Page 462 - Clinical Immunology_ Principles and Practice ( PDFDrive )

ChaPTEr 31 Immune Responses to Helminth Infection 441

mansoni, where it has been strongly associated with infection- influence of ILC2. Apart from the rapid kinetics of recruitment,
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induced, immune-mediated pathology. More recently, it has eosinophils in blood and tissue also exhibit morphological and
also been demonstrated in human infections, in which children functional changes attributable to eosinophil activation. Eosino-
with S. hematobium–associated pathology have higher Th17 phils possess a range of immunomodulatory factors that are
responses compared with those who are pathology-free. Similarly, released upon cell activation, including cytokines, growth factors,
a strong association of Th17 responses with pathological responses and chemokines. Unlike T and B cells, eosinophils can rapidly
has also been demonstrated in lymphatic filariasis. Finally, Th22 release cytokines within minutes in response to stimulation, since
cells are yet another subset of CD4 T cells that typically secrete most of the cytokines are stored in a preformed fashion in
IL-22. To date, only a few studies have examined the role of secretory vesicles. Moreover, eosinophils can participate in the
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Th22 cells in helminth infections. IL-22 was shown to be induced regulation of IgE and goblet cell mucus production; they also
in the intestinal mucosa after infection with T. trichiura or Necator serve as effector cells in protective immune responses and as
americanus in humans, whereas the frequency of Th22 cells was regulatory cells influencing both innate and adaptive immunity
shown to be higher in individuals with filarial infection compared in helminth infections.
with endemic healthy controls.
Helminths and Basophils/Mast Cells
Helminths and B Cells Basophils are an important component of the immune response
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Helminth interactions with B cells occur both at the B-cell to helminth infections. Basophils are capable of secreting a
cytokine level and at the level of antibody production. Interactions variety of mediators, including histamines, cytokines, chemokines,
at the cellular level primarily result in B-cell activation and and lipid mediators that promote Th2 responses. Basophils in
cytokine production, most notably by the induction of IL-10. B humans and mice also readily generate large quantities of IL-4
cells have been shown to be important for the Th2 responses to in IgE-dependent and IgE-independent manners. Basophils appear
certain helminths, with IL-2 producing B cells supporting optimal to play an important role in protective immunity to secondary
development of effector and memory Th2 cells and LTα1β2- infection (similar to eosinophils) with N. brasiliensis, H. polygyrus
expressing B cells supporting the recruitment of a Th2 promoting bakeri, and L. sigmodontis; they also play an active role in resistance
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DCs. Immune regulation by B cells has also been recognized to primary infection (through secretion of IL-4 and IL-13) with
in schistosome infection, where B-cell deficiency leads to enhanced T. muris and T. spiralis. In addition, basophils have been shown
Th2 cell–dependent immunopathology. However, it is at the level to be critical APCs for driving Th2 cell differentiation in different
of antibody production that B cells play a profound role in models of helminth infection.
helminth infections. Susceptibility to secondary infection is Mast cells may contribute to inflammatory reactions directed
increased in the absence of B cells in infection with Litomosoides against invasive helminth parasites. These cells express high
sigmodontis, S. mansoni, T. muris, and Heligmosomoides polygyrus affinity Fcε receptors that are sensitized with parasite antigen–
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bakeri. IgG is reported as an antibody isotype that is important specific IgE and can be triggered by parasite antigens. It has
for protection against intestinal helminths, and IgM (typically been postulated that cytokines and other mediators released by
produced in a T cell–independent manner) has been linked to sensitized mast cells contribute to (i) the recruitment and activa-
timely elimination of filarial parasites. One of the most consistent tion of effector eosinophils; (ii) increased local concentrations
findings in helminth infections, both in mice and humans, is of antibody and complement; and (iii) enhanced mucus hyper-
the elevated level of IgE that is observed after exposure to hel- secretion and increased peristalsis of the gastrointestinal (GI)
minths. Most of the IgE produced is not antigen specific, perhaps tract that plays an important role in resistance to certain GI
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representing nonspecific potentiation of IgE-producing B cells nematode infections. More recently, a role for mast cells (in
or deregulation of a normally well-controlled immune response. an IgE-independent manner) in mediating the secretion of
Interestingly, these IgE antibodies persist many years after the epithelial-derived cytokines (IL-25, IL-33, and TSLP) and optimal
infection has been treated, indicating the presence of long-lived migration of DCs was shown in H. polygyrus bakeri infection.
memory B cells or plasma cells in helminth infections. IgE
production both in mice and humans is absolutely dependent Helminths and Neutrophils
on IL-4 or IL-13. Other isotypes that are commonly elevated in Although neutrophils are typically considered more important
humans with chronic helminth infection are IgG4 and IgG1, the in bacterial and fungal infections, a number of studies have
former being most dependent on both IL-4 and IL-10. Recent revealed that neutrophils can act in conjunction with macrophages
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studies have highlighted the role of regulatory B cells in sup- to contain or kill helminth parasites. Thus neutrophils are major
pression of immune responses to helminth parasites. This B-cell components of the granulomas forming around filarial parasites
function involves the secretion of IL-10 and IL-35 and is similar and the cysts containing larvae of intestinal helminths. Neutrophils
to the regulatory activity of B cells in autoimmune diseases. have been demonstrated to collaborate with macrophages in the
immobilization and killing of S. stercoralis larvae in a process
Helminths and Eosinophils that is complement dependent and involving neutrophil extracel-
Blood and tissue eosinophilia is characteristic of helminth infec- lular traps (NETs). Similarly, neutrophils contribute in the early
tion and is mediated by IL-5 (probably in concert with IL-3 and antifilarial response through oxidative burst, degranulation, and
GM-CSF). Recruitment of eosinophils to the site of infection NETosis and protect against infective larvae in skin. A seminal
occurs very early in experimental helminth infection—as early study reported that neutrophils adopt an “N2” phenotype during
as 24 hours after exposure. Kinetics of blood eosinophilia in experimental infection with N. brasiliensis in the lung and express
humans is harder to determine but is postulated to occur as the genes for IL-13, IL-33, RELM-α, and Ym1. These “N2”
early as 2–3 weeks after infection, as demonstrated in experimental neutrophils can train macrophages to acquire a memory phe-
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infections of volunteers. Both basal eosinophil levels and tissue notype that protects against secondary infection. Finally, it was
accumulation during helminth infection appear to be under the also shown that even during primary infection, the absence of