Special Contribution

Yonago Acta medica 2009;52:95–104

Helminth Infections Prevent Autoimmune Diseases
through Th2-Type Immune Response
Soji Fukumoto, Hideyuki Iriko and Hitoshi Otsuki*
Division of Medical Zoology, Department of Microbiology and Immunology, School of Medicine,
Tottori University Faculty of Medicine, Yonago 683-8503 and *Department of Molecular Parasitology, Ehime University Graduate School of Medicine, Toon 791-0295 Japan

Helminth parasites are known to elicit the immune response towards T helper 2 (Th2)type, characterized by Th2 related cytokines, that typically include interleukin-4 (IL4), IL-5 and IL-13. In this review we will describe the mechanisms involved in helminth
induced Th2 immune response. Intestinal epithelial cells (IECs) produce thymic stromal
lymphopoietin (TSLP), which is both necessary and sufficient for the initiation of Th2
cytokine-driven inflammation. IL-33 mRNA is expressed early during parasite infection
and IL-33 binds ST2 receptor, both of which are associated with optimal CD4+ Th2 polarization. Following innate immune cell recognition, basophils and mast cell can secrete Th2
type cytokines that are thought to contribute to CD4+ Th2 differentiation. Additionaly,
dendritic cell conditioned with some helminth products can promote CD4+ Th2 differentiation. Alternatively activated macrophages, activated by the Th2 cytokines IL-4 and IL13 in parasitic infections, contribute to the host protective response: control of Th1-typeinflammation, wound healing and worm expulsion. Experimentally, helminths have been
associated with protection against a number of autoimmune disorders, including inflammatory bowel diseases and type 1 diabetes. It may be a novel strategy to ameliorate autoimmune inflammation by expanding and activating the Th2 response originated fromparasites.
Key words: alternatively activated macrophage; autoimmune disease; helminth; T helper 2;
thymic stromal lymphopoietin
Helminth infections are characterized by a strong
T helper 2 (Th2)-type response, which includes the
combined innate and adaptive immune responses
to clearly distinguish it from the adaptive Th2cell response (Anthony et al., 2007). Th2-type
responses are typically characterized by increases
in the levels of Th2-type cytokines such as interleukin-4 (IL-4), IL-5, IL-13 and IL-21. In this re-view we will first describe the mechanism of Th2cell response evoked by helminth parasite (Fig. 1).
Second the characterization and the function ofalternatively activated macrophages (AAM s) activated by IL-4/IL-13-dependent signal pathway will
be discussed, and third we will give an overview
that helminth parasites prevent the autoimmune
diseases through Th2-type response.

Abbreviations: AAM , alternatively activated macrophage; AMAC, alternative macrophage activation-associated CC
chemokine; AMCase, acidic mammalian chitinase; CAM , classically activated macrophage; CCR4, CC chemokine receptor 4; DC, dendritic cell; ERK, extracellular signal regulated kinase; ES, excretory/secretory; Fc RI, Fc receptor for IgE; IEC,
intestinal epithelial cell; IL, interleukin; iNOS, inducible nitric oxide synthase; JNK, c-Jun N-terminal kinase; LPS, lipopolysaccharide; MAPK, mitogen-activated protein kinase; NF- B, nuclear factor- B; MDC, macrophage derived chemokine; SEA,
schistosome egg antigen; SWA, soluble worm antigen; TARC, thymus and activation-regulated chemokine; TIMP, tissue inhibitor of metalloproteinase; TGF- , transforming growth factor- ; Th2, T helper 2; TLR, Toll-like receptor; TSLP, thymic stromal
lymphopoietin

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S. Fukumoto et al.

Fig. 1. The orchestration of CD4+ Th2 cell differentiation following innate cell recognition and response to parasite infection and the inhibitory mechanism of Th1-dependent autoimmune diseases. Following innate cell recognition, Th2-type cytokines including IL-4, IL-13 and IL-33, or TLSP are secreted. These cytokines are thought to contribute to CD4+ Th2 celldifferentiation. DC conditioned with helminth products also induces Th2 cell polarizing. Th2 cytokines and AAM s prevent Th1-dependent autoimmune diseases. AAM , alternatively activated macrophage; DC, dendritic cell; Eo, eosinophil;IEC, intestinal epithelial cell; IL, interleukin; MC, mast cell; Th, T helper; TLR, Toll-like receptor; TSLP, thymic stromal
lymphopoietin.

the high-affinity Fc receptor for IgE (Fc RI), IL18R and the Toll-like receptors (TLRs), and IL-4/
IL-13 secretion (Yoshimoto and Nakanishi, 2006).
They have also been shown recently to derive froma common progenitor (Arinobu et al., 2005). However, unlike basophils, which circulate in the blood,
mast cells reside in peripheral tissues and are thus
well situated to respond immediately to invasive
agents. Increased numbers of mucosal mast cells
are often observed in affected tissues during helminth infections and this increase is dependent on
Th2-type cytokines.

Th2-type response
induced by helminth parasites
Innate immune responses: basophils andmast cells
Innate immune cells are essential for both the initiation and effector phases of Th2-type immune
responses. Following helminth infection, basophils
increase in number in the blood and tissues. In Nippostrongylus brasiliensis infection, IL-4-producing
basophils are readily detected in the lungs, liver andspleen (Shinkai et al., 2002; Min et al., 2004). Basophils and eosinophils might be a major source of
IL-4 at early stages of the Th2-cell response, suggesting that they promote the development of Th2
cells or their recruitment to sites of inflammation.
Mast cells share many characteristics withbasophils, including the cell-surface expression of

TSLP
Intestinal epithelial cells (IECs) are a critical cell
population that maintains intestinal immune homeostasis through both barrier function and theability to actively modulate intestinal immune re96

Parasites prevent autoimmune diseaseTh2 immune responses after infection with 2 helminth, Heligmosomoides polygyrus and N. brasiliensis (Massacand et al., 2009).

sponses (Zeuthen et al., 2008). One IEC-derived
cytokine with immunomodulatory properties isthymic stromal lymphopoietin (TSLP). TSLP is afour-helix bundle cytokine that is expressed both inhumans and mice. Despite poor sequence homology, human and mouse TSLP exhibit similar biological functions (Liu et al., 2007). Expression of
TSLP is regulated by nuclear factor (NF)- B andcan be induced by exposure to viral, bacterial andparasitic pathogens, and inflammatory cytokines
IL-1 and TNF (Allakhverdi et al., 2007; Lee etal., 2007). TSLP binds to its high affinity receptor(R), a heterodimer composed of a unique TSLPR
chain and the IL-7R chain, that is expressed on hematopoietic cell lineages, including B cells, T cells,
mast cells and dendritic cells (DCs) (Soumelis etal., 2002; Allakhverdi et al., 2007; Chappaz et al.,2007; Liu et al., 2007).
TSLP-conditioned human DCs can promote
Th2 cell responses (Soumelis et al., 2002; Ito et al.,2005; Rimoldi et al., 2005). TSLP-treated DCs exhibit reduced production of IL-12/23p40 upon TLR
ligation, and the ability of DC-derived OX40L todrive Th2 cell differentiation is critically dependent
on the absence of IL-12 (Soumelis et al., 2002; Itoet al., 2005; Rimoldi et al., 2005). TSLP treatmentof human DCs induces expression of the chemokines CCL17 and CCL22, known ligands for CCR4,
a chemokine receptor found on effector Th2 cells(Soumelis et al., 2002). More recently, TSLP has
been reported to act directly on naïve mouse CD4+
T cells to promote IL-4 production and to induce
Th2 cell differentiation in the absence of exogenous
IL-4 and antigen presenting cells in vitro (Omori
and Ziegler, 2007). TSLP is both necessary andsufficient for the initiation of Th2 cytokine-driven
inflammation (Ziegler and Liu, 2006; Liu et al.,2007). TSLP–TSLPR interactions are critical for
immunity to the intestinal pathogen Trichuris.
Monoclonal antibody-mediated neutralization of
TSLP or deletion of the TSLPR in normally resistant mice resulted in defective expression of Th2
cytokines and persistent infection (Taylor et al.,2009). However, TSLP-TSLPR interaction has nofunctional impact on the development of protective

IL-33
IL-33 is produced very early during Trichuris muris
infection (Humphrey et al., 2008). IL-33 is structurally closely related to IL-18, requires posttranslational processing, and binds the receptor complex
consisting of the orphan IL-1R family member ST2
and the IL-1R accessory protein (Acosta-Rodriguez
et al., 2007). ST2 is expressed on mast cells andTh2 cells (Nakanishi et al., 2001) and has beenshown to play an important role in Th2 responses(Yoshimoto and Nakanishi, 2006). IL-33 induces
IgE-independent production of IL-13 from bothhuman and mouse mast cells (Florian et al., 2006)
and can operate in coordination with the epithelial
cell-restricted cytokine TSLP on mast cells to maximize Th2-associated cytokines and chemokine
production (Brunner et al., 2004). Likewise, IL33 has been described as a chemoattractant of Th2
cells (Oshikawa et al., 2001). The ability of IL-33
to enhance TSLP-induced responses from mature
mast cells has recently been demonstrated (Brunner
et al., 2004). It is conceivable that IL-33 can act via
TSLP to promote Th2-driven immunity to T. muris
infection.
The IL-17-related cytokine IL-25 (also known
as IL-17E) is also associated with the Th2-type
response and can promote Th2-cell differentiation and nematode parasite expulsion (Fallon et al.,2006; Owyang et al., 2006).
The induction of Th2 responses by DCs
DCs play a central role in activating CD4+ Th cells.
The ability of DCs to interpret helminth-inherent
signals and induce Th2 responses has been illustrated by experiments in which mice injected with
DCs that have been pulsed with extracts of helminths in vitro develop Th2-biased helminth-specificresponses (MacDonald et al., 2001; Balic et al.,
2004; Leech et al., 2006). The Th2-polarizing
97

S. Fukumoto et al.

Table 1. Specially upregulated genes in alternatively activated macrophages
Marker

Alternatively activated macrophage

Reference

Pattern recognition receptors
		
Other receptors
		L-arginine metabolism
Tissue remodeling factors
				Chemokines						Anti-inflammatory effects
Th2 type inflammation		

Mannose receptor (CD206)-glucan receptor
IL-4R
Fc RII (CD23)
Arginase-1
TGFTIMP1, TIMP2
Fibronectin
MDC (CCL22)
TARC (CCL17)
AMAC-1 (CCL18)
IL-10
Ym1, FIZZ1/RELM
AMCaseStein et al., 1992
Goerdt and Orfanos, 1999
Herbert et al., 2004
Goerdt and Orfanos, 1999
Loke et al., 2002
Song et al., 2000
Sandler et al., 2003
Gordon, 2003
Bonnecchi et al., 1998
Imai et al., 1999
Goerdt and Orfanos, 1999
Goerdt and Orfanos, 1999
Raes et al., 2002
Nair et al., 2005

AMAC-1, alternative macrophage activation-associated CC chemokine; AMCase, acidic mammalian chitinase; IL, interleukin; TGF- , transforming growth factor- ; MDC: macrophage derived chemokine; TARC, thymus and activation-regulated
chemokine; TIMP, tissue inhibitor of metalloproteinase.

not (Kane et al., 2004).
Exposure of DCs to helminth products has
also been reported to stimulate NF- B activation.
For example, LNFPIII stimulates rapid, transient
NF- B nuclear translocation and activation (Thomas et al., 2005). Consistent with these findings, neither SEA nor LNFPIII-dextran pulsed NF- B1−/−
DCs are able to induce Th2 responses (Thomas etal., 2005; Artis et al., 2005). LNFPIII and excretory/secretory products (ES)-62, a phosphorylcholine-containing protein secreted by the nematode
Acanthocheilonema viteae, condition DCs to induce Th2 responses through TLR4 (Thomas et al.,
2003; Goodridge et al., 2005). Lysophosphatidylserine from schistosomes has been reported to trigger DC activation by binding to TLR2 in DCs (vander Kleij et al., 2002).
There has been great interest recently in thepossibility that C-type lectins represent the majorclass of pattern recognition receptors for helminthproducts. N-Glycans containing fucose, expressedin multiple schistosome life stages, as possessing
many of the Th2-inducing properties of SEA, as
described above (Faveeuw et al., 2003; Thomas etal., 2003, 2005), and generally indicated a role forglycans in the priming of Th2 responses by helminths.

properties of helminths appear to reflect the conditioning of DCs to induce these types of immune
response, because helminth products can act as
Th2 adjuvants for unrelated antigens (Holland etal., 2000; Okano et al., 2001; Gomez-Garcia et al.,2006).
The response of DCs to microbial pathogens
is mediated in large part via TLRs, with input
from other pattern recognition receptors such as
lectins (Medzhitov 2007; van Vliet et al., 2008).
A striking and significant difference between Th2
responses and Th1 responses is that the former develop normally in the absence of MyD88 (Helmby
et al., 2003; Layland et al., 2005). Analyses ofsignalling events within the NF- B and mitogenactivated protein kinase (MAPK) pathways haverevealed significant differences between DCs exposed to helminth products and those stimulatedwith microbial products such as bacterial lipopolysaccharide (LPS). For example, extracellular signal
regulated kinase (ERK), c-Jun N-terminal kinases(JNK) and p38 are heavily phosphorylated after
exposure of DCs to LPS, but in DCs exposed toschistosome egg antigen (SEA), a soluble extractof schistosome eggs that is capable of conditioning
DCs to induce strong Th2 responses, ERK and toa lesser extent p38 are phosphorylated, but JNK is98

Parasites prevent autoimmune disease

are also indicative of AAM differentiation (Lokeet al., 2002).
Human AAM s specifically express alternative macrophage activation-associated CC
chemokine-1 (AMAC-1; CCL18) (Goerdt and Orfanos, 1999), macrophage-derived chemokine (MDC;
CCL22) (Bonecchi et al., 1998), and thymus andactivation-regulated chemokine (TARC; CCL17)(Imai et al., 1999). These chemokines preferentially recruit Th2 cells through interaction with the
CC chemokine receptor 4 (CCR4).
AAM s express certain chitinase and FIZZ
(found in inflammatory zone) family member proteins, including: FIZZ1/RELM , Ym1 and acidic
mammalian chitinase (AMCase) (Nair et al., 2005);
the Ym1 transcript shows the highest upregulationof any gene in AAM s during nematode infection(Raes et al., 2002) .

Alternatively activated macrophages inhelminth infections
Recent studies suggest that macrophages, conventionally associated with IFN -dominant Th1-type
responses to many bacteria and viruses, also play
an essential role in the Th2-type inflammatory
response. These macrophages are referred to as
AAM s as they express a characteristic pattern ofcell surface and secreted molecules distinct fromthat of classically activated macrophages (CAM s)
associated with microbe infections.
Characterization and phenotype
The concept of AAM s was first introduced to
distinguish specifically between the phenotype ofcells “activated” in the presence of IL-4 and cells“deactivated” in the presence of IL-10 (Stein et al.,1992). Gordon (2003) later included the effects of
IL-13 in the definition of alternative activation because IL-13 shares a common receptor chain with
IL-4 and exerts similar effects on macrophages.
Administration of recombinant peroxiredoxisin
from Fasciola hepatica and Schistosoma mansoni
to wild type and IL-4–/– and IL-13–/– mice induced
the production of AAM s independently of IL-4/
IL-13 signaling (Donnelly et al., 2008) (Fig. 1).
AAM s are observed in a variety of helminth
infections, including Th2-type immune responses
to S. mansoni (Herbert et al., 2004), Taenia crassiceps (Rodriguez-Sosa et al., 2002), Trichinella spiralis (Dzik et al., 2004), F. hepatica (Donnelly etal., 2005) and filarial parasites (Nair et al., 2003).
A number of markers are used to identify AAM s(Table 1). Cell surface IL-4R and the mannose
receptor (CD206), are readily detected using either flow cytometric (Herbert et al., 2004) or immunohistologic (Anthony et al., 2006) techniques.
Arginase-1 is upregulated in AAM s and, due
to its higher affinity for arginine, competes withinducible nitric oxide synthase (iNOS), which metabolizes arginine in CAM s. Then, AAM failto generate NO from arginine, and arginase-1 andits metabolic products, including urea and proline,

Control of inflammation
AAM s have multiple roles during helminth infection, one of which is regulation of the immune
response. A dominant role for helminth-elicited
AAM s is suggested to control the underlying
Th1-type inflammatory responses that may otherwise contribute to pathogenesis. Suppressive effects of AAM s on T cell proliferation can occur
in murine models of filarial infections. Brugia malayi L3 injected into the peritoneal cavity can elicit
AAM s with potent T cell suppressive properties(Nair et al., 2005). Infection with Litomosoides
sigmodontis also induces AAM s, which can suppress in vitro T cell proliferation. Further in vitro
studies suggest that the mechanism of T cell suppression is independent of IL-10 and CTLA-4, butpartially dependent on transforming growth factor(TGF)- (Taylor et al., 2006). Thus, AAM s appear to be more important in blocking underlying
Th1-type responses than promoting Th2-type responses, including Th2 cells.
Wound healing
AAM s can contribute to fibrosis and repair at thesite of injury (Martin and Leibovich, 2005), which99

S. Fukumoto et al.

Table 2. Helminth infections or products that prevent autoimmune diseases in animal models or humans
Immunological disease

Helminth

Agent or product

Reference(a) Animal models
Type 1 diabetes
Schistosoma mansoni
		S. mansoni
		Trichinella spiralis		
Dirofilaria immitis
Experimental autoimmune
S. mansoni
encephalitis
S. mansoni
Collagen-induced arthritis
Acanthocheilonema viteae
Experimental colitis
S. mansoni
		S. mansoni
		Heligmosomoides polygyrus					Hymenolepis diminuta		
T. spiralis		Trichuris suis

Infection
SWA, eggs or SEA
Infection
Recombinant antigen
Infection
Eggs
ES-62
Infection
Eggs
Infection or transfer of
MLN from infected mice
Infection
Infection
Infection

Cooke et al., 1999
Zaccone et al., 2003
Saunders et al., 2007
Imai et al., 2001
La Flamme et al., 2003
Sewell et al., 2003
McInnes et al., 2003
Smith et al., 2007
Elliott et al., 2003
Elliott et al., 2004(b) Human diseases
IBD: Crohn’s disease		
IBD: ulcerative colitis

Infection
Infection
Infection

Summers et al., 2005a
Croese et al., 2006
Summers et al., 2005b

T. suisNecator americanus
T. suisReardon et al., 2001
Khan et al., 2002
Summers et al., 2003

ES-62, excretory/secretory products of 62 kDa; IBD, inflammatory bowel disease; MLN, mesenteric lymph node; SEA,
soluble egg antigen; SWA, soluble worm antigen.

sion. For example, AAM s recruit eosinophils
to the lung and peritoneum during N. brasiliensis
infection (Voehringer et al., 2007). Two candidates
for eosinophil recruitment are leukotriene B4 (Reese et al., 2007) and Ym1, a chitinase-like peptidethat lacks chitinase activity (Owhashi et al., 2000).
Related to Ym1, AMCase is a functional chitinase,which shows elevated gene expression during H.
polygyrus or B. malayi infection (Anthony et al.,2006; Nair et al., 2005). It is tempting to speculatethat AMCase may function to damage chitin-containing parasites, including developing microfilaria.
If so, this would be in addition to its recently described function in augmenting Th2-type responses
by stimulating production of monocyte chemotactic
protein-1 and eotaxin (Zhu et al., 2004). The potential multiple roles of Ym1 and AMCase during
helminth infection make these related moleculescompelling subjects for future investigations of
AAM function.
These AAM effector functions can be generally separated into three categories contributing
to the host protective response: control of Th1-typeinflammation, wound healing, and worm expulsion.

may be of considerable importance during helminth infection. These large metazoan parasites cancause extensive damage as they pass through tissue,
releasing proteolytic enzymes that damage cells
and tissues. Genes involved in tissue remodeling,including tissue inhibitors of metalloproteinases(TIMPs), are upregulated (Sandler et al., 2003).
FIZZ1/RELMa has recently been implicated inwound healing (Liu et al., 2004).
Worm expulsion and resistance
Elements of the Th2-type response can control
pathologic Th1-type inflammation and also marshal effective helminth resistance; for example,
the Th2-type response has a demonstrated role in
the expulsion of several intestinal nematode parasites (Gause et al., 2003; Finkelman et al., 2004).
Clearly AAM s may contribute to resistance bycontrolling Th1-type immunity and thereby promoting a potent and polarized Th2-type response.
Recently, it is becoming increasingly apparent that
AAM s may also promote certain components of
the Th2-type response important in worm expul100

Parasites prevent autoimmune disease

was associated with a down-regulation of the Th1
response (Khan et al., 2002). This was correlatedwith a down-regulation of myeloperoxidase activity, IL-1 production and inducible nitric oxide
synthase (iNOS) and an up-regulation of IL-13
and TGF- production in the colon (Motomura etal., 2008). It may be a novel strategy to amelioratecolonic inflammation with helminth antigens byexpanding and activating the Th2 response.
Recent clinical studies provide evidence that
Trichuris suis ova therapy is effective in treating
both Crohn’s disease and ulcerative colitis without
any adverse effects (Summers et al., 2005a, 2005b)(Table 2b). The outcome of these trials supports
further the concept that de-worming the population
has led to the rising prevalence of inflammatory
bowel disease.
The ability of TSLP to inhibit IL-12/23p40
and IFN- production suggests that TSLP-based
biologics may also offer a novel therapeutic modality in the treatment of inflammatory bowel disease
and other chronic inflammatory disorders. Consistent with this, TSLP expression was decreased
in intestinal biopsies from patients with Crohn’sdisease, suggesting that increased TSLP expression
may provide therapeutic benefits (Rimoldi et al.,2005). Thus, the TSLP–TSLPR pathway may be anovel therapeutic target for a variety of inflammatory conditions associated with the overproductionof proinflammatory cytokines.

Prevention of
autoimmune diseases by helminthExperimentally, helminths have been associatedwith protection against a number of autoimmune
disorders, including inflammatory bowel disease
and diabetes (Table 2a). The incidence of autoimmune type 1 diabetes is on the increase in developed countries while remaining relatively uncommon in the developing world. This trend coincides
with a decrease in helminth infection (Gale, 2002).
Previous studies have shown that infection
with S. mansoni, T. spiralis and H. polygyrus cansignificantly inhibit or delay the development ofdiabetes in nonobese diabetic mice (Cooke et al.,1999). This appeared to be due to a skewing of thediabetes-associated Th1 response towards protective Th2 responses including IL-4, IL-5, IL-10 and
IL-13 production (Zaccone et al., 2003). Administration of schistosome eggs has been shown to
reduce the severity of experimental autoimmune
encephalomyelitis (Sewell et al., 2003) as well as
preventing the development of both trinitrobenzene
sulfonic acid-induced colitis (Elliott et al., 2003)
and diabetes in the nonobese diabetic mouse model(Cooke et al., 2004; David et al., 2004).
Inflammatory bowel disease is the most common and serious chronic inflammatory condition of
the gut. Among the distinct Th cell subsets, a Th1
type response is associated predominantly with
Crohn’s disease while helminth infections generate
a strong Th2 type response. Inflammatory bowel
disease is most prevalent in developed countries butrare in countries where infections with helminths
are common. Both Crohn’s disease and ulcerative
colitis have a prevalence range of 10 to 200 per
100,000 individuals per year in North America andEurope (Bouma et al., 2003). Inflammatory bowel
disease can begin relatively early in life and persist
for long periods, leading to substantial morbidity and decreased quality of life (Blumberg et al.,2001).
Previously it is shown that prior infection
with the helminth parasite, T. spiralis, ameliorates
subsequent hapten-induced colitis in mice and thisReferences
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Received and accepted September 10, 2009
Corresponding author: Soji Fukumoto, MD, PhD

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