Page 454 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPTEr 30 Host Defenses to Protozoa 433

Fig. 30.3). The factors responsible for the structural changes in Cryptosporidium parvum AND
the small bowel are not well defined but may include injury Cryptosporidium hominis
from adherence, parasite-induced apoptosis of epithelial cells,
and the release of cytotoxins, including proteases. Additional In humans, there are four intestinal coccidians that are intracel-
epithelial damage may be mediated by the host cellular immune lular parasites of enterocytes: Isospora belli, Cyclospora cayetanensis,
response. Diarrhea arises from epithelial barrier dysfunction, and two species of Cryptosporidium, C. parvum, and C. hominis.
reduction in microvillous surface area, chloride hypersecretion, Of the four coccidians, Cryptosporidium has the greatest epide-
and glucose and sodium malabsorption. 31 miological significance: in 1993, a huge outbreak involving 403
000 persons occurred in Milwaukee, Wisconsin, in the United
Innate Immunity States. Because of their similarity, only the immunology of
As G. lamblia does not invade the intestinal epithelium, host cryptosporidiosis will be discussed.
defense and immune factors present within the lumen are essential
for preventing and controlling infection. Increased intestinal Pathogenesis
motility contributes to G. lamblia clearance, by impairing the Cryptosporidium typically causes self-limited (but often prolonged)
ability of the parasite to attach to the epithelium and resist the diarrhea in the immunocompetent host. However, in the
luminal bulk flow. Antimicrobial peptides derived from Paneth immunocompromised host Cryptosporidium can cause severe
cells, including cryptdins, neutrophil defensin, and cathelicidin, diarrhea, with malabsorption and wasting, and cholangiopathy.
effectively kill G. lamblia trophozoites in vitro. Infection begins with the ingestion of food or water contaminated
NO, produced by both epithelial cells and macrophages, with oocysts. The acidic environment of the stomach induces
inhibits excystation trophozoite division. Despite the protective excystation and the release of four sporozoites into the small
effect of NO, the parasite can circumvent this defense by compet- intestines. Glycoproteins on the surface of sporozoites facilitate
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ing with host cells for arginine uptake. Mast cells have a sig- attachment and invasion of epithelial cells. After entry into
nificant role in protecting against the parasite. Mice deficient in epithelial cells, the parasite resides within a unique intracellular
mast cells fail to clear G. lamblia infection, in part because they but extracytoplasmic vacuole, that protects the pathogen from
are unable to mount parasite-specific IgA. Mast cells also con- environmental and host insults. Inside a vacuole the sporozoites
tribute to B-cell survival, activation and differentiation into develop into trophozoites and undergo schizogony, with a resultant
plasma cells, and together with NO induce peristalsis. merozoite-containing schizont. The merozoites are extruded and
invade neighboring epithelial cells. The merozoites may continue
Adaptive Immunity an asexual cycle or develop into macro- or microgametes that
Several lines of evidence suggest the importance of the humoral fuse to form oocysts. Before being excreted in feces, oocysts
immune response in the control of giardiasis. Infection with undergo sporulation to become infectious. Histologically, infection
Giardia results in the production of anti-Giardia antibodies causes villous atrophy and blunting, and crypt hyperplasia with
in the serum and mucosal secretions. Patients with severe increased infiltration of lymphocytes, macrophages, and plasma
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B-cell defects or selective IgA deficiency have an increased risk cells. Intraepithelial lymphocytes are uncommon; neutrophils
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of developing chronic infections. Studies in mice have dem- and occasional eosinophils are present between the epithelium
onstrated key functions of secretory IgA and the polymeric and the lamina propria. Disorganized cells undergoing necrosis
immunoglobulin receptor, which is responsible for IgA transport replace normal enterocyte architecture (see Fig. 30.3). There is
into the intestinal lumen in controlling parasite burden and an association between the degree of intestinal injury and
eliminating infection. 30 malabsorption and the intensity of infection, as measured by
There is also evidence for a role of T cell–dependent immunity oocyst excretion.
in the control of giardiasis. A reduction or absence of CD4 T The neuropeptide substance P, which is produced by endo-
cells can lead to chronic infection. IFN-γ- and IL-17A-producing thelial cells, lymphocytes, and monocytes in the lamina propria,
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CD4 T cells develop following infection and are important for contributes to diarrhea by increasing intestinal chloride secretion
mediating parasite clearance. Although the mechanisms are still and glucose malabsorption. Increased expression of substance
being defined, IL-17A is likely involved in modulating transport P is observed in patients with AIDS as well as cryptosporidiosis
of IgA into the intestinal lumen. Epidemiological studies indicate and severe diarrhea. 34
that partial immunity is acquired from Giardia infection, which
leads to reduced risk and severity of subsequent infections. 30 Innate Immunity
The type I and type II IFNs play a key role in the innate
Evasion of Host Immunity protective response against cryptosporidium. Because of
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Giardia evades the host humoral immune response by undergoing the parasite’s intracellular location near the luminal surface
surface antigenic variation by altering a group of variant-specific of the enterocyte, the macrophages of the lamina propria are
surface proteins (VSPs). Selection occurs by an immune-mediated spatially isolated from the parasite. Thus the intestinal epithe-
process because switching occurs when intestinal anti-VSP IgA lium mounts its own assault on the invading microbe through
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responses are first detected. G. lamblia also produces a protease TLR2/TLR4–dependent activation of NF-κB and release of the
that cleaves IgA. Although Giardia activates dendritic cells for microbicidal peptide β-defensin-2, TNF-α, and the chemokines
antigen presentation, it also inhibits IL-12 production, in part IL-8, RANTES, and GRO-α, which act as chemoattractants and
by enhancing IL-10 release; the net result is the dampening of activators of neutrophils. In patients with AIDS and crypto-
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a local antiparasitical inflammatory response. The trophozoite sporidiosis, the HIV Tat protein may sabotage host defense
also releases arginine deiminase, which degrades arginine, making against Cryptosporidium by inhibiting cholangiocyte TLR4
it less available for host NO production. 31 expression. 33