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ChaPTEr 31 Immune Responses to Helminth Infection 445

(MIFs), which are known to activate an antiinflammatory pathway can then act as messengers of communication between the parasite
through SOCS-1, a molecule involved in cytokine signaling. T. and the host cell. These exosomes (containing microRNA) can
muris is known to express a homologue of IFN-γ, which binds then enter the host cell and modulate host gene expression. 32
to the IFN-γ receptor in vitro and induces signaling. As T. muris
is expelled by IL-4, secretion of an IFN-γ–like protein can prolong Host-Related Factors
its survival. Regulatory T and B Cells
Similarly, helminth parasites utilize chemokine- or chemokine- Evidence for the involvement of Tregs in helminth-mediated
receptor like proteins to evade protective immunity. Ascaris suum downmodulation of the immune response has been accumulating
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is known to express a neutrophil chemoattractant with chemokine in recent years (Chapter 18). IL-10 and TGF-β, both factors
binding properties. S. mansoni eggs secrete a protein (S. mansoni associated with Tregs, are elicited in response to helminth infec-
chemokine-binding protein [smCKBP]) that binds the chemo- tions, and in vitro neutralization of IL-10 and TGF-β at least
kines CXCL8 and CCL3 and inhibits their interaction with host partially restores T-cell proliferation and cytokine production
chemokine receptors and their biological activity, resulting in in lymphatic filariasis. Similar reversals of immunosuppression
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suppression of inflammation. Similarly, B. malayi (and all of are observed in onchocerciasis and schistosomiasis, with IL-10
the other filariae sequenced to date) has been shown to express producing natural Tregs (nTregs) from egg-induced granulomas
galectins that can bind host immune cells in a carbohydrate- (in S. mansoni infection) being important for host survival. More
dependent manner. recently, Tregs from patients with filarial infections have also
Helminths secrete two major classes of protease inhibitors been shown to express high levels of other suppressive molecules,
called cystatins and serpins, each with proposed immunomodula- such as CCL4, IL-29, LAG-3, and Foxo3. Moreover, filarial infec-
tory roles. Cystatins inhibit cysteine proteases (cathepsins and tion is associated with an expansion of T cells expressing the
aspartyl endopeptidases) required for antigen processing and IL-10 superfamily cytokine members (IL-19 and IL-24), and
presentation and therefore inhibit T-cell activation. They also inhibition of these cytokines results in increased Th1 and Th2
elicit the regulatory cytokine IL-10, leading to direct impairment responses. Tregs play a vital role in limiting host pathology by
of T-cell proliferation. The serpins are serine protease inhibitors, downregulating harmful Th1/Th17 responses in filarial infection
which can cause specific inhibition of the neutrophil proteinases and schistosomiasis. In addition, low level Treg activity is essential
cathepsin G and neutrophil elastase. Aspartic proteases from for type 2 effector immunity to expel certain intestinal helminths,
Ascaris lumbricoides have been shown to block efficient antigen and transdifferentiation of Th17 cells into Tregs during helminth
processing that is dependent on proteolytic lysosomal enzymes. infection is important for resolution of inflammation.
Other parasite products mediate their effect by blocking A number of studies have recently reported that B cells might
effector functions, including recruitment and activation of have an active regulatory role in helminth infections. For example,
inflammatory cells and limiting the destructive potential of purified B cells from mice infected with B. malayi produce IL-10
hi
activated granulocytes or macrophages in the local extracellular in response to filarial antigens. Similarly, IL-10 producing CD1d
milieu. For example, the host chemoattractant platelet-activating B cells are induced in both mice and humans and are suppressed
factor (PAF) is inactivated by a complementary enzyme PAF after anthelmintic treatment. This induction occurs, in part,
hydrolase secreted by N. brasiliensis. Eotaxin-1, a potent eosinophil through a mechanism involving the ICOS-B7RP-1 pathway.
chemoattractant, is degraded by metalloproteases from hook-
worms. A. caninum secretes a protein called neutrophil inhibitory Hyporesponsive T Cells
factor, which binds the integrins CD11b/CD18 and blocks Effector T cell responses can be turned off or modulated through
adhesion of activated neutrophils to vascular endothelial cells a variety of mechanisms, including through cytotoxic T lym-
and also the release of hydrogen peroxide (H 2 O 2 ) from activated phocyte antigen-4 (CTLA-4) and programmed death-1 (PD-1).
neutrophils. N. americanus ES products also bind to host NK Interestingly, increased expression of CTLA-4 and PD-1 has been
cells and augment the secretion of IFN-γ, which might cross- demonstrated in filarial infections, and blocking of CTLA-4 can
regulate deleterious Th2 responses. Other modulators, such as partially restore a degree of immunological responsiveness in
prostaglandins, and other arachidonic acid family members, such cells from infected individuals. Moreover, T cells have decreased
as PGE2 and PGD2, are known to inhibit IL-12 production by induction of T-bet, the Th1 master regulatory gene indicating a
DCs. Finally, helminths susceptible to oxidant-mediated killing failure at the transcriptional level to differentiate into Th1 cells.
express both secreted and membrane-associated enzymes, such Finally, T cells from individuals with filarial infection exhibit
as superoxide dismutase, glutathione-S-transferase, and gluta- classic signs of anergy, including diminished T-cell prolifera-
thione peroxidase, molecules that are thought to play a significant tion to parasite antigens, lack of IL-2 production, and increased
role in assisting parasite survival in inflamed tissues. Recently, expression of E3 ubiquitin ligases. Similarly, anergic T cells are
a family of helminth defense molecules secreted by parasitic found in both humans and mice with F. hepatica infection and
helminths has been shown to exhibit biochemical and functional schistosomiasis; in the latter case, these T cells express high
characteristics similar to human antimicrobial peptides. These levels of the anergy molecule GRAIL (gene related to anergy in
molecules can modulate innate cell activation by classic TLR lymphocytes).
ligands, such as lipopolysaccharide.
It has been also been reported that parasitical helminths can Modulation of Apc Function
produce exosomes and other secretory vesicles that facilitate the DCs are the first APCs usually to encounter parasites, and
transfer of intracellular cargo. Exosomes derived from helminths helminth modulation of DC function has been well character-
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have been shown to possess immunomodulatory capacity with ized. Filarial parasites induce downregulation of MHC class I
the ability to modulate immune responses by altering the function and class II molecules, as well as cytokines and other genes
of ILC2. In addition, secreted vesicles from B. malayi, O. volvulus, involved in antigen presentation, thereby rendering DCs sub-
and S. mansoni have been shown to contain microRNAs that optimal in their ability to activate CD4 T cells. Schistosomes