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In this review, we examine the evidence that intestinal helminths can control harmful inflammatory responses and promote homeostasis by triggering systemic immune responses. Induction of separable components of immunity by helminths, which includes type 2 and immune regulatory responses, can both contribute toward the reduction in harmful type 1 immune responses that drive certain inflammatory diseases. Despite inducing type 2 responses, intestinal helminths may also downregulate harmful type 2 immune responses including allergic responses. We consider the possibility that intestinal helminth infection may indirectly affect inflammation by influencing the composition of the intestinal microbiome. Taken together, the studies reviewed herein suggest that intestinal helminth-induced responses have potent systemic effects on the immune system, raising the possibility that whole parasites or specific molecules produced by these metazoans may be an important resource for the development of future immunotherapies to control inflammatory diseases.

Helminth infection can prevent type 1 diabetes (T1D); however, the regulatory mechanisms inhibiting disease remain largely undefined. In these studies, nonobese diabetic (NOD) IL-4−/− mice were infected with the strictly enteric nematode parasite, Heligmosomoides polygyrus. Short-term infection, 5–7 weeks of age, inhibited T1D onset, as late as 40 weeks of age. CD4+ T-cell STAT6 phosphorylation was inhibited, while suppressed signal transducer and activator of transcription 1 phosphorylation was sustained, as were increases in FOXP3−, CD4+ T-cell interleukin (IL)-10 production. Blockade of IL-10 signaling in NOD-IL-4−/−, but not in NOD, mice during this short interval abrogated protective effects resulting in pancreatic β-cell destruction and ultimately T1D. Transfer of CD4+ T cells from H. polygyrus (Hp)-inoculated NOD IL-4−/− mice to NOD mice blocked the onset of T1D. These studies indicate that Hp infection induces non-T-regulatory cells to produce IL-10 independently of STAT6 signaling and that in this Th2-deficient environment IL-10 is essential for T1D inhibition.

MRL-lpr/lpr mice develop a generalized autoimmune disease which includes increased autoantibody production, glomerulonephritis, and development of lymphadenopathy. The lpr genetic defect has been identified as a mutation in the Fas apoptosis gene that results in low expression of Fas mRNA. To determine the significance of the lpr mutation and T cells in the development of the autoimmune disease, we constructed transgenic MRL-lpr/lpr mice using a full-length murine Fas cDNA under the regulation of the T-cell-specific CD2 promoter and enhancer. Here we show that the early correction of the lpr gene defect in T cells eliminates glomerulonephritis and development of lymphadenopathy and decreases the levels of autoantibodies. In this model, early correction of the lpr defect in T cells is sufficient to eliminate the acceleration of autoimmune disease even in the presence of B cells and other cells that express the mutant lpr gene.

Studies with rodents infected with Trichinella spiralis, Heligmosomoides polygyrus, Nippostrongylus brasiliensis, and Trichuris muris have provided considerable information about immune mechanisms that protect against parasitic gastrointestinal nematodes. Four generalizations can be made: 1. CD4C T cells are critical for host protection; 2. IL-12 and IFN- inhibit protective immunity; 3. IL-4 can: (a) be required for host protection, (b) limit severity of infection, or (c) induce redundant protective mechanisms; and 4. Some cytokines that are stereotypically produced in response to gastrointestinal nematode infections fail to enhance host protection against some of the parasites that elicit their production. Host protection is redundant at two levels: 1. IL-4 has multiple effects on the immune system and on gut physiology (discussed in this review), more than one of which may protect against a particular parasite; and 2. IL-4 is often only one of multiple stimuli that can induce protection. Hosts may have evolved the ability to recognize features that characterize parasitic gastrointestinal nematodes as a class as triggers for a stereotypic cytokine response, but not the ability to distinguish features of individual parasites as stimuli for more specific protective cytokine responses. As a result, hosts deploy a set of defense mechanisms against these parasites that together control infection by most members of that class, even though a specific defense mechanism may not be required to defend against a particular parasite and may even damage a host infected with that parasite.

Key Points Helminth parasites cause chronic disease in billions of people, however, the immune response associated with helmith infection can also reduce the severity of certain harmful inflammatory autoimmune and allergic diseases. Studies of tissue-dwelling parasites in murine models reveal the development of T helper 2 (T H 2)-type granulomas consisting of cellular infiltrates that resemble T H 1-type granulomas; however, the cells are activated differently and have distinct functions. The T H 2-type response can affect host protection by mediating helminth expulsion or by controlling otherwise pathological inflammatory responses that are driven by T H 1 and T H 17 cells. T H 2 cells are the primary source of T H 2-type cytokines but innate cells can also produce these cytokines. T H 2-type cytokines, including interleukin-4 (IL-4) and IL-13, orchestrate a potent T H 2-type response by direct stimulation of both bone-marrow-derived and non-bone-marrow-derived cell populations. A similarly complex and multi-faceted T H 2-type response is elicited following infection with a wide variety of helminths; however, only certain components of this broad response are effective against a particular species. The discovery of new effector cell types and molecules contributing to the host protective T H 2-type response provides additional targets for the development of novel therapies against helminths. Helminths infect millions of people worldwide. In this Review, William Gause and colleagues outline the current understanding of immune responses against helminth infections, focusing on results obtained in mouse models of infection with Heligmosomoides polygyrus and Schistosoma mansoni . Important insights have recently been gained in our understanding of how host immune responses mediate resistance to parasitic helminths and control associated pathological responses. Although similar cells and cytokines are evoked in response to infection by helminths as diverse as nematodes and schistosomes, the components of the response that mediate protection are dependent on the particular parasite. In this Review, we examine recent findings regarding the mechanisms of protection in helminth infections that have been elucidated in murine models and discuss the implications of these findings in terms of future therapies.

This study was conducted to evaluate the immunological response to an exhaustive treadmill exercise test in 20 female chronic fatigue syndrome patients compared to 14 matched sedentary controls. Venipuncture was performed at baseline and 4 min, 1 hr, and 24 hr postexercise. White blood cells were labeled for monoclonal antibody combinations and were quantified by FACsan. Cytokines were assayed utilizing quantitative RT/PCR. No group difference was seen in VO2peak (28.6 +/- 1.6 vs 30.9 +/- 1.2 ml.kg-1.min-1; P > 0.05). However, 24 hr after exercise the patients' fatigue levels were significantly increased (P < 0.05). The counts of WBC, CD3+ CD8+ cells, CD3+ CD4+ cells, T cells, B cells, natural killer cells, and IFN-gamma changed across time (P's < 0.01). No group differences were seen for any of the immune variables at baseline or after exercise (P's > 0.05). The immune response of chronic fatigue syndrome patients to exhaustive exercise is not significantly different from that of healthy nonphysically active controls.

Multiple pathways may be involved in the development of interleukin 4 (IL-4) producing T helper (Th) cells and the associated type 2 immune response. Increasing evidence suggests that the strength of signals delivered to the T cell may favor the development of the type 2 response. In contrast, antigen-presenting cell- (APC) derived stimuli produced following pattern recognition receptor binding during the innate response promotes the development of interferon-gamma (IFN-gamma) producing cells and the associated type 1 immune response. In many cases, the balance between increased signaling strength and the innate response may determine whether the type 2 response develops. T cell receptor (TCR), CD4, and costimulatory molecule interactions may all contribute to signal strength, but the type 2 immune response may be particularly dependent on the availability of coreceptor and costimulatory molecule interactions. B7 ligand interactions are required for the development of the type 2 immune response and interaction of CD28 with either B7-1 or B7-2 can provide sufficient signals for its initiation. In B7-2-deficient mice, the initial type 2 immune response is intact, but the response is not sustained, suggesting that B7-2 is important at later stages of the type 2 immune response. The roles of CD28 and CTLA-4 during the type 2 response remain unclear. The type 2 response to infectious pathogens is pronounced in CD28-/- mice, suggesting that other costimulatory molecule interactions can substitute for CD28 for the development of IL-4 producing T cells and the associated type 2 immune response.

Multiple pathways may be involved in the development of interleukin 4 (IL-4) producing T helper (Th) cells and the associated type 2 immune response. Increasing evidence suggests that the strength of signals delivered to the T cell may favor the development of the type 2 response. In contrast, antigen-presenting cell-(APC) derived stimuli produced following pattern recognition receptor binding during the innate response promotes the development of interferon- gamma (IFN- gamma ) producing cells and the associated type 1 immune response. In many cases, the balance between increased signaling strength and the innate response may determine whether the type 2 response develops. T cell receptor (TCR), CD4, and costimulatory molecule interactions may all contribute to signal strength, but the type 2 immune response may be particularly dependent on the availability of coreceptor and costimulatory molecule interactions. B7 ligand interactions are required for the development of the type 2 immune response and interaction of CD28 with either B7-1 or B7-2 can provide sufficient signals for its initiation. In B7-2-deficient mice, the initial type 2 immune response is intact, but the response is not sustained, suggesting that B7-2 is important at later stages of the type 2 immune response. The roles of CD28 and CTLA-4 during the type 2 response remain unclear. The type 2 response to infectious pathogens is pronounced in CD28 super(-/-) mice, suggesting that other costimulatory molecule interactions can substitute for CD28 for the development of IL-4 producing T cells and the associated type 2 immune response.