet)
been adopted.
Recruitment of neutrophils
During helminth infection, as with inflammatory models,
neutrophils are the first cells to be recruited. For example,
in filarial models in which B. pahangi L3 are injected into
the peritoneal cavity of mice or in the dermis of gerbils,
there is an innate peak of neutrophil recruitment at 24 h,
however by day 4 post-infection this influx disappears
(137,138). In mice even in the absence of T cells, B cells or
both, neutrophils are still recruited. In contrast to neutro-
phils, eosinophil recruitment, starts at day 10 and is
dependent on the presence of T cells.
In fact during L. sigmodontis filarial infections, neu-
trophils have been suggested to play a protective role.
IFN-c) ⁄ ) (BALB ⁄ c) mice have a twofold increase in worm
recovery, reduced neutrophilic infiltration and the worms
are less encapsulated in nodules than in wild-type mice.
TNF-a, a major neutrophil activation factor is greatly
reduced in IFN-c) ⁄ ) compared to wild-type mice. Further-
more neutrophil chemotactic and phagocytic ability is
impaired (139). Similarly, in the absence of IL-5 alone,
worm recovery was increased and there were no nodules
around the worms (140). When IFN-c, in addition to IL-
5, was absent the worm recovery was more greatly
enhanced suggesting a synergy between IFN-c and IL-5 in
induction of immune responses. The authors concluded
that higher adult worm counts were mediated by lower
neutrophil recruitment however these doubly-deficient
mice had lower neutrophils, macrophages, NK cells, CD4+
cells, reduced phagoctyosis and reduced TNF-a from mac-
rophages compared to wild-type mice. Interestingly, higher
microfilarial counts associated with reduced level of accu-
mulation of neutrophils in the thoracic cavity were found
in IL-5) ⁄ ) mice, but there was no additional increase in
microfilariae with the loss of IFN-c, suggesting that
microfilariae are not be affected by loss of neutrophilia
(140).
In our own studies (Simons et al., in preparation),
reduced survival of B. malayi microfilariae in the blood
stream of CBA mice was associated with an early peak
(24 h) of blood neutrophilia compared to C57Bl ⁄ 6 mice.
In addition, microfilarial, but not adult nematode, survival
in the peritoneal cavity was greatly reduced in the absence
of IL-10 and this was associated with an influx of
 2010 Blackwell Publishing Ltd, Parasite Immunology, 32, 1–19
Granulocytes in helminth infection
neutrophils. However, anti-Gr1 treatment (which com-
pletely abrogated neutrophils but did not affect other leu-
cocytes) showed that neutrophils were not essential for
clearance of primary or secondary infections of intrave-
nous microfilariae. In contrast neutrophils have however
been reported to play a role in the clearance of secondary
O. volvulus L3 infections in mice (27).
Recruitment of neutrophils to the site of filarial worm
infection may in part be a response to the symbiotic Wol-
bachia sp. bacteria contained in these worms. This is evi-
denced by the fact that neutrophils accumulate around
O. volvulus worms (which contain Wolbachia sp.) while
neutrophil accumulation is reduced in infected patients
following doxycycline (DOC) treatment, which kills
Wolbachia. Interestingly the deer filariae, O. flexuosa which
does not contain Wolbachia does not attract neutrophils
around it. Furthermore, O. volvulus extracts induce TNF-a
and IL-8 in monocytes but following treatment with DOC
they no longer induce these cytokines (141).
That neutrophils can be protective against nematode
parasites has been shown most definitively in the Strongy-
loides sp. model. Immune serum or purified IgM or IgG
can transfer protective immunity against S. stercoralis L3
in mice. The protective IgM response is complement and
granulocyte dependent but ADCC-independent (142). If
deoxycholate-solubilized L3 are used to immunize, the
protective response is IgG-dependent in an ADCC-inde-
pendent manner (143). In contrast if IgG is raised in mice
immunized with live S. stercoralis L3 (rather than antigen)
the response requires complement activation and neu-
trophils for killing through an ADCC mechanism. Thus,
IgM and IgG antibodies can both be protective against
larval S. stercoralis, but they recognize different antigens
and utilize different killing mechanisms which may or may
not involve neutrophils (144) [granulocytes, most likely
neutrophils, are also crucial in controlling S. ratti in mice
(145)]. Importantly, neutrophils are shown to be required
for killing S. stercoralis L3 in the diffusion chamber
mouse model in CXCR2) ⁄ ) mice. These mice are deficient
in the IL-8 receptor homologue, have a defect in neutro-
phil recruitment and in both innate and adaptive immu-
nity to S. stercoralis L3 (41). Later studies showed that
Gai2 protein is required for neutrophil recruitment and
efficient larval killing of S. stercoralis in mice (146).
Neutrophil modulation of helminth-induced immune
responses
Neutrophils can also play an immuno-modulatory role in
helminth infections and in some circumstances they can
drive the response toward the Th2 phenotype. In N. brasil-
iensis infection, Gr1+ cells expressing TGF-b and TNF-a,
7
E. T. Cadman & R. A. Lawrence
transiently enter the dLN at 18 h post-infection. Anti-
Gr1+ treatment causes an increase in IFN-c and serum
IgG2a together with a systemic bacterial infection (pre-
sumably due to carry of bacteria from faecally derived
L3), decreased host survival, reduced Th2 (IL-4 and IL-
13) differentiation and serum IgE and delayed worm
expulsion (147). Interestingly, treatment of N. brasiliensis
L3 with antibiotic before inoculation eliminated bacteria
and restored the protective Th2 response in anti-Gr1-trea-
ted mice. Therefore neutrophils limit inflammation and
host mortality (60–80% mortality if Gr1-treated) generated
by nematode-associated bacterial infection and help to
induce optimal Th2 responses. Indeed during Leishmania
major infections in BALB ⁄ c mice neutrophils are a source
of early IL-4 (148). CCL2 is a chemokine that is known
to attract neutrophils in an endotoxin lung model and to
induce Th2 in a sepsis model (149). It is surprising, in
light of the above results, that although neutrophil infiltra-
tion into the lymph node following N. brasiliensis in
CCL2) ⁄ ) (MCP-1) ⁄ )) mice is abrogated neither worm
recovery nor egg deposition are not significantly affected.
T. muris expulsion is delayed in CCL2) ⁄ ) mice and
absence of CCL2 results in decreased monocytes in the
large intestine, increased IL-12, lower IL-4, and higher
Th1 induction, however the role of neutrophils was not
examined in this study (150).
In mouse models of schistosomiasis there is some evi-
dence that neutropenia augments egg-induced granuloma
formation, through an increase in Th2 cytokines, however
this differs with different genetic mouse strains (151). Neu-
trophils may modulate the epithelial cell response to
T. spiralis as during infection, epithelial cells produce
interleukin-1b (IL-1b), the neutrophil chemotactic factor,
macrophage inflammatory protein-2 (MIP-2), and an IL-1
antagonist, type II IL-1 receptor (152). Blocking neutro-
phil migration results in reduced levels of epithelial cyto-
kine mRNA, suggesting that neutrophil infiltration
stimulates the epithelial cell cytokines.
The role of neutrophils in helminth-induced pathology
In some infections neutrophils have been found to exacer-
bate helminth-induced pathology. In a mouse model of
corneal disease caused by O. volvulus infection, antibody
to PECAM inhibited neutrophil, but not eosinophil,
recruitment to the cornea and corneal opacification was
significantly diminished. In contrast if eosinophil but not
neutrophil, infiltration was diminished by antibody to
ICAM corneal opacification was unchanged (153). TLR2
(but not TLR4 or TLR9) is necessary for neutrophil infil-
tration and in the absence of TLR2, mice do not develop
corneal haze. It is thought that Wolbachia may activate
8  2010 Blackwell Publishing Ltd, Parasite Immunology, 32, 1–19
Parasite Immunology
TLR2 (154). Further evidence supporting the role of neu-
trophils in this model is seen in CXCR2) ⁄ ) (homologue
for IL-8) mice in which neutrophil, but not eosinophil
recruitment was significantly impaired and they develop
only mild corneal opacification (155). Interestingly Wolba-
chia surface protein has been shown to inhibit apoptosis
of human neutrophils which may further exacerbate
pathology caused by filarial parasites (156).
Counter active immune evasion
Several helminths secrete products that aid neutrophil
recruitment. For example, A. suum and T. canis products
induce a strong chemotactic response in human neutro-
phils, they induce neutrophil shape change, and they induce
rapid and strong Ca2+ responses in the cytosol. A. suum
products also interact with pertussis toxin-sensitive G pro-
teins through the IL-8R pathway and induce activation
and chemotaxis of neutrophils (157). Necator americanus
also produces a neutrophil recruitment factor Na-ASP-2
(158) while B. malayi asparaginyl-transfer RNA synthetase
is an immunodominant antigen that induces chemotaxis of
human neutrophils, eosinophils, leukocytes and activates
G-protein-coupled receptors CXCR1 and CXCR2 (159).
As yet the evolutionary significance of attracting these
cells is not fully understood.
Other helminths produce factors, which may regulate
the pro-inflammatory action of neutrophils. A protein,
gp55, secreted by blood-feeding adult stages of H. contor-
tus, but not L3 stages, inhibits neutrophils by binding via
CD11b ⁄ CD18 and reduces their H2O2 production (160).
Moyle et al. also identified a neutrophil inhibitory factor
(NIF) from Ancyslostoma caninum, which binds
CD11b ⁄ CD18 and there is a homologue in A. ceylanicum
(161,162). Fasciola hepatica is known to secrete a factor
that inhibits superoxide output from activated neutrophils
(163) and secretory products from L3 of N. brasiliensis
(164) also inhibit neutrophil recruitment into the bronc-
hoalveolar lavage.
Schistosoma mansoni eggs secrete smCKBP (chemokines
binding protein) which can bind CXCL8, CCL3 and
CX3CL1 (fractalkine), CCL2 (MCP-1) and CCL5 (165).
SmCKBP blocks CXCL8 and the infiltration of neutro-
phils but it does not block CCL11 (eotaxin)-induced
eosinophilia. Brugia malayi secretes BmSPN2 which was
previously reported to inhibit human neutrophil elastase
and cathepsin G, however when cloned and sequenced by
other workers BmSPN2 was found not to inhibit these
neutrophil proteinases (166,167).
As yet the role of neutrophils in immunity to helminths
has been most thoroughly studied in the filarial models
of disease, in part driven by the possible induction of
Volume 32, Number 1, January 2010
neutrophils by symbiotic bacteria. However, the fact that
so many helminths produce either neutrophil regulatory or
inhibitory factors suggests that their importance in protec-
tion and ⁄ or modulation of immune responses to a range
of different helminths is more important than has so far
been realized.
BASOPHILS
Basophils are rare polymorphonuclear granulocytes in
peripheral blood (<1% of the leukocytes). They have baso-
philic granules in their cytoplasm, they release histamine
and they express high-affinity IgE receptor (FceR1) on
their surfaces. The level of IgE regulates the amount of
FceR1 on basophils (168). These characteristics are shared
with mast cells. In contrast to mast cells however, baso-
phils are c-kit- and they undergo their full maturation in
the bone marrow before entering the blood; mast cells exit
the bone marrow as progenitors and mature in the tissues.
Until the recent discovery that basophils are a source of
Th2 cytokines, basophils were treated as a subset of mast
cells.
Basophils are a rich source of IL-4, which can be rap-
idly produced in an IgE-dependent or an IgE-independent
process (169). In addition, basophils produce IL-3 (either
IgE-dependently or independently) and this IL-3 regulates
both IL-4 and IL-13 expression. Basophils also make IL-4
de novo when activated and release a second peak of IL-4
after 4 h. IL-13 is first produced after 24 h (170). The life-
span of basophils is several days, whereas mast cells sur-
vive for weeks or months, and while mast cells proliferate
following maturation, basophils undergo expansion in the
bone marrow before their release. Human basophils were
thought to be most closely related to eosinophils, and they
are found in the respiratory mucosa in late-phase allergic
reactions. They respond to the chemoattractants, RAN-
TES, MCP-3, MCP-1 and MIP-1a and are activated to
degranulate when a multivalent antigen binds several IgE
molecules. Basophils can also be activated IgE-indepen-
dently in response to histamine-releasing factor, MCP-1
and MCP-3 (171), and they respond to a variety of agon-
ists including fMLP, C5a, C3a, PAF, IL-8, MCP-1,
MCP-2, MCP-3, MCP-4, eotaxin, RANTES, MIP-1a,
IL-3, IL-5, GM-CSF and nerve growth factor (NGF)
which can all enhance chemotaxis and mediator release.
Degranulation can be piecemeal or anaphylactic, if IgE-
mediated, and upon degranulation, basophils can release
histamine, chondrotin sulphate, neutral protease, elastase,
b-glucoronidase, MBP, cathepsin G-like enzyme, CLC,
tryptase, chymase and carboxypeptidase, leukotriene C4,
PAI-1, IL-4, IL-13 and MIP-1a (171). Activated basophils
express CD63 and interestingly basophils can express
 2010 Blackwell Publishing Ltd, Parasite Immunology, 32, 1–19
Granulocytes in helminth infection
CD40L as well as IL-4 and IL-13 and so can induce B
cells to switch to IgE.
BASOPHILIA DURING INFECTION WITH
HELMINTHS
Suprisingly, although covered in many textbooks, there is
little robust data showing basophilia during human hel-
minth infections. Indeed a worldwide study of basophilia
in different helminth infections showed that IgE and
eosinophils were raised in all 668 confirmed helminth-
infected patients even if they had concurrent protozoal
infections, while people infected with protozoal infections
alone or uninfected people did not have raised eosinophils
or IgE. In contrast, basophils were raised in only four
helminth-infected patients (172).
Falcone et al. (173) however did report basophilia in
N. americanus infected patients. Despite this paucity of
reports of raised basophils in human helminth infections,
basophils from humans infected with Toxocara canis,
O. volvulus, W. bancrofti, Loa loa, S. stercoralis and Schisto-
soma sp. all release histamine in response to parasite anti-
gens in vitro (171,174–177). Basophils from filarial-infected
patients have been shown to release more IL-4 per cell
than CD4+ cells and at 100-fold lower antigen concentra-
tion (178). Indeed basophils are a major source of IL-4 in
filarial patients from Papua New Guinea (PNG). Interest-
ingly, basophils preferentially release IL-4 in response to
L3 rather than adult or microfilarial homogenate suggest-
ing that L3 invasion could initiate Th2 responses (179).
Patients with invasive helminth infections have 100 times
the normal IgE levels compared to 10 times normal levels
in allergic disorders. Thus, one theory for immunological
incompetence of helminth-infected individuals and their
inability to remove parasites, is that nonspecific polyclonal
stimulation of IgE by parasites and ⁄ or the generation of
autoantibodies blocks the FceR1 and disarms the mast
cell ⁄ basophil response (180). However, basophils collected
from hookworm-infected people from PNG could only be
stimulated to release histamine with the specific hook-
worm allergen, calreticulin, or anti-human IgE, and not to
a nonspecific antigen, ovalbumin (180).
Despite the apparent lack of basophilia during human
helminth infection, basophils are highly induced in rodent
helminth models. Ordinarily, basophils are rare in the
peripheral blood of rodents, but infection with T. spiralis
or N. brasiliensis induces a 50-fold blood basophilia. This
basophilia is T-cell dependent and does not occur in athy-
mic animals (181). In gerbils, blood basophilia and baso-
philic clusters in the bone marrow peak after 2 weeks, and
are gone by 4 weeks. T. spiralis infection in rats ⁄ guinea
pigs leads to a basophilia that occurs 1 week earlier than
9
E. T. Cadman & R. A. Lawrence
eosinophilia (182). Several other helminths induce baso-
philia in guinea pigs including Strongyloides, Ascaris, Fas-
ciola and Trichostrongylus colubriformis which increase
basophils in bone marrow, small intestine and blood (183).
Do specific helminth antigens induce basophils to stimu-
late type 2 responses
It has long been suggested that during invasion, helminth-
released proteases induce the predominant type 2
responses seen in these infections. Importantly, Sokol et al.
(184) recently showed that immunization with the cysteine
protease allergen, papain, activates basophils to initiate a
type 2 response. Basophils were transiently recruited to the
dLN at day 1, prior to the peak of CD4+ IL-4-producing
T cells. Although the mechanism of basophil recruitment
to the dLN is unknown, they do possess CCR1, CCR2
and CXCR4, and anti-CD62L prevented recruitment, sug-
gesting that they enter via crossing high endothelial ven-
ules. These basophils express TSLP, an IL-7-like molecule
primarily produced by epithelial cells and known to be
involved in Th2 cell differentiation. In vivo depletion of
either TSLP, IL-4R or basophils (by anti-FceR1) corre-
lated with reduced Th2 responses while mast cell defi-
ciency or deficiency in TLR2 ⁄ 4 ⁄ Myd88 did not alter Th2
responses to papain. Induction of basophils to release IL-
6, IL-4 and TNFa, but not histamine, in vitro was found
to lie within the protease activity of papain (184). This
showed that basophils have a vital role in the induction of
Th2 responses to some proteases and basophils may be
critical for generation of Th2 responses during helminth
infection. However, it has still to be determined whether
this induction occurs during the basophil’s transient entry
into the lymph node.
Interestingly chitin, a biopolymer of N-acetyl-b-d-gluco-
samine and a component of both parasitic and free-living
nematode egg shells, also induces basophilia. Heligmo-
somoides polygyrus egg shells are made up of 5% chitin
and chitin is a component of the microfilarial sheath of
filarial nematodes. Intranasal administration of chitin
leads to accumulation of eosinophils and basophils in the
lungs of mice, which peak at days 2–3 and return to basal
levels by day 9 (185). Chitin also induces eosinophil accu-
mulation and alternately activated macrophages as early as
6 h post-infection after i.p. administration. Recruitment of
innate immune cells to chitin is dependent on the high
affinity receptor for leukotriene B4, BLT1, and macro-
phages. Indeed expulsion of S. venezuelensis, but not
N. brasiliensis, is prevented in BLT1-deficient mice. Nippo-
strongylus brasiliensis infection upregulates Stat6-depen-
dent genes such as acidic mammalian chitinase (AMCase),
Ym1 and Ym2 (chitinase-3-like proteins). AMCase and
10
Parasite Immunology
Ym2 are expressed in the lung after 9 days. Mice over-
expressing AMCase, or immunization of mice with
AMCase (but not Ym2) treated-chitin, causes loss of
the ability to recruit eosinophils and basophils to either
the lung or peritoneum (185). Thus, recognition of chitin
elicits tissue infiltration and accumulation of IL-4 ⁄ 13 pro-
ducing innate cells that are implicated in helminth and
allergic immunity, including alternatively activated macro-
phages, eosinophils and basophils. AMCase appears to
negatively regulate chitin-induced innate immune
responses by degrading chitin and thus decreasing eosino-
phil and basophil recruitment.
Helminth antigens that directly stimulate the release of
IL-4 from basophils are sometimes termed ‘super-aller-
gens’ (171). For example, during the first weeks of schisto-
some infection, the immune response is characterized by a
Th1 response to worm antigens; subsequently, when eggs
are deposited, the response turns to a Th2 response direc-
ted against egg antigen. Th2 cells are not induced in
response to either single-sex male worm or radiation-atten-
uated cercarial infections. Indeed, it is now known that a
major secretory egg glycoprotein antigen, interleukin-4-
inducing factor from schistosome eggs (IPSE ⁄ alpha-1),
can stimulate human basophils to rapidly produce IL-4,
trigger degranulation and release IL-13 and histamine.
IPSE induces IL-4 production through an antigen-inde-
pendent but nonspecific IgE-dependent manner. Similarly
Echinococcus multilocularis extracts induce release of IL-4
and IL-13 from basophils via an IgE-dependent mecha-
nism (186). Both Derp1, host dust mite allergen, and
N. americanus secretions stimulate basophils to secrete IL-
4 and IL-13, in a non-IgE-specific manner (187). Thus,
these helminth antigens may trigger innate IL-4 and
induce early Th2 differentiation (188).
Filarial worms and schistosomes produce a homologue
of mammalian translationally controlled tumour protein
(TCTP), a calcium-binding protein that directly stimulates
histamine release from basophils (189). However, basophils
from filarial patients stimulated with B. malayi extract
release IL-4 whereas those of uninfected patients do not,
which may suggest that the levels of TCTP in extract are
not high (178). The lack of IL-4 from uninfected individu-
als in this study also suggests that in filarial infection
basophils are probably not the primary IL-4 source, that
the IL-4 release is an antigen-specific response and that
the response may be IgE-dependent. Similarly, A. viteae
extract in conjunction with sera from infected gerbils can
stimulate rat basophil leukaemia cells to degranulate.
Adult A. viteae extract is more allergenic than infective
larval or microfilarial extract, and it has been proposed
that the molecule, cystatin may be the stimulating allergen
(190).
 2010 Blackwell Publishing Ltd, Parasite Immunology, 32, 1–19
Volume 32, Number 1, January 2010
MODE OF ACTION OF BASOPHILS IN
PRIMARY AND SECONDARY RESPONSES
The mode of action of basophils in directing innate
immune responses is just beginning to be unravelled. The
processes of induction of Th2 responses are complex and
many cells have overlapping functions. Our current under-
standing of these processes is given below.
The initial IL-4 production of basophils can be gener-
ated directly in response to parasite allergens (as discussed
above) or in response to IL-3. Hida et al. (191) showed
that the FcR c-chain, a constitutive component of the IL-
3 receptor, is required for IL-3-induced IL-4 production in
basophils. Basophils lacking FcRc develop normally and
proliferate efficiently in response to IL-3, but are severely
impaired in IL-3-induced production of IL-4 and in sup-
porting Th2 differentiation (191). However, IL-3 is not
essential for basophil generation or basophil recruitment.
IL-18, in conjunction with IL-3, is also able to induce IL-
4, IL-13 and histamine release from basophils (192).
Indeed in vivo Yoshimoto treated S. venezuelensis infected
mice with IL-2 plus IL-18, which stimulated CD4+ cells to
produce IL-3 and IL-9, which in turn activated mast cells
to produce mMCP-1, and resulted in tissue accumulation
of basophils that could act as major IL-4 producers and
initiators of Th2 responses.
During N. brasiliensis infection, basophils are known to
produce IL-4 and to peak at 10-day post-infection in liver,
lung, spleen and blood but they are not found in the
lymph nodes (193). In the spleen they accumulate near the
marginal zone (194). Basophil expansion in the blood and
IL-4 expression is Stat6, Ig-FcR cross-linking and CD4+
cell-independent (38). However, recruitment of basophils
to lung and other tissues is Stat6-independent but highly
dependent on activated CD4+ cells (38). Although IL-3
and IL-18 together could stimulate basophil IL-4 produc-
tion without FcR cross-linking, neutralization of IL-3 or
IL-18 during N. brasiliensis infection does not completely
abrogate basophil recruitment or basophil-IL-4 production
respectively (193). Thus, the exact identification of the sig-
nals, for bone marrow release of basophils, CD4+ cell-
mediated recruitment of basophils to the lung and IL-4
release from basophils have yet to be identified in this sys-
tem. It is likely that initially T cells responsive to parasite
antigens produce chemokines ⁄ cytokines, possibly partially
IL-3-mediated that attract basophils and induce IL-4 pro-
duction. The recruitment of basophils during N. brasilien-
sis infection may in fact be too late for basophils to bias
the initial response toward Th2, however they are likely to
help drive newly emerging CD4+ cells to continue the
ongoing Th2 response by their production of IL-4 (193).
Indeed one of the functions of IL-4 is to increase the Ag-
 2010 Blackwell Publishing Ltd, Parasite Immunology, 32, 1–19
Granulocytes in helminth infection
presenting and co-stimulatory potential of DC, therefore
basophil-IL-4 production may also increase Th2 responses
indirectly by maturing DC for optimal Ag presentation
and Th2 priming. Basophils also produce IL-5 and
increase eosinophilia during N. brasiliensis infection and
this occurs independently of mast cells and Th2 cells. The
importance of basophils in protection against N. brasilien-
sis infection has recently been highlighted; basophils were
depleted in mice that have no Th2 response (rag) ⁄ ) recon-
stituted with IL-4 ⁄ IL-13) ⁄ ) lymphocytes) and worm expul-
sion was reduced (194).
Naive T cells require some time to initiate IL-4 produc-
tion during a primary immune response, most likely
because their Il4 genes are initially inaccessible. Newly
activated T cells make relatively small quantities of IL-4,
which may be sufficient for Th2 cell differentiation and B
cell isotype switching to IgE. In contrast, the rapid, easily
triggered, short-lived production of much larger quantities
of IL-4 (and additional cytokines) by basophils may acti-
vate nonimmune cells, such as vascular endothelium,
smooth muscle and mucosal epithelial cells, which can
modify their function when stimulated with large amounts
of IL-4 to promote the expulsion of enteric nematodes.
Basophils are more sensitive than mast cells to FceRI
cross-linking, which suggests that basophil IL-4 secretion
precedes mast cell degranulation during worm infection.
This pre-exposure to IL-4 sensitizes nonbone marrow-
derived cells, such as intestinal cells, to mediators released
by mast cells that promote rapid expulsion of parasites.
Indeed, T. spiralis expulsion requires mast cells, IL-4 or
IL-13, and nonbone marrow-derived cells that are
IL-4 ⁄ IL-13 responsive. Thus, basophils may be able to
contribute to IL-4-mediated immunity and inflammation
during helminth infection through two distinct mecha-
nisms: an IgE-independent mechanism that induces persis-
tent production of small amounts of IL-4 and is likely
important during primary infection for Th2 differentiation
and an IgE-dependent mechanism that rapidly induces the
secretion of large amounts of this cytokine and kick-starts
the secondary immune response (193) (Figure 1).
Several studies have modelled the role of basophils in
secondary responses. Khodoun et al. (195) showed that
the secondary basophil IL-4 response to a T-dependent
antigen is much larger and faster than the primary
response. During the early phase (<4 h) of a secondary
response, basophils, but not mast cells or eosinophils,
secrete IL-4. Later in the response (4–72 h) when Ag stim-
ulates IgE-FceR1 on the surface, memory T cells also
become important (195). Further significance for the need
for basophils in secondary immune responses has been
shown in a more physiological context with Streptococcus
pneumoniae. Basophils increased humoral memory
11
E. T. Cadman & R. A. Lawrence
Bone marrow
? Basophils
Innate ?
Parasite IL-18
allergen
IL-3
Naïve CD4+
B cell
IL-4
TSLP
DC
IL-4
IL-13 IgE
Type 2 CD4+
Basophil
IL-5
Eosinophilia
Figure 1 Current model of the role of basophils in generation of type 2 responses. CD4+ cell differentiation and IgE production in innate
responses following direct activation of basophils by parasite antigens or IL-3 or IL-18. In secondary responses basophils produce large
amounts of IL-4 in an IgE-dependent manner further assisting type 2 response generation.
responses by producing IL-4 and IL-6 in a secondary
infection (196). Basophils trap antigen plus antigen-spe-
cific IgE with their FceR and then release IL-4 and IL-6.
Basophils not only capture antigen by trapping soluble
antigens when Ag-specific IgE binds FceR1 on their sur-
face; they can also capture Ag-IgG complexes, particularly
IgG1 complexes (197,198). Basophils are the main source
of IL-4 and IL-6 in the spleen and bone marrow and
basophil depletion leads to increased sepsis, decreased sur-
vival following S. pneumoniae and decreased B-cell prolif-
eration and antibody production. Thus, basophils are
important in the humoral memory response for supporting
B-cell proliferation and antibody production in the pres-
ence of CD4+ cells through IL-4 and IL-6 production and
cell–cell contact (Figure 1). They also induce Th2 differen-
tiation, which further helps B cells. Thus the ability of
basophils to make large amounts of IL-4 following FcR
triggering during secondary helminth infection is likely to
allow rapid generation of Th2 responses and consequent
worm expulsion.
Regulation of basophils
Interferon regulatory factor 2 (IRF-2) is a transcription
factor that controls inflammation by attenuating the sig-
nals evoked by spontaneously produced IFN-a ⁄ b (199). In
the absence of IRF-2 (IRF-2) ⁄ ) mice) Th2 cells are prefer-
12
Parasite Immunology
Secondary
Naïve CD4+ Memory type 2 CD4+
IL-4
IL-13
DC
B cell
IL-4 IL-4
IL-6
IL-4
Basophil IgE
Blood
entially induced. Interestingly, in nave IRF-2) ⁄ ) mice ba-
sophils are upregulated in spleen and peripheral blood,
(independently of Stat6), there is elevated levels of IgE,
increased numbers of T1 ⁄ ST2+ cells, and isolated T cells
produce more IL-4. Indeed, IRF-2) ⁄ ) macrophages do
not produce IL-12 although CPG-activated IRF-2) ⁄ ) DC
are unaffected. IRF-2 negatively regulates the signal from
IL-3 that leads to basophil proliferative expansion but not
basophil cytokine production. As mentioned above, IL-3
is important for IL-4 production by basophils. IRF-2 does
not affect bone marrow, suggesting that it acts purely at
the IL-3-dependent level. IL-3 treatment also increases
basophilia and accelerates Th2 differentiation (200).
Overall these are exciting times in granulocyte biology.
The modulation of immune responses by eosinophils, mast
cells and neutrophils are beginning to be elucidated. Most
importantly the basophil is currently centre-stage as a cell
that secretes very large amounts of IL-4 and is necessary
for promotion of type 2 responses. Further elucidation of
these pathways will be possible with the identification of
antigens ⁄ allergens that can directly stimulate granulocytes
to produce particular cytokines and in this light it will be
important to identify such antigens that may be able to
stimulate basophils to initiate Th2 responses. Furthermore
the future generation of mice that lack basophils will
definitively elucidate their role in these complex immune
responses.
 2010 Blackwell Publishing Ltd, Parasite Immunology, 32, 1–19
 Table 1 Summary of known protective and ⁄ or modulatory roles of granulocytes in mouse models of helminth infection
Pathogen
Brugia sp.
Onchocerca volvulus
Litmosoides sigmodontis
Schistosoma mansoni
Heligmosomoides polygyrus
 2010 Blackwell Publishing Ltd, Parasite Immunology, 32, 1–19
Trichinells spiralis
Trichuris muris
Nippostrongylus brasiliensis
Strongyloides venezuelensis
Strongyloides stercoralis
Strongyloides ratti
Haemonchus contortus
13
Eosinophils Mast cells Neutrophils Basophils
Protective in primary L3 and
microfilariae but NOT secondary
infections
Volume 32, Number 1, January 2010
Protective in primary and Protective in secondary L3
secondary L3 infection infection
Protective in primary and Protective in primary L3
secondary infection, modulatory infection?
Protective in vitro but not in vivo
Protective
Protective against newborn larvae Protective in primary Modulatory
in vitro. Protective in secondary infection
but not primary infection
Partially protective in
primary infection
Partial role in secondary but Modulatory in primary Partially protective in
not primary infections infection primary infection?
Protective in primary
infection
Protective in primary infection. Protective in primary and
Modulatory in secondary infection secondary infection,
modulatory
Protective in primary
infection
Protective in secondary
infection
Granulocytes in helminth infection
E. T. Cadman & R. A. Lawrence
ACKNOWLEDGEMENTS
We would like to thank Amanda de Mestre for critical
reading of the manuscript and the BBSRC
(BB ⁄ D013550 ⁄ 1) for supporting the authors’ work.
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