Autoimmunity

ISSN: 0891-6934 (Print) 1607-842X (Online) Journal homepage: http://www.tandfonline.com/loi/iaut20

Inflammatory arthritis and systemic bone loss are

attenuated by gastrointestinal helminth parasites

Kerstin Sarter, Manuel Kulagin, Georg Schett, Nicola L. Harris & Mario M.
Zaiss

To cite this article: Kerstin Sarter, Manuel Kulagin, Georg Schett, Nicola L. Harris & Mario M.
Zaiss (2017): Inflammatory arthritis and systemic bone loss are attenuated by gastrointestinal
helminth parasites, Autoimmunity, DOI: 10.1080/08916934.2016.1261837

To link to this article: http://dx.doi.org/10.1080/08916934.2016.1261837

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ISSN: 0891-6934 (print), 1607-842X (electronic)

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! 2017 Informa UK Limited, trading as Taylor & Francis Group. DOI: 10.1080/08916934.2016.1261837

SHORT COMMUNICATION

Inflammatory arthritis and systemic bone loss are attenuated by

gastrointestinal helminth parasites
Kerstin Sarter1, Manuel Kulagin2, Georg Schett3, Nicola L. Harris2, and Mario M. Zaiss2,3
1
Interdisciplinary Center for Clinical Research Laboratory (IZKF Würzburg), Department of Internal Medicine II, University of Würzburg, Würzburg,
Germany, 2Ecole Polytechnique Fédérale de Lausanne (EPFL), Global Health Institute, Lausanne, Switzerland, and 3Friedrich-Alexander-University
Erlangen-Nürnberg (FAU), Department of Internal Medicine 3 - Rheumatology and Immunology, Universitätsklinikum Erlangen, Erlangen, Germany

Abstract Keywords
Infections with different helminth species have been observed to ameliorate a variety of chronic Arthritis, helminths, excretory–secretory
inflammatory diseases. Herein, we show that the natural murine helminth species, products, bone metabolism, osteoclast
Heligmosomoides polygyrus bakeri (Hp) is capable of attenuating disease severity in two different
inflammatory arthritis models. Furthermore, we show that excretory–secretory (ES) products from History
Hp directly suppress osteoclast differentiation in vitro. Taken together, these results demonstrate
that helminth infections can dampen autoimmune diseases and highlight a previously Received 17 July 2016
unrecognized and important role for ES products, by directly impacting on bone destruction. Revised 6 October 2016
Accepted 16 October 2016
Published online 11 January 2017

Introduction susceptibility loci for RA have been discovered, which are

In developing countries intestinal helminths (worms) are
found to infect the majority of the population with 2 billion
people infected worldwide. Severe helminth infection can
result in disease; however, severe infections are uncommon
and most adults suffer only mild, asymptomatic infections.
The absence of helminth infections in industrialized countries
is widely believed to account for the increasing rates of
inflammatory diseases because of its immunomodulatory
capacities [1]. Such diseases are caused by inappropriate
immune responses against innocuous environmental proteins
or self-proteins. They include allergies (hay fever, asthma,
food allergies and eczema), autoimmune diseases (rheumatoid
arthritis (RA), multiple sclerosis, etc.) and inflammatory
bowel diseases (Crohn’s disease, ulcerative colitis). Both
epidemiological studies and experimental animal models have
suggested that helminth infection can ameliorate some of
these inflammatory diseases. Recent evidence suggested that
one alternative pathway how helminths could modulate
inflammatory disease is through changing the gut microbiota
composition in favor of more beneficial bacterial species and
their secreted metabolites [2–4].
RA is a highly prevalent chronic inflammatory disease
affecting 1% of the population. It mostly affects the peripheral
joints, leading to tissue destruction, functional decline and
increased mortality [5]. Although several genetic
Correspondence: Mario M. Zaiss, Department of Rheumatology &
Immunology, Universitatsklinikum Erlangen, Universitätsstrasse 25A,
Erlangen 91054, Germany. E-mail: mario.zaiss@uk-erlangen.de
linked to the development of RA-associated autoimmunity
[6], additional factors may exist which either facilitate or
inhibit the transition from asymptomatic autoimmunity to
inflammatory disease.
Here, we show that infection with the natural mouse
helminth parasite, Heligmosomoides polygyrus bakeri (Hp)
not only attenuates the development of arthritis in two
different inflammatory arthritis mouse models, including the
collagen-induced arthritis model (CIA), which is based on
active immunization with collagen, and the collagen anti-
body-induced arthritis model (CAIA), which is built on the
passive transfer of collagen-specific antibodies but also
impacts positively on systemic bone metabolism.
Materials and methods
Mice, parasites and treatments
C57BL/6 mice were bred and maintained under specific
pathogen-free (SPF) conditions at Ecole Polytechnique
Fédérale de Lausanne, Switzerland. To standardize the
intestinal bacteria within different groups of mice contained
within one experiment, all mice were co-housed or beddings
were mixed for 2–3 weeks prior to parasite infection. Where
indicated mice were then infected orally with 200 L3 Hp.
Adult worm burdens were determined by manual counting
using a dissecting microscope. Egg production was quantified
by collection of moist feces, flotation using saturated NaCl
and counting using a McMaster Worm Egg Counting
Chamber (Weber Scientific International, Ltd, Hamilton,
2 K. Sarter et al.
NJ). Both procedures were undertaken to ensure the success-
ful and similar helminth infection among mice.
Generation and collection of Hp ES (HES) products
For the generation of HES products, L5 Hp helminths were
washed extensively in sterile PBS supplemented with peni-
cillin and streptomycin (Gibco, Waltham, MA), then
incubated for 1 h in RPMI (Gibco, Waltham, MA) supple-
mented with penicillin and streptomycin and cultured in
RPMI plus antibiotics (penicillin, streptomycin, and genta-
micin; Sigma-Aldrich, Taufkirchen, Germany) and 1% glu-
cose (Sigma-Aldrich, Taufkirchen, Germany). The
supernatant was collected every 2 days for a period of 2
weeks, followed by sterile filtration and concentration of the
supernatant by centrifugation through a 10 000 MWCO
cellulose membrane (Centriprep; Millipore). LPS contamin-
ation was removed from HES using an EndoTrap Blue LPS-
binding affinity column (Hyglos GmbH, Bernried, Germany).
The concentration of residual endotoxin was determined using
the Limulus Assay, which has a sensitivity of 0.06 Endotoxin
Units/ml (6 pg/ml) (Lonza, Cologne, Germany). The final
preparation used for this study contained 31 pg/ml LPS in the
purified HES vs. 643 pg/ml in the non-purified HES. The
purified HES were used for all experiments. As control in our
in vitro studies, we used the culture medium treated the same
way but without the addition of adult Hp worms.
Collagen-induced arthritis (CIA)
CIA was induced in male C57BL/6 mice by one (day 0)
intradermal immunization in the base of the tail with 100 g
bovine type II collagen (CII; Chondrex, Redmond, WA) in
complete Freund adjuvant (CFA; Difco Laboratory, Detroit,
MI), containing 5 mg/mL killed Mycobacterium tuberculosis
(H37Ra). CII-immunized mice received 2 intraperitoneal
injections (days 5 and 10) with CD22/cal or control GG5/cal
(160 g/kg/injection). The paws were evaluated for clinical
arthritis and each paw was individually scored using a 4-point
scale: 0, normal paw; 1, minimal swelling or redness; 2,
redness and swelling involving the entire forepaw; 3, redness
and swelling involving the entire limp; 4, joint deformity or
ankylosis or both.
Collagen antibody-induced arthritis (CAIA)
On day 0, 300 ml/mouse of the Arthrogen-CIA monoclonal
antibody cocktail (2–4 mg total) was administered i.p. On
day 3, 100 ml of LPS (50ug) per mouse was administered i.p.
per mouse. Administration of nonspecific immunoglobulin
(day 0) and LPS (day 3) was used in control naive mice [7].
As of day 1, mice were examined daily for signs of arthritis
and given a clinical score ranging from 0 to 4 (0 ¼ no
evidence of erythema and swelling: 1 ¼ Erythema and mild
swelling confined to the tarsals or ankle joint: 2 ¼ Erythema
and mild swelling extending from the ankle to the tarsals:
3 ¼ Erythema and moderate swelling extending from the
ankle to metatarsal joints: 4 ¼ Erythema and severe
swelling encompassing the ankle, foot and digits, or
ankylosis of the limb). Animals were also weighed every
second day.
Autoimmunity, Early Online: 1–7
Bone histomorphometry
Histomorphometric analyses were performed on methacrylate-
embedded un-decalcified plastic sections following von Kossa
and Goldner staining. Quantifications were performed by
digital image analysis (OsteoMeasure; OsteoMetrics, Decatur,
GA). Histological analyses were performed on formalin-fixed,
decalcified, paraffin-embedded tissue sections stained with
H&E, TRAP or toluidine blue. Synovial inflammation,
osteoclast numbers and cartilage destruction were quantified
by digital image analysis (OsteoMeasure).
Isolation and culture of osteoclast precursors
Bone marrow was isolated from 5–8-wk-old C57BL/6 WT
mice by flushing femoral bones with complete media. Bone
marrow cells were plated in 96-well plates (2.5  105/well) in
MEM supplemented with 10% FCS, 30 ng/ml M-CSF, and
50 ng/ml RANKL (R&D Systems, Wiesbaden-Nordenstadt,
Germany). Medium was changed after 72 h. Osteoclast
differentiation was evaluated by staining fixed cells for
tartrate-resistant acid phosphatase (TRAP) using a Leukocyte
Acid Phosphatase Kit (Sigma-Aldrich, Taufkirchen,
Germany), according to the manufacturer’s instructions.
Statistical analysis
Statistical analysis was performed using Student’s t-test, one-
way or two-way ANOVA with post tests as appropriate. All
experiments were conducted at least two times using two
independent batches of Hp larvae. p-Values of 0.05 were
considered significant and are shown as p50.05 (*), p50.01
(**), or p50.001 (***). Graph generation and statistical
analyses were performed using Prism version 4c software
(GraphPad, La Jolla, CA).
Results
Hp infection induces a TH2 response
First, we validated our Hp infection model by analyzing the
induction of TH2, TH1 and eosinophil cells after worm
challenge. This was important as different studies showed
different peak time points of the TH2 response after Hp
infection. In line with previous reports, we observed a robust
increase of CD4+ IL-4+ TH2 cells, CD4 + IL-13+ TH2 and
CD11b + Siglec-F+ eosinophils in the spleen and to a lesser
extent also in the mesenteric lymph nodes and peritoneal
washes starting from 7 days after the challenge with Hp
(Figure 1A–C). We also observed a very low impact on
CD4 + IFNg+ TH1 cells in the spleen 11 days after challenge
with Hp (Figure 1D). These data showed that in our hands the
Hp infection resulted in a peak TH2 immune response after 11
days post infection. Accordingly, we started the following
arthritis experiments at that time point to study the effects of
worm-associated immune activation on arthritis.
Hp infection attenuates the development of arthritis
We next determined whether Hp infection attenuates inflam-
matory arthritis. We challenged naive specific-pathogen-free
(SPF) wild-type (WT) mice with 200 infective Hp L3 stage
DOI: 10.1080/08916934.2016.1261837 Helminths impact on bone metabolism 3
(A) 4 10 0 5 (B) 3 10 0 5
***
***

Absolute cell numbers

2 10 0 5
3 10 0 5

2 10 0 5 ***
2 10 0 5 ** *
*
* 1 10 0 5
1 10 0 5 *
5 10 0 4

0 0
0dpi 4dpi 7dpi 11dpi 14dpi 0dpi 4dpi 7dpi 11dpi 14dpi

(C) (D)
8 10 0 5 3 10 0 4
***
Absolute cell numbers

6 10 05 *** 2 10 0 4

*** 2 10 0 4
4 10 0 5
1 10 0 4
**
2 10 0 5
5 10 0 3

0 0
0 dpi 4 dpi 7dpi 11dpi 14dpi 0dpi 4dpi 7dpi 11dpi 14dpi 20dpi

MLN PP PW spleen
Figure 1. Induction of Type 2 immune response after Heligmosomoides polygyrus (Hp) infection. (A) CD4+, IL-4 + T cells, (B) CD4+, IL-13 + T
cells, (C) CD11b+, Siglec-F + eosinophils, and (D) CD4+, INFgamma + T cells in mesenteric lymph nodes (MLN), Peyres patches (PP), peritoneal
wash (PW) and spleen single cell suspensions analyzed by flow cytometry after Hp infection. Data are expressed as the mean ± S.D. from n ¼ 5 mice.
One out of two individual experiments is shown. Statistical significance was determined with one-way ANOVA. *p50.05; **p50.01; ***p50.001.

(A) 1.5 (B) 1.2 (C) 130

** naive
naive naive **
Mean arthritic score

1.0 Hp infected
Total arthitis score

Hp infected Hp infected 120

Weight (%)

1.0 0.8

0.6 110
*
0.5 0.4
100
0.2

0.0 0.0 90
14

21

28

32

35

42

51
4
14

21

28

32

35

42

51
4

14

21

28

32

35

42

51
4

Days post first CIA challenge Days post first CIA challenge Days post first CIA challenge

Figure 2. Heligmosomoides polygyrus (Hp) helminth infection attenuated collagen induced arthritis (CIA). Total (A) and mean (B) arthritic scores are
shown during the timecourse of the CIA mouse model in naive versus Hp infected wild-type mice. (C) Weight curves from naive versus Hp infected
wild-type mice expressed as percentage of starting weight. Data are expressed as the mean ± S.D. (n ¼ 7 mice). Statistical significance was determined
with two-way analysis of variance (ANOVA) followed by the Bonferroni post-test. *p50.05; **p50.01.

larvae 2 weeks before the induction of CIA (Figures 2 and 3) bone parameters were significantly better in CIA- and CAIA-
or CAIA (Figures 4 and 5). Naive mice gavaged with PBS induced arthritic mice when challenged with Hp (Figures 3
served as controls. Interestingly, Hp infection significantly and 5). In non-arthritic controls, there was also a trend of the
attenuated local signs of joint inflammation as reflected by Hp infection itself towards increased systemic bone mass,
decreased total and mean arthritic sores in Hp infected although this did not reach significant levels (Figure S1).
(Hp infected) compared with non-infected mice (naive) Bone mass analysis in non-Hp infected wild-type mice had
(Figures 2 and 4). been undertaken at 42 days post Hp infection in order to
guarantee a chronic, established helminth infection, not
interfering with the induced early immune response after
Hp infection inhibits the arthritic bone loss
Hp infection. In CIA and CAIA mouse models, we observed
When assessing systemic bone loss in conjunction with increased systemic trabecular bone density measured in the
inflammatory arthritis, we observed that systemic structural metaphysis of the tibial bones, as indicated by a higher
4 K. Sarter et al. Autoimmunity, Early Online: 1–7

(A) 15 (B) 40 *** (C) 4 * (D) 20 ** (E) 50 *

*
40
35 3 15

Oc.S/BS (%)
BV/TV (%)
10

N.Oc/T.Ar
Tb.Nr..
30

Tb.Th.
30 2 10
20
5
25 1 5
10

0 20 0 0 0

IA

IA
IA

IA

IA

IA

IA

IA
IA

IA

C
C

C
C

C
C

ed
e

ed

ed

ed
e

ed

iv
iv

iv

iv
iv

ct
ct

ct

ct
ct

na
na

na

na
na

fe
fe

fe

fe
fe

in
in

in

in
in

p
p
p

p
H
H

H
Figure 3. Heligmosomoides polygyrus (Hp) infection changes systemic bone parameters in the CIA mouse model. (A) Bone volume, (B) trabecular
thickness, (C) trabecular number, (D) osteoclast surface and, (E) osteoclast numbers measured in the tibia from naive or Hp-infected wild-type mice
during the CIA model. Data are expressed as the mean ± S.D. (n ¼ 7 mice). Statistical significance was determined with Students’ t-test. * ¼ p50.05;
** ¼ p50.01; *** ¼ p50.001.
***

(A) naive (B) 3 naive (C) 150

8

***
Hp infected
***
***

Hp infected
*
Mean arthritic score
Total arthitis score

***
6

Weight (%)
2
100

4 * *
1 50
2 naive
Hp infected
0 0 0
0 2 4 6 8 10 12 14 0 2 4 6 8 10 12 14 0 2 4 6 8 10 12 14
Days post first CAIA challenge Days post first CAIA challenge Days post first CAIA challenge

Figure 4. Heligmosomoides polygyrus (Hp) helminth infection attenuated collagen antibody induced arthritis (CAIA). Total (A) and mean (B) arthitic
scores are shown during the timecourse of the CAIA mouse model in naive versus Hp infected wild-type mice. (C) Weight curves from naive versus
Hp-infected wild-type mice expressed as percentage of starting weight. Data are expressed as the mean ± S.D. (n ¼ 7 mice). Results shown are from one
experiment and are representative of two individual experiments. Statistical significance was determined with two-way analysis of variance (ANOVA)
followed by the Bonferroni post-test. *p50.05; ***p50.001.

(A)
15
(B)
40 *** (C)
4 * (D)
20 ** (E)
50 *
*
40
35 3 15
Oc.S/BS (%)
BV/TV (%)

10
N.Oc/T.Ar

30
Tb.Th.

Tb.Nr.

30 2 10
20
5
25 1 5
10

0 20 0 0 0
A
A
A

A
A
A

AI
AI

AI

AI
AI

AI

AI

AI
AI

AI

C
C

C
C

ed

e
e

ed

e
ed

ed
e

ed

iv
iv

iv

iv
iv

ct
ct

ct

ct
ct

na
na

na

na
na

fe
fe

fe

fe
fe

in
in

in

in
in

p
p

p
H
H

Figure 5. Heligmosomoides polygyrus (Hp) infection changes systemic bone parameters in the CAIA mouse model. (A) Bone volume, (B) trabecular
thickness, (C) trabecular numbers, (D) osteoclast surface and, (E) osteoclast numbers measured in the tibia from naive or Hp-infected wild-type mice
during the CAIA model. Data are expressed as the mean ± S.D. (n ¼ 7 mice). Statistical significance was determined with Student’s t-test. *p50.05;
**p50.01; ***p50.001.

fraction of bone volume per total volume (BV/TV) (Figures 3 Excretory–secretory products from Hp inhibit
and 5A). In line with this, we could detect increased osteoclast differentiation
trabecular thickness and trabecular numbers (Figures 3 and
Given that our data showed increased systemic bone density
5B, C). Additionally, when analyzing general osteoclast
and decreased osteoclast numbers in Hp infected mice
numbers per tibial section, and the ratio of osteoclast surface
(Figures. 3 and 5), we hypothesized that some of the
per bone surface, we found that both measurements revealed a
protective effects of infection may be directly mediated by
significant decrease in osteoclast numbers in vivo as well as a
the helminth through the action of its secreted products on
reduced osteoclast covered bone surface in Hp-infected mice
osteoclast cell differentiation. To test this hypothesis, we
(Figures 3 and 5D, E).
DOI: 10.1080/08916934.2016.1261837 Helminths impact on bone metabolism 5

Figure 6. ES products of heligmosomoides polygyrus (HP) (HES) suppress osteoclast differentitation. (A) Mature, multinucleated TRAP positive cell
counts from in vitro bone marrow cell cultures after stimulatin with M-CSF and RANKL with different concentration of HES. (B) Cell counts TRAP
positive osteoclast precursors (less than 3 nuclei) from in vitro bone marrow cell cultures after stimulation with M-CSF and RANKL with different
concentartions of HEs. (C) Representative pictures of bone marrow cell cultures shown in (A) and (B). Data are expressed as the mean ± S.D. from
triplicates. One out 2 individual experiments is shown. Statistical significance was determined with one-way ANOVA. **p50.01; ***p50.001.

cultured bone marrow cells from C57BL/6 wild-type mice
stimulated with M-CSF and RANKL in the presence of
different concentrations of excretory–secretory (ES) products
from adult Hp worms (HES). Hewitson et al. have taken a
proteomic approach to identify the majority of proteins
secreted by adult Hp and showed that there is a predominance
of VAL/ASP-like products [8]. In addition, Moreno et al.
underwent a different approach to target exact HES compos-
ition using RNA-seq technique [9]. Together, both studies
highlight the high complexity of identified products found in
HES. After 5 days, cells were stained with tartrate-resistant
acid phosphatase (TRAP), and TRAP positive, multinucleated
cells resembling mature bone-degrading osteoclasts were
counted. HES significantly suppressed osteoclast differenti-
ation in a dose-dependent manner as indicated by the TRAP
positive multinucleated cells shown in Figure 6(A).
Interestingly, there was a corresponding increase of TRAP
positive osteoclast precursor cells in the HES-treated groups
indicating a possible defect in cell–cell fusion during
osteoclastogenesis and a developmental stop on the pre-
osteoclast stage (Figure 6B, C).
Discussion
Intestinal helminths have co-evolved with their mammalian
hosts over several hundred million years [10]. In industria-
lized countries, helminth infections are very rare but still,
about 2 billion people, mainly children from areas without
adequate sanitation, suffer from chronic intestinal helminth
infections [11]. Higher sanitary standards that led nearly to
the complete eradication of intestinal helminths from
industrialized countries have been linked to autoimmunity
per se [12] and to the increased incidence of autoimmune
diseases observed in these regions [13]. Consequently, live
helminths are currently being employed in at least 15 clinical
trials in efforts to alleviate allergic and autoimmune disorders
[14]. Despite the extensive organismal complexity of different
helminth species, in the majority of cases the immune
responses of the infected hosts to helminth infection are
remarkably similar, namely a TH2-like response [15] with the
production of significant quantities of IL-4, IL-5, IL-9, IL-10
and IL-13 and consequently, the development of strong
immunoglobulin E (IgE), eosinophil and mast cell responses.
Helminth infections appear to have a substantial immuno-
modulatory potential of limiting disease severity in experi-
mental models, such as type 1 diabetes [16,17], colitis [18] and
allergic airway inflammation [19–22]. Herein, we show that
Hp is not only capable of suppressing models of inflammatory
arthritis but also impacting on arthritis-associated bone loss.
Moreover, we could show a tendency towards increased bone
density in Hp infected mice, highlighting the beneficial effect
of the ES products of Hp (HES) on bone metabolism per se.
These findings support previous findings that a TH2 response
induced by Hp infection improved arthritis damage and
diminished the incidence of local joint tissue damage that is
directly linked to the neighboring inflammation in the
6 K. Sarter et al.
joints [23]. Also, it was shown that Schistosoma mansoni
infection two weeks prior to immunization with type II
collagen (IIC) significantly reduced the severity of CIA [24].
In this study, helminth infection resulted in reduced anti-IIC
IgG and IgG2a serum antibody levels, decreased pro-inflam-
matory cytokine levels (TNFa, IL-17A), while at the same time
the anti-inflammatory cytokine IL-10 levels were increased
[24]. Another helminth, Acanthocheilonema viteae, belonging
to the roundworms, secretes within their ES products
phosphorylcholine-containing glycoprotein 62 kDa (ES-62).
ES-62 was found to have anti-inflammatory properties in the
murine collagen-induced arthritis (CIA) model [25]. In
addition, it was shown that this helminth mediates anti-
inflammatory properties on human RA-derived synovial tissue
cultures [25]. Another group showed that ES-62 could inhibit
TH1-type responses [26] and also reduces antigen-specific
IgG2a (a TH1-promoting antibody subclass), with no modu-
lation of IgG1, IgG3 and IgM levels [27]. ES-62 was also able
to significantly reduce levels of IL-17-producing lymphocyte
cells infiltrating the joint [28]. In addition, a very recent study
showed that eosinophils – induced by the helminth
Nippostrongylus brasiliensis – play a central role in the
modulation of arthritis probably through the increase of anti-
inflammatory macrophages in arthritic joints [29].
For the current study we have chosen the helminth species
Hp because it is a natural pathogen of mice, and it provides the
most natural laboratory model for studying central features of
the mouse-helminth interactions. The life cycle of Hp is
relatively simple compared with other helminth parasites, with
infection localized to only one tissue, the small intestine. Under
natural conditions, Hp transmission occurs via the fecal–oral
route that is mimicked in experimental infections by simple
oral gavage. Despite inducing a strong immune response, long
co-evolution has resulted in primary chronic infections that
persist for months in C57BL/6 mice [30,31]. Using Hp
infection during two mechanistically different induced arthritis
mouse models, we could show that Hp does have the potential
to significantly attenuate the severity of inflammatory arthritis.
Interestingly, this was not only seen locally at the paws – the
site of inflammation – but also systemically as Hp also
provides protection against arthritis-induced systemic bone
loss. Possible mechanisms involved might be the shift from a
pro-arthritic TH1/TH17 cell response to an anti-arthritic TH2
immune response or as it was shown previously by Hp-induced
changes in the gut microbiota and its secreted metabolites.
Clearly, further studies investigating the effects of the changed
gut microbiota need to be done. Another possibility how Hp
impacts on bone metabolism per se could be through its ES
products. It has been demonstrated that parasite ES products
from helminths contain immunomodulatory molecules respon-
sible for nematode immune evasion [8,32]. Interestingly, in this
study we could show that these ES products also suppress
osteoclast differentiation and thereby the negative conse-
quences of arthritis on the bone.
Hence, the use of helminths or their ES products to
modulate inflammatory arthritis by shifting immunity towards
a type 2 immune response or by directly suppressing
osteoclast differentiation constitutes a highly appealing
therapeutic strategy for RA.
Autoimmunity, Early Online: 1–7
Declaration of interest
The authors report no conflicts of interest. The authors alone
are responsible for the content and writing of this article.
The research leading to these results has received funding
from the Deutsche Forschungsgemeinschaft (CRC1181 to
G.S.), and the European Research Council under the
European Union’s Seventh Framework Program (FP/2007-
2013)/ERC Grant Agreement n. 310948.
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