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444 ParT ThrEE Host Defenses to Infectious Agents

life-threatening, generalized, or systemic hypersensitivity reaction, MECHANISMS OF EVASION AND IMMUNE
and is associated with IgE interaction with high-affinity IgE REGULATION BY HELMINTH PARASITES
receptors on basophils and mast cells (Chapter 23). The risk of
anaphylaxis in individuals with helminth infections can vary, Helminths exert profound immunoregulatory effects on the host
depending on the parasite, tending to occur more frequently immune system with parasite antigen–specific immune suppres-
with echinococcosis or after Anisakis infection, while being sion as well as more generalized levels of immune suppression.
extremely rare in most other helminth infections. It has been shown that patients with schistosomiasis or filariasis
have markedly diminished responses to parasite antigens and
Wound Healing to some measurable attenuation in responses to bystander antigens
Recent studies have shown a close association of type 2 cytokine and routine vaccinations. Thus host immunosuppression is usually
responses with many aspects of wound healing and repair. 25,26 antigen specific, whereas chronic infection can be associated
It has been proposed that the type 2 cytokine response has evolved with some spillover effects. Among the mechanisms utilized by
to not only mediate resistance to helminth infection but also parasites to avoid immune-mediated elimination are those of
activate the wound healing apparatus to repair and reconstruct evasion—the use of sequestration, camouflage, and antigenic
tissue, since tissue damage is intricately associated with helminth variation—and suppression, regulation, or blockade of immune
infections. Thus AAMs are intimately involved in this process effector pathways.
as they produce MMPs, Arginase-1, insulin-like growth factor
1 (IGF1), VEGF, and TGF-β, which together promote myofibro- Parasite-Derived Factors
blast activation, angiogenesis, epithelial cell turnover, and Parasite-derived products play a very important role in host
extracellular matrix deposition. immune evasion. 29,30 Parasite products, such as the schistosome-
secreted proteins, alpha-1 and omega-1, promote Th2 differ-
Lymphangiogenesis entiation. Alpha-1 (also known as IL-4–inducing principle of
The anatomical changes in the architecture of lymphatics, which schistosome eggs [IPSE]), released by schistosome eggs, induces
range from lymphangiectasia and granulomatous responses to IL-4 release and degranulation by human and mouse basophils by
the development of collaterals, suggest that active lymphatic cross-linking surface IgE. Omega-1 is a ribonuclease abundantly
remodeling involving endothelial cell growth, migration, and secreted by eggs, shown to condition DCs to drive Th2 polariza-
proliferation is an important feature of early lymphatic filarial tion. Omega-1 binds to and is internalized by DCs in a mannose
disease. Live filarial parasites (and their excretory/secretory receptor–dependent process and then suppresses protein synthesis
products) have been shown to induce activation, proliferation, through degradation of messenger RNA (mRNA).
and tube formation in lymphatic endothelial cells (LECs) and Phosphorylcholine (PC) is a small hapten-like moiety present
27
their differentiation into tubelike networks. This was found to in the excretory/secretory products of many helminths, and one
be associated with significantly increased levels of MMPs and particular PC-containing molecule, called ES-62, from filarial
TIMPs. Recent studies have also implicated the VEGF family in worms has been shown to have a wide variety of immunomodula-
lymphangiogenesis, with VEGF-C being associated with lymph- tory properties. Thus ES-62 can inhibit the proliferation of CD4
23
edema and VEGF-A with hydrocele. Finally, TLR-mediated T cells and conventional B cells, decrease IL-4 and IFN-γ produc-
events are considered to be the main drivers of this angiogenic/ tion, promote proliferation and IL-10 production by B1B cells,
lymphangiogenic process in filarial disease. 27 modulate complement activation, and condition APCs to drive
Th2 differentiation with concomitant inhibition of Th1 responses.
Carcinogenesis ES-62 has also been shown to exhibit bystander antiinflammatory
Infection with Opisthorchis viverrini, Clonorchis sinensis, and activity in collagen-induced arthritis, rheumatoid arthritis,
Schistosoma hematobium are classified as group 1 biological chemical contact sensitivity, lupus-associated atherosclerosis, ear
carcinogens (i.e., definitive causes of cancer). The former (liver inflammation, chronic asthma, and airway hyperreactivity.
fluke) is associated with cancer of the bile duct (cholangio- Helminths utilize glycans within glycoproteins and glycolipids,
carcinoma) and cancer of the liver (hepatocarcinoma), and which mimic host glycans, to regulate host immune responses.
the latter is associated with carcinoma of the urinary bladder. In addition, these host-like helminth glycans can directly interact
The mechanisms of helminth-induced cancer include chronic with host glycan–binding proteins, such as C-type lectin receptors
inflammation, sustained cellular proliferation, modulation of and galectins, to shape innate and adaptive immune responses.
the host immune system, reprogramming of glucose metabo- Similarly, helminth lipids have also been implicated in immune
lism and redox signaling, induction of genomic instability and modulation; schistosome phosphatidylserine induces DCs to
destabilization of tumor proteins, stimulation of angiogen- polarize IL-4–producing T cells, whereas schistosome lysophos-
esis, resistance to apoptosis, and activation of invasion and phatidyl serine induces DCs to induce IL-10–secreting Tregs.
metastasis. 28 Helminth parasites utilize mechanisms involving cytokine
mimicry and interference to establish chronic infection. Thus
Epileptogenesis parasites produce cytokine- and chemokine-like molecules to
Neurocysticercosis, caused by the larval form of Taenia solium, is interfere with the function of host innate immune products.
the most common preventable risk factor for epilepsy worldwide The first helminth cytokines were found to be homologues of
and accounts for nearly 30% of all epilepsies in some endemic TGF-β expressed by B. malayi, and both schistosomes and filarial
areas. The manifestations are variable, depending on the parasites express members of the TGF-β receptor family. Similarly,
location, number, and size of the cysts in the central nervous E. granulosus expresses a TGF-β ligand, and thus all helminth
system as well as the degree of accompanying inflammation, groups might have the potential to exploit TGF-β–mediated
provoked by cyst degeneration, calcification, and/or perilesional immune suppression. Various helminths, including B. malayi,
edema. produce homologues of macrophage migration inhibitory factors