Page 464 - Clinical Immunology_ Principles and Practice ( PDFDrive )

ChaPTEr 31 Immune Responses to Helminth Infection 443

KEY CONCEPTS Granulomatous Reactions
Helminth-Induced Immune Responses Granuloma formation is the mainstay of the protective immune

Characterized by immunoglobulin E (IgE) antibody production, tissue and response to certain helminths, but it can also lead to deleteri-
peripheral blood eosinophilia, mast cell involvement, innate lymphoid ous effects in the form of pathology. Although granulomatous
cell type 2 and Th2 cell expansion, and production of type 2 reactions occur in many helminth infections (e.g., toxocariasis,
cytokines. Angiostrongylus infections and lymphatic filariasis), parasitical
Implicated both in pathogenesis of helminth infections and in mediating granulomata have been best studied in S. mansoni infections,
immunological protection.
In mucosal immunity to helminths, T-helper 2 (Th2) cell responses are where granulomatous and fibrosing reactions against tissue-
initiated and sustained by innate populations (including tuft cells and trapped eggs is orchestrated by CD4 T cells and the fibrosis
innate lymphoid cells) through interleukin (IL)-25, IL-33, and thymic that results from the cellular response is the principal cause
stromal lymphopoietin (TSLP). of morbidity in infected individuals. The severity of the
In tissues, helminths are acted upon by the host innate effectors, including inflammatory process markedly varies both in humans and in
macrophages, neutrophils, eosinophils, and basophils. experimental animal models, with severe pathology associated
Regulated by T cells and other cells producing IL-4, IL-5, IL-9, IL-10, and/ with Th1 and Th17 responses and milder pathology with Th2-
or IL-13. 21
Characterized by the induction of regulatory T cells (Tregs) that mediate dominant responses. Studies in murine models of granuloma
downmodulation of immune responses to helminth infections and formation have demonstrated the important roles of IL-13 and
impact bystander phenomena, such as allergy and autoimmunity. TNF-α.
Fibrosis
Fibrosis is commonly associated with chronic helminth infections
is the AAM, which is exemplified by the targeting of the glycan that result in chronic inflammation and dysregulated wound
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chitin that is frequently expressed by helminths but not by the healing. These infections activate macrophages and fibroblasts,
host. The chitinase and fizz family proteins (ChaFFs), which resulting in the production of TGF-β, platelet-derived growth
include chitinase and chitinase-like secreted proteins, are prime factor (PDGF), IL-1β, and other factors. Macrophages also
candidates for mediating host resistance. These proteins include promote inflammation by recruiting and activating monocytes
acidic mammalian chitinase (AMCase) and the RELM family and neutrophils, as well as activating CD4 T cells. In addition,
proteins and are capable of enzymatic activities that potentially fibroblasts are stimulated to synthesize matrix metalloproteinases
damage certain helminths. (MMPs) and tissue inhibitors of metalloproteinases (TIMPs),
leading to extracellular matrix remodeling and fibrosis. Another
PATHOLOGY ASSOCIATED WITH IMMUNE consequence of chronic schistosomiasis is pulmonary arterial
RESPONSES IN PARASITIC HELMINTH INFECTION hypertension, which has been shown to be associated with
IL-4– and IL-13–mediated type 2 inflammation resulting in
Typically, pathological findings associated with each parasitic TGF-β−induced pulmonary vascular disease. In the same manner,
infection are different and relate to the presence of the parasites IL-10 and IL-12 are known to modulate IL-13–mediated fibrosis;
in host tissues, but there are pathological reactions that stem in the combined absence of IL-10, IL-12, and IL-13Rα, IL-13–
directly from the host response. dependent fibrosis in chronic schistosomiasis proceeds rapidly
to lethal cirrhosis. Infection with Wuchereria bancrofti (one of
Immune Complexes the causative agents of lymphatic filariasis) is associated with
Immune complexes are potent mediators of localized inflam- similar fibrotic reactions.
matory processes that form in many parasitic infections presum-
ably as a result of the chronic low-dose antigen release seen in Toll-Like Receptors
these infections. Circulating immune complexes have been Immunopathology in lymphatic filariasis is associated with the
identified in both experimental and human filarial and schisto- presence of an endosymbiotic, Rickettsia-like bacteria called
somal infections. These have been shown to induce lymphatic Wolbachia. Wolbachia are known to stimulate immune cells
inflammation and vasculitis in filarial infections as a result of through TLR2 and TLR4 and release proinflammatory cytokines,
their deposition. In addition, a common manifestation of immune as well as vascular endothelial growth factors (VEGFs), which
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complex–mediated pathology, immune complex glomerulone- might contribute to lymphatic pathology. Wolbachia-TLR4
phritis (ICGN), has been documented by renal biopsy in patients interaction has also been shown to be the major mechanism of
with schistosomiasis and filarial infections. Other manifestations corneal inflammation in onchocerciasis, and a TLR signaling
of immune complex–mediated damage, such as reactive arthritis molecule, IL-1 receptor associated kinase-2 (IRAK-2), regulates
and dermatitis, have also been described in patients with helminth pathogenic Th17-cell development in S. mansoni infection.
infections.
Immediate Hypersensitivity Responses
Autoantibodies and Molecular Mimicry Immediate hypersensitivity responses are associated with the
Autoantibodies have been implicated as causing disease in a early and/or acute phase of infections with invasive helminth
variety of helminth infections, including filarial infections, parasites, such as Ascaris, hookworm, schistosomes, or filariae.
schistosomiasis, and hookworm infection, and are thought to Patients do manifest symptoms suggestive of allergic reactivity,
reflect a polyclonal B cell expansion that often accompanies these such as wheezing or urticaria. Furthermore, in clinical syndromes
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infections. Autoantibodies against nuclear material have been associated with Loa loa infection (with its angioedematous Calabar
found in a vast majority of patients with chronic schistosomiasis, swellings), with tropical pulmonary eosinophilia, and with larva
and antibodies against human calreticulin and defensin have currens in strongyloidiasis, IgE-mediated reactions are thought
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been found in onchocerciasis. to underlie these signs and symptoms. Anaphylaxis is a severe,