IL-4-regulated enteropathy in an intestinal nematode infection

Abstract

The relationship between intestinal pathology and immune expulsion of gastrointestinal nematodes remains controversial. Parasite expulsion is associated with intestinal pathology in several model systems and both of these phenomena are T cell dependent. Immune expulsion of gastrointestinal helminth parasites is usually associated with Th2 responses, but the effector mechanisms directly responsible for parasite loss have not been elucidated. In contrast, the intestinal pathology observed in many other disease models closely resembles that seen in helminth infections, but has been attributed to Th1 cytokines. We have used infection with the nematode Trichinella spiralis in mice defective for cytokines or their receptors to investigate cytokine regulation of both immunopathology and parasite rejection. Consistent with previous findings, we found that parasite expulsion is IL-4 dependent. Contrary to expectations, however, the enteropathy is not regulated by IFN-gamma but by IL-4. Moreover, abrogation of severe pathology in TNF receptor-defective animals does not prevent parasite expulsion. TNF is therefore involved in intestinal pathology in nematode infections, apparently under regulation by IL-4- and Th2-mediated responses. This work therefore not only reveals a novel interplay between IL-4 and TNF, but also that the IL-4-dependent protective response against the parasite operates by a mechanism other than merely the gross degradation of the parasite's environment brought about by the immune enteropathy.

Intraepithelial NK Cell-Derived IL-13 Induces Intestinal Pathology Associated with Nematode Infection

“…This is the first study that identifies IL-13 as the critical cytokine in the generation of the aberrant intestinal pathology characteristic of nematode infection. A previous study has shown that TNF-␣, under the control of IL-4, is important for villus atrophy and crypt hyperplasia during T. spiralis infection (33). Our study has found that the absence of IL-4 had no effect on tissue architecture or parasite resistance, but suggests that it may be required for optimal goblet cell hyperplasia in concert with IL-13.…”

The effect of the hookworm Ancylostoma ceylanicum on the mucosal architecture of the small intestine in hamsters

“…In contrast to the mouse-T. spiralis model, where enteropathy is rapidly ameliorated after the worms have been expelled in weeks 2 and 3 (Lawrence et al, 1998), here almost complete loss of villi was still evident on day 63 pi (fig. 6) when worms were present.…”

“…Much of this analytical work has used the mouse-Trichinella spiralis model and this has generated hypotheses based on immunologically driven mechanisms of enteropathy, both Th2-mediated (Garside et al, 1992;Lawrence et al, 1998) and, more recently, mediated via innate immunity (McDermott et al, 2005). The key parameters quantified in such studies have been villus height, crypt depth and mucosal cellular division as reflected by mitotic figures.…”

Eosinophils and Trichinella infection: toxic for the parasite and the host?

“…Studies using IL-4 or IL-4-receptor-α deficient mice revealed that IL-4 has a crucial role in worm expulsion [43,44]. However, it is not clear whether IL-5 and/or eosinophils can be implicated in the protective response of the host against the parasite.…”