Heligmosomoides polygyrus bakeri induces tolerogenic dendritic cells that block colitis and prevent antigen-specific gut T cell responses.

Immunological diseases such as inflammatory bowel disease (IBD) are infrequent in less developed countries, possibly because helminths provide protection by modulating host immunity. In IBD murine models, the helminth Heligmosomoides polygyrus bakeri prevents colitis. It was determined whether H. polygyrus bakeri mediated IBD protection by altering dendritic cell (DC) function. We used a Rag IBD model where animals were reconstituted with IL10⁻/⁻ T cells, making them susceptible to IBD and with OVA Ag-responsive OT2 T cells, allowing study of a gut antigenic response. Intestinal DC from H. polygyrus bakeri-infected Rag mice added to lamina propria mononuclear cells (LPMC) isolated from colitic animals blocked OVA IFN-γ/IL-17 responses in vitro through direct contact with the inflammatory LPMC. DC from uninfected Rag mice displayed no regulatory activity. Transfer of DC from H. polygyrus bakeri-infected mice into Rag mice reconstituted with IL10⁻/⁻ T cells protected animals from IBD, and LPMC from these mice lost OVA responsiveness. After DC transfer, OT2 T cells populated the intestines normally. However, the OT2 T cells were rendered Ag nonresponsive through regulatory action of LPMC non-T cells. The process of regulation appeared to be regulatory T cell independent. Thus, H. polygyrus bakeri modulates intestinal DC function, rendering them tolerogenic. This appears to be an important mechanism through which H. polygyrus bakeri suppresses colitis. IFN-γ and IL-17 are colitogenic. The capacity of these DC to block a gut Ag-specific IFN-γ/IL-17 T cell response also is significant.

Heligmosomoides polygyrus abrogates antigen-specific gut injury in a murine model of inflammatory bowel disease.

BACKGROUND: Developing countries have a low incidence of inflammatory bowel disease (IBD), perhaps prevented by the high prevalence of helminth infections and other alterations in intestinal flora and fauna. Helminth infections prevent colitis in various murine models of IBD. IBD may be driven by an aberrant immune response to luminal antigen(s). METHODS: We developed a murine model of IBD in which gut injury was induced by a specific antigen to better simulate the IBD disease process and to determine if helminth infections could abolish gut injury induced by an orally administered antigen. The model features pan-enterocolitis triggered by feeding ovalbumin (OVA). RESULTS: The intestinal inflammation is antigen-specific and generates interleukin (IL)-17 and interferon-gamma (IFN-γ), but not IL-4. Full expression of the disease required T cells with defective capacity to make IL-10 and treatment with a noninjurious, low dose of a nonsteroidal antiinflammatory drug. Exposure to Heligmosomoides polygyrus abrogated this antigen-induced gut injury. H. polygyrus colonization induced Foxp3(+) T regulatory cells (Tregs) and mucosal production of IL-10 from non-T cells. Lamina propria mononuclear cells from H. polygyrus-infected mice released less IL-17 and IFN-γ constitutively and when stimulated with OVA or anti-CD3/CD28 monoclonal antibodies. CONCLUSIONS: We developed a murine IBD model featuring antigen-specific enterocolitis and demonstrate for the first time that gut inflammation induced by an antigen could be abrogated by H. polygyrus infection. Protection was associated with suppressed IL-17 and IFN-γ production, induction of Foxp3(+) Tregs, and elevated secretion of non-T-cell-derived IL-10, all of which could be part of the protective processes.

MyD88-dependent pathways mediate resistance to Cryptosporidium parvum infection in mice.

Cryptosporidium spp. cause diarrheal disease worldwide. Innate immune responses mediating resistance to this parasite are not completely understood. To determine whether MyD88-dependent pathways play a role in resistance to Cryptosporidium parvum, we compared the course of infection in MyD88(-/-) mice to that in their wild-type (WT) littermate controls. Three- to 4-week-old mice were infected with C. parvum, and infection was monitored by quantifying fecal oocyst shedding. Twelve days postinfection, the histology of the intestines was examined to quantify intestinal parasite burden and to determine if there were any pathological changes. Fecal oocyst shedding and intestinal parasite burden were significantly greater in MyD88(-/-) mice than in littermate controls. Nonetheless, both WT and MyD88(-/-) mice cleared the infection within 3 weeks. These results indicate that MyD88-dependent pathways are involved in mediating initial resistance to C. parvum. Since gamma interferon (IFN-gamma) is known to mediate resistance to C. parvum, we also studied infection in MyD88(-/-) mice and WT controls in which this cytokine was temporarily neutralized. Fecal oocyst shedding, as well as intestinal parasite burden, intestinal inflammation, and mortality, was significantly greater in MyD88(-/-) mice in which IFN-gamma was neutralized than in IFN-gamma-neutralized WT mice or in MyD88(-/-) mice in which this cytokine was active. These results suggest that MyD88 and IFN-gamma had an additive effect in conferring protection from C. parvum infection. While this study confirms the importance of IFN-gamma in conferring resistance to infection with C. parvum, it suggests that MyD88-mediated pathways also play a role in innate immunity to this parasite.

The role of arachidonic acid regulatory enzymes in colorectal disease.

PURPOSE: Nonsteroidal anti-inflammatory drugs have a wide ranging effect on diseases of the colon and rectum. Interestingly, nonsteroidal anti-inflammatory drugs seem to play a beneficial role in colorectal cancer chemoprevention and adenoma regression, but may have a deleterious effect in inflammatory bowel disease. Prostaglandin inhibition is central to both the beneficial and toxic effects of this class of drugs. Arachidonic acid metabolism is essential to prostaglandin synthesis. METHODS: A Medline search using "nonsteroidal anti-inflammatory drugs," "colon cancer," "inflammatory bowel disease," "colitis," "COX inhibitors," "arachidonic acid," and "chemoprevention" as key words was performed for English-language articles. Further references were obtained through cross-referencing the bibliography cited in each work. RESULTS: Based on numerous studies, nonsteroidal anti-inflammatory drugs have a beneficial role in colon cancer and colonic adenomas. However, they have been reported to have a deleterious effect on the colon in inflammatory bowel disease and have been shown to cause colitis. Nonsteroidal anti-inflammatory drugs work via multiple pathways, some well defined, and others unknown. CONCLUSIONS: In the new millennium, nonsteroidal anti-inflammatory drugs may be used for chemoprevention of colorectal and other cancers. In addition, they may be used in combination with surgery and chemotherapy to primarily treat colorectal carcinoma. Undoubtedly, the use of novel cyclooxygenase inhibitors with less of a toxicity profile will allow more widespread use of nonsteroidal anti-inflammatory drugs for a variety of diseases. The future of this class of drugs is promising.

Human pentastomiasis discovered postmortem.

The autopsy of an 18-year-old girl who had died suddenly at home revealed generalised pentastomiasis. The location of this disease in the intestines was responsible for death by hemorrhagic enterocolitis. This discovery constituted an atypical case in our daily practice of forensic medicine.

[Clinical and laboratory characteristics of cryptosporidiosis in Turkmenistan]. / Kliniko-laboratornye osobennosti kriptosporidioza v Turkmenistane.

AIM: The study of clinical symptoms of gastrointestinal lesions in subjects invaded with cryptosporidia. MATERIALS AND METHODS: From 1994 to 1997 383 patients with monocryptosporidiasis were observed. 75.7% of them were children. Cryptosporidia oocysts were identified in fecalia using Fulleborn technique. The specimens were stained according to Cill-Nilsson. RESULTS: Clinically, the invasion was characterized by acute onset, severe course in children, involvement of the whole gastrointestinal and respiratory tracts. CONCLUSION: Monocryptosporidiasis runs in Turkmenistan a more severe course compared to countries with moderately hot climate.

Strongyloides stercoralis eosinophilic granulomatous enterocolitis.

Six patients suffering from an unusual form of colitis produced by Strongyloides stercoralis hyperinfection are described. In contrast to the usual Strongyloides hyperinfection syndrome, in which small intestinal and pulmonary manifestations are seen in patients with some forms of immunodeficiency, the patients described here presented with only a characteristic transmural eosinophilic granulomatous inflammation affecting mostly the colonic wall and clinically mimicking ulcerative colitis or Crohn's disease. This Strongyloides eosinophilic granulomatous enterocolitis apparently results from a florid inflammatory response by eosinophils, histiocytes, and giant cells with formation of granulomas that destroy the larvae entering the colon. This morphologic picture differs from that of the well-described hyperinfection syndrome, in which the bulk of the larvae pass through the colonic wall to complete the life cycle, with only a few larvae destroyed in the colon. The probable pathophysiologic mechanism of this unusual manifestation of hyperinfection is discussed based on the anatomic and clinical observations of patients who presented at different stages in the evolution of their condition and whose length of follow-up varied.

Eosinophilic colitis associated with larvae of the pinworm Enterobius vermicularis.

Various helmintic parasites, most of which are uncommon in economically developed countries, can cause abdominal pain and eosinophilic inflammation of the bowel. A homosexual man presented with severe abdominal pain and haemorrhagic colitis, eosinophilic inflammation of the ileum and colon, and numerous unidentifiable larval nematodes in diarrhoeal stool. His symptoms resolved with anthelmintic treatment alone. Using comparative morphology and molecular cloning of nematode ribosomal RNA genes, we identified the parasites as larvae of the pinworm Enterobius vermicularis, which are rarely observed or associated with disease. Occult enterobiasis is widely prevalent and may be a cause of unexplained eosinophilic enterocolitis.

Angiostrongyliasis in a European patient: a rare cause of gangrenous ischemic enterocolitis.

Angiostrongylus costaricensis causes a clinicopathologic disease first observed in Costa Rica, mainly in children characterized by highly symptomatic eosinophilic gastroenteritis involving the terminal ileum, cecum, appendix, and ascending colon. A case of angiostrongyliasis in an adult Spaniard infected during a brief stay in Nicaragua is reported. We examined the macro-microscopic features of a right ileocolic resection of a 52-year-old patient. In the surgical specimen, multiple confluent ulcers, some perforated, were observed particularly in the terminal ileum. The intestinal wall was thickened, and the arterial branches presented necrotizing arteritis with thrombosis and a heavy infiltrate of eosinophils around the vessels. In addition, some granulomas were observed. Adult male and female forms of A. costaricensis were found in the lumen of many arterial branches and in the tissue of the omentum, surrounded by dense eosinophilic infiltrate. A. costaricensis causes an intense eosinophilic, necrotizing arteritis associated with thrombosis leading to severe ischemic lesions. This is the first case to be diagnosed in Europe. Incubation time was able to be established within a period of at least 14 days.