Immune
response to filariae
Our lab studies
the immune response to filariae. Filariae
are tissue-invasive roundworms which are
transmitted by insects. Pathogenic human
filariae include Wuchereria bancrofti and Brugia
malayi, which cause lymphatic
filariasis (elephantiasis), Onchocerca
volvulus, the cause of river blindness, and Loa loa,
which causes African eyeworm. Lymphatic
filariasis alone affects
approximately 120 million people world-wide and, after malaria, is the
second-most burdensome parasitic disease as measured by
disability-adjusted
life years. Onchocerciasis affects 18
million people, causing blindness or severe visual impairment in
750,000
people, mostly in sub-Saharan Africa.
The
immune response to filariae is markedly different than that to most
viral,
bacterial, and fungal infections. Like
other helminths, filariae induce a type 2 immune response characterized
by
eosinophilia, elevated serum levels of Ag-specific and polyclonal IgE,
and
increases in T-cell production of IL-4, IL-5, and IL-13.
Most interestingly, when a person is infected
for a long time, the immune response to filarial worms diminishes,
though the
rest of the immune system continues to work well against other
infections. While it is clear that
IL-4
plays a central role in driving type 2 responses, the exact factors
responsible
for the initiation, maintenance, and eventual diminution of these
responses in
filarial infections remain unknown. The mission of our lab
is to
understand the mechanisms behind the development, maintenance, and
cessation of
IgE-mediated responses in filarial infections in order to ultimately
develop
new modalities of prevention and treatment for parasitic, allergic, and
autoimmune diseases.
To
accomplish this, our lab utilizes the Litomosoides
sigmodontis model of filaria
infection, the
only mouse model of filariasis in which larvae fully complete their
development
from infective L3 stage larvae into mature, sexually reproducing adult
filarial
worms.
Protection
against Type 1 diabetes by filariae
In
addition to being advantageous for the survival of the parasite,
immunomodulatory responses induced by parasitic worms may have
beneficial
effects for the host. Both animal and
human studies have demonstrated that chronic parasitic worm infections
are
protective against autoimmune diseases. Recently,
our laboratory has demonstrated that
infection of non-obese
diabeteic (NOD) mice with L. sigmodontis
protects against the development of diabetes. This
protection is associated with an increase in
T-regulatory cell
numbers and with an autoantigen-specific Th2 shift.
Live infection is not required for
protection, as injection of a crude homogenate of L.
sigmodontis antigens also protects against diabetes.
Currently, we are working to determine the
mechanisms by which L. sigmodontis protects
against the development of diabetes in NOD mice and to identify
specific
molecules of L. sigmodontis that can
induce this protection.
Human
Immunology
In
addition to mouse immunology, we also have ongoing
collaborations for studies on human immunology. Specifically,
we collaborate with Dr. Phil Cooper’s
group in Ecuador
to
study the effects worm infections have on allergic responses and on the
development
of the immune system. Additionally, we
have
an ongoing collaboration with investigators at NIH evaluating the
effects H2
receptor blockers have on the clinical course and immune function of
patients with
the hyper-IgE syndrome. |
