REVIEW doi: 10.1111/sji.

12533
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Immunity in Filarial Infections: Lessons from Animal

Models and Human Studies
A. Kwarteng*,† & S. T. Ahuno*

*Department of Biochemistry and
Biotechnology, Kwame Nkrumah University of
Science Technology, PMB, Kumasi, Ghana;
†Kumasi Centre for Collaborative Research in
Tropical Medicine (KCCR), KNUST, PMB, Kumasi,
Ghana
Received 15 October 2016; Accepted in revised
form 27 January 2017
Correspondence to: Dr. A. Kwarteng, Department
of Biochemistry and Biotechnology, Kwame
Nkrumah University of Science Technology,
KNUST, Private Mail Bag, Kumasi, Ghana. E-
mail: akwarteng
@knust.edu.gh
Abstract
Our understanding of immunity to filarial infection is enigmatic and continues
to be passionately debated. The mechanisms whereby filarial nematodes are killed
in vivo and how these parasites avoid these mechanisms are poorly understood.
Although vaccination studies in permissive animals took off seven decades ago,
the exact mechanisms driving protective immunity are extensively being
investigated. Currently, little is known regarding the collective functions or
counter-regulatory mechanisms of the antibody isotypes in filarial infection with
respect to protective immunity. Establishing the functional role of antibody
isotypes and cytokines in the various infection phenotypes can contribute
immensely to current knowledge in filarial immunology. This paper reviews
insight into protective immunity in filarial infection with focus on humoral and
cellular responses from animal models and human studies.

epidemiological circumstances are favourable [3, 4]. To

Introduction
Human filarial infections affect approximately 200 million
people worldwide and account for majority of the debil-
itating morbidities and disabilities in endemic regions [1].
The collective DALYs (disability-adjusted life years) for
these infections are 3.3 million. Infections with these
thread-like viviparous nematodes are usually associated
with chronic disease; however, a proportion of individuals
develop severe pathologies (lymphedema and elephantiasis
in the case of lymphatic filariasis (LF), and skin disease,
visual impairment and blindness in the case of onchocer-
ciasis) [2]. Control of these infections can be achieved
through mass drug administration (MDA) programmes
that aim to reduce the prevalence of infection to <1%. In
the case of LF, this requires annual treatment for at least
5 years or more with ivermectin (150–200 lg/kg) or
diethylcarbamazine (6 mg/kg) depending on the endemic
region. However, albendazole (400 mg) is used in areas
where onchocerciasis is not endemic. On the other hand, in
areas where onchocerciasis is co-endemic, ivermectin (150–
200 lg/kg) plus albendazole (400 mg) must be used. In
addition, both regimes may be augmented by use of bed-
nets and mosquito control programs. By contrast, control
of onchocerciasis relies primarily on the sole use of
ivermectin [2] but current predictions suggest it will take
at least another 30 years of continuous treatment to achieve
control even in countries where the political, financial and
these current challenges, must be added to the eventual
spread of resistance to ivermectin [5, 6] and its contraindi-
cation for use in areas co-endemic for loiasis because of the
risk of severe adverse reactions [7].
Protective immunity in human filariasis, on the other
hand, is and continues to be passionately debated on among
several filarial immunologists. In general, individuals with
filarial infections mount a polarized T-helper 2 (Th2)
response. Th2 responses are protective against filarial
infections, particularly. For instance, persons with a
pronounced Th2 response have lower levels of circulating
microfilariae (MF). However, prolonged Th2 response is
detrimental to the surrounding tissue as seen similarly
with Th1-mediated pro-inflammatory response. An excess
Th2 response in sowda patients inasmuch as is crucial to
clearing skin MF, could also be at the expense of skin
pathology. In filarial infections of mice, Th2 response is
observed in the presence of third-stage larvae (L3);
however, depletion of the Th2-mediated cytokines leads
to impaired MF clearance [8].
Life cycle of filarial parasites
Human filarial infections are transmitted by the bite of
arthropods (vectors) usually during a blood meal from a
living host. Filarial nematodes have a thread-like body
with simple anterior ends with inconspicuous oral lips and

Ó 2017 The Foundation for the Scandinavian Journal of Immunology 251

252 Immunity Against Human Filarial Infections A. Kwarteng & S. T. Ahuno
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a cylindrical oesophagus, lacking a bulbus and dissimilar
copulatory spicules in the male. Brugia malayi, B. timori
and Wuchereria bancrofti are predominantly spread by
mosquitoes while the Simulium spp. (black flies) have
been identified as key vectors mediating the transmission of
onchocherca volvulus, the agent of river blindness. Con-
versely, the transmission of Loa loa and Mansonella in
endemic regions has been associated with (Tabanidae) flies
and biting midges (Culicoides spp), respectively.
Interestingly, infections usually begin with the depo-
sition of an infective larva (L3) in the skin during a bite
from a vector. These larvae then enter through the
punctured wound, making their way through the lym-
phatics then finally to the lymph nodes. It is at these sites
that they undergo several developmental stages and
moulting to form the fourth larval stage (L4), which
subsequently develops into adult worms. After mating, the
adult worms release millions of live progeny usually called
microfilariae into the bloodstream. However, these micro-
filariae can be taken up by the vector during a subsequent
blood meal. The ingested microfilariae then undergo
further development from the second larval stage (L2) to
the infective (L3) third larvae stage as shown in Fig. 1 [9].
Human filarial infection phenotypes
Generally, only a few percentage of individuals in filarial
endemic regions develop clinical conditions to filarial
infections, suggesting a differential response of the host
immune response to these filarial nematodes [10]. In LF,
individuals presenting overt clinical pathologies such as
lymphedema, elephantiasis and hydrocele in the extremi-
ties are usually MF negative [11]. However, the exact
aetiology facilitating the development of these pathologies
is not known, but vascular endothelial growth factors
(VEGFs) have been implicated [12, 13]. Conversely,
asymptomatic infections of LF could be further stratified
into patent (MF+), characterized by high levels of circu-
lating MF, and latent (MF ) infection states, where such
individuals are amicrofilaremic but are usually harbour
adult worms.
However, the two latter groups appear in equal
proportions in endemic regions, and majority do not even
develop severe pathological manifestations even after
several years of follow-up [14]. Similarly, it appears both
latent and patent infection states are driven by several
actors, given that both predisposition and susceptibility of
the infections are mediated by genetics. However, there
remains much to be elucidated in understanding the
immune permissive states [15].
On the other hand, there are a significant number of
individuals, commonly termed as endemic normals, who
usually fail to show any parasitological or pathological
manifestation despite prolonged exposure to infection.
Such individuals therefore display protective immunity, a
phenomenon which requires further characterization.

Figure 1 Life cycle of filarial infections (Adapted from [9]). The infective larvae (L3) are transmitted by vectors to the human host, during a blood meal.
L3 migrate to specific locations (lymphatic vessels, scrotal regions or dermis depending on the kind of infection) where they mature, mate and produce first-
stage larvae (MF) in the host. Several of these MF are released to circulate in the bloodstream or skin depending on the filarial species. MF are subsequently
ingested, after which they undergo several developmental stages in the vector.

Scandinavian Journal of Immunology, 2017, 85, 251–257

A. Kwarteng & S. T. Ahuno
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In onchocerciasis, two main phenotypes have been
categorized: the generalized onchocerciasis (GEO) and
hyperreactive onchocerciasis (HO) infection states. In
generalized onchocerciasis (GEO), individuals harbour
high worm and MF loads with an associated regulatory
immune phenotype resulting in the suppression of pro-
inflammatory responses [16]. Conversely, individuals rep-
resenting the hyperreactive onchocerciasis (HO) group are
characterized by a dominant infection inflammatory
immune response [17]. Besides the two polar forms, a
third group, usually amicrofilaridermic (without MF), has
been identified in endemic regions. Although, it becomes
difficult to pinpoint the exact origin of this phenotype,
some studies suggest that the development of this peculiar
phenotype may be due to prepatent infection; the domi-
nance of non-fertile worms; and ivermectin treatment [18].
Furthermore, another cluster of individuals in onchocer-
ciasis endemic areas usually present skin irritations with
intense itching and associated dermatitis largely due to the
heavy burden of MF in the skin. In addition, a small
percentage of individuals presents a unilateral dermal
pathology often termed as sowda. Studies involving
biopsies from sowda patients revealed the increased
presence of cellular infiltrates believed to mediate MF
killing and clearance. In addition, heavy MF burden in
subjects leads to MF invasion of the conjunctiva, cornea
and posterior regions of the eye resulting in the copious
release of multiple antigens and inflammatory responses
and subsequently visual impairment [19].
Vaccination studies in permissive animals took off
seventy years ago; however, no complete immunity in these
animals has been achieved [20]. This is considerably linked
to complexity of the filarial parasite life cycle. Indeed,
comparing the bulky extracellular systemic nematode with
the size of the immune effector cells of the mammalian host
presents a challenge whether the concept ‘protective
immunity’ is real during filarial infections. Although the
average lifespan of adult filarial worms is estimated to be
between 5 and 15 years, nonetheless some female worms
live to produce MF up to 20 years. Adult filarial worms are
located in the lymphatic vessels, for years in the case of
lymphatic filariasis or in subcutaneous tissues in the case of
onchocerciasis. Our group and others have used ultrasound
technique extensively to document the presence of adult
worms in lymphatics, particularly in scrotal lymphatic
vessels in male filarial infected subjects in several endemic
regions [21–25]. As the lymphatic system is considered the
fulcrum of the host immune system, the concept of
‘protective immunity’ is constantly challenged as to
whether it is operational in the human host.
Nevertheless, the introduction of the circulating filarial
antigens (CFA) test has identified individuals infected with
adult worms that do not show microfilaremia (CFA+,
MF ), whereas a larger number of the population living in
the endemic regions do not show signs of the infection or
Ó 2017 The Foundation for the Scandinavian Journal of Immunology
Immunity Against Human Filarial Infections 253
disease [26]. Interestingly, others have also reported age-
dependent decrease in the prevalence of filarial infection in
highly endemic communities [27] further emphasizing the
fact that protective immunity does occur in human
filariasis. Not belabouring the point, several murine studies
have also demonstrated that operational protective immu-
nity exists.
Existence of herd immunity in filarial endemic com-
munities as well as age-prevalence pattern of infection
possibly depends on exposure to parasites [28]. Indeed, it
has been observed that microfilaria rates may increase with
transmission intensity until regulated by the development
of herd immunity. This therefore suggests that the
acquisition of immunity in human filariasis is transmission
driven [29] especially in high diverse vector transmission
areas [30]. Interestingly, the nature of protective immunity
response in association with development of acquired
immunity in only high transmission areas is now difficult
to explain. In previous studies by King et al. [31], they
observed stronger Th2 cytokine responses in high trans-
mission areas than in low transmission areas. This study
accorded a protective role for IL-5 in human filariasis as
demonstrated in other filarial models [32–34]. In fact, the
cellular proliferation of antigen-specific IL-5 [35] has been
linked to its ability to recruit eosinophils to site of
infection [36].
The T-helper story: when and how they are
induced?
Over the years, research has proven beyond doubts, from
both animal and human models, that canonical immune
response to lymphatic filariasis is that of T-helper 2 (Th2)
response coupled with the production of key cytokines
such as IL-4, IL-5, IL-9, IL-10, IL-13 in addition to
antibody isotypes IgG1, IgG4 (as in the case of humans)
and IgE [37]. Notwithstanding, filarial infections have
also be associated with profound populations of eosino-
phils and alternatively activated macrophages. The dis-
covery of Th17 cells has introduced another dimension to
the concept of immunity in filarial infection. These cells
are highly regulated in patients with chronic pathology as
demonstrated in LF [38]. Recently, our group showed that
Th17-producing IL-17 cells contribute significantly to the
development of hyperactive form during human onchocer-
ciasis [17].
Major players responsible for early initiation of host
immune response associated with filarial nematodes include
dendritic cells, macrophages, basophils and innate lym-
phoid cells (ILCs). However, the detailed mechanism still
remains elusive to current knowledge of filarial immuno-
biology. Recently, blood ILCs populations were restored in
children with schistosome infection following anti-
helminth treatment in Zimbabwe [39]. Dendritic cells
(DC), another class of professional antigen presentation
254 Immunity Against Human Filarial Infections
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cells, play a crucial role in presenting filarial antigen to T
cells to initiate immune. Differentiation and maturation of
DC in the presence of filarial antigens in vitro can stimulate
Th2 response accompanied with down-modulation of IL-12
production [40]. More interestingly, recent studies have
indicated that live parasites are able to induce cell death in
human dendritic cells in addition to inhibiting their
ability to produce IL-10 and IL-12 thereby diminishing
their capacity to activate CD4+ T cells [41].
Protective immunity: insight from animal models
To establish the functionality of protective immunity,
animals that are permissive to several filarial parasites are
used [20, 42]. Indeed, studies in mice suggest that some
knockout strains of the permissive Bagg Albino (BALB/c)
background harbour MF in the thoracic cavity, yet they do
not appear in the periphery in Litomosoides sigmodontis
infection [43], thus implying that BALB/c mice are fully
permissive to L. sigmodontis infection. Interestingly, a study
has reported that susceptibility of BALB/c mice to
L. sigmodontis infection is mediated by increased recruit-
ment of Tregs in early infection, which dampens immune
responses [44]. More recently, Specht et al. [45] demon-
strated that overexpression of IL-10-producing macro-
phages enhances patency by significantly reducing the
number of IL-5-producing CD4+ T cells in L. sigmodontis.
In contrast, another inbred mouse strain C57 black 6
(C57BL/6) is more resistance to the infection [46].
Currently, the mechanisms dictating protective immunity
in C57BL/6 are not fully understood; however, increased
cellular responses have been implicated to be vital [20]. In
addition, it has been documented that compared to BALB/c,
C57BL/6 mice express higher numbers of T and B cells,
macrophages as well as eosinophils in the pleural cavities
during filarial infection [46]. In the same study, the authors
observed that while BALB/c mice produce more polarized
Th2 responses, C57BL/6 mice were characterized with both
Th1 and Th2 responses. While the role of Th1 response is
yet to be delineated, Th2 responses exhibit resistance.
Furthermore, studies in cotton rats vaccinated with MF
and later infected showed that adult worms were able to
develop in the rat but MF did not appear in the circulatory
blood [47]. These convincing evidences demonstrate the
effectiveness of protective immunity in filarial infection.
Nonetheless, there remains a crucial immunological chal-
lenge in the use of genetic manipulations, which has
prevented the use of these animals to clearly define the
functionality of protective immunity in experimental
filariasis. Elsewhere, the effects of antibodies produced
against the third stage larvae (L3) as well as antigens
associated larval moulting [48, 49], antibodies to micro-
filariae sheath [50], effector cells such as eosinophils [51]
and basophils [52–55], cytokines such IL-5, IL-4, TNF-a
and nitric oxide appear [56] to impair larval development
A. Kwarteng & S. T. Ahuno
and facilitate microfilariae clearance have been docu-
mented. These studies among others demonstrate that
cytokines, antibodies and specific population of immune
cells are used extensively to understand the protective
immunity in filariasis [10, 57] nonetheless, a clear
consensus remains to be established.
Protective immunity in human filarial studies: the
immunoglobulins crosstalk
Immunoglobulins (Ig) contribute significantly in the
defence against several pathogens [58], and their response
is well-documented in filarial infection as well. Total IgG
is predominant in serum and primarily differs in number
and location of disulphide bonds and the size of the hinge
regions. Several studies have attempted to elucidate the
role of immunoglobulins in protective immunity during
filarial infections [59]. However, protective immunity as
proposed in filarial infection has been challenged by other
findings. For instance in O. volvulus infection, neither B
cells nor antibodies were found to exhibit profound impact
on MF levels [60]. Elsewhere, survival of the host been
associated with several species of filarial parasites as in the
case of uMT mice [61] as well as Xid mice [62]. These
conflicting results possibly indicated that the functionality
of immunoglobulins may be significantly influenced with
respect to the site of infection. In LF, MF primarily
inhabits peripheral blood and lymphatic vessels whereas in
onchocercal infections, MF is found in skin. The differen-
tial infection sites could play a major role in mounting an
immune response. With the exception of IgG4, all the IgG
subclasses fix complement. In human studies, increased
levels of filarial-specific IgG4 has been reported in patent
infected subjects [63], whereas IgA associates with endemic
normals [57]
Upregulation of serological IgG4 isotype [63] in patently
infected persons is believed to be driven by regulatory T
cells. In uninfected individuals, the IgG isotype consists of
5% of the total circulatory antibody but rises sharply in
active filarial infection to about 95% [10]. Studies indicate
that the immunomodulatory potential of filarial parasites
[64] and the role of IgG4 as a marker for immunoregulation
[65] in filarial infection. IgG4 antibodies are upregulated in
the presence of the immunoregulatory cytokine such as IL-
10. IgG4 fixes complement poorly and promotes patency
and competes for binding sites with IgE, a cytotoxic
antibody. Field studies suggest a correlation between that of
IgG4 and MF levels. The positive correlation between titres
of IgG4 antibodies and MF infection intensity lends support
to the concept of IgG4 functioning in some kind of
blocking capacity, that is interfering with the effector
pathways needed to clear MF from the host. Such immune
deviation to a regulatory phenotype in patently infected
individuals is governed by the female adult worm. Almost a
decade ago, our group documented a strong relationship
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A. Kwarteng & S. T. Ahuno
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between IgG4 and Tregs in a coculture assay system of Tr-1
clones and highly purified B cells in onchocerciasis patients
[66]. In the same study, Tr-1 clones were observed to
strongly drive the production of IgG4. This was achieved by
inducing B cells to produce the immunoregulatory cytokine
IL-10 [66]. Overexpression of IL-10 by macrophages has
recently been reported to dampen immune responses and
promote patency in murine [45]. These observations suggest
that adult female worms promote the interaction of T–B
cells during patency to produce IL-10 and subsequent IgG4
to create an immunological milieu necessary for the survival
of MF.
One of the most studied antibodies during helminths
infection in general and filarial infection in particular is
IgE. IgE antibody generation is enhanced in the presence of
IL-4. Interestingly, it has been reported that IgG4
antibodies compete with IgE for binding sites and thus
obstruct the protective activity of IgE in association with
other cells types. Others have implicated IgE [51, 67, 68]
and IgA [57] to promote immunity in filariasis. However, a
careful regulation of IgE is crucial as it promotes pathology
in helminth infections. Increased levels of IgE is associated
with latent infection and individuals with chronic filarial
pathology compared to patent infection. This clearly
suggests that the ratio of IgG4: IgE immunoglobulin is
crucial to infection phenotype. However, the regulators of
the class-switching mechanism between these two
immunoglobulins are yet to be defined.
While different antibody isotypes have distinct biolog-
ical function, an isotype can affect the fine specificity of an
antibody [69]. IgG1 and IgG3 have special prospects to
neutralize pathogens at ports of entry into the body, thus
preventing infection. IgG1 and IgG3 have been implicated
in parasite clearance via opsonization, sensitization of NK
cells and/or activation of the complement system [70].
Interestingly, other studies have demonstrated the role of
the cytophilic IgG (IgG1 and IgG3) in protection from
malaria [71, 72]. IgG2 responds to polysaccharides,
whereas protein antigens usually induce IgG1 and IgG3
antibody responses. In human onchocerciasis, IgGs has
been associated with hyperactive oncho-dermatitis. Isotype
analysis of IgG antibody subclass IgG1, IgG2 and IgG3
associates with low concentration in individuals with MF,
while higher concentrations were observed in persons with
filarial pathology. IgGs that mediate phagocytosis in
infected erythrocytes have been reported in in vitro,
confirming a possible role of parasite elimination in
humans as well.
In onchocerciasis, human antibody that responds to Ov-
CHI showed elevated IgG3 isotype responses in putative
immune individuals and IgG3 bond to the carbohydrate
epitopes by the induction of anti-Ov-CHI [73]. IgG3 has
been proposed to be involved in protective immunity
mechanisms against the filarial parasites on the basis of its
powerful ability to fix complement [74].
Ó 2017 The Foundation for the Scandinavian Journal of Immunology
Immunity Against Human Filarial Infections 255
Although conflicting data on parasite-specific antibodies
exist, interpreting clinical data requires the consideration
of several factors such as transmission intensity [29], age,
gender [57] among others. This notwithstanding IgG1,
IgG2 and IgE have been established to negatively correlate
with MF. IgG3 shows negative correlation with circulating
filarial antigen CFA, and IgG4 positively associates with
CFA [75], whereas IgA negatively correlate with MF and
CFA [57]. These findings clearly suggest that a possible
combinatorial regulation of immunoglobulins may signif-
icantly determine filarial infection outcome.
Conclusion
The limited understanding of the precise mechanisms by
which filarial nematodes are killed in vivo contributes to
our confusion of how the protective mechanisms are
orchestrated during infection. Immunosuppression is one
key mechanism filarial parasites use to promote their
survival during infection as seen in the downregulation of
both Th1 and Th2 immune responses with a concomitant
increase in the expression of regulatory molecules. Cellular
and humoral agents induced during filariasis provide a
good platform in understanding protective immunity,
suggesting that the fight against filarial nematodes is not
unilateral. The mechanisms discussed above may explain in
part how immunity to filarial parasites is developed,
however, further investigations are required in the area of
gene expression and proteomics. Such approaches have
potentials to unravel underlying molecular mechanism(s),
pathways and networks and therefore may be warranted to
address unanswered questions regarding protective immu-
nity in filarial infections.
Acknowledgment
We would like to thank Dr. Alex Aboagye at North
Carolina A&T University, USA for reading through the
manuscript.
Conflict of interest
The authors declare no conflict of interest.
Authors’ contribution
AK conceived the idea. AK and STA equally critically
wrote and edited the manuscript. All authors approved the
final version of this article.
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