Cathryn Nagler-Anderson

Concurrent enteric helminth infection modulates inflammation and gastric immune responses and reduces helicobacter-induced gastric atrophy.

Helicobacter pylori is causally associated with gastritis and gastric cancer. Some developing countries with a high prevalence of infection have high gastric cancer rates, whereas in others, these rates are low. The progression of helicobacter-induced gastritis and gastric atrophy mediated by type 1 T-helper cells may be modulated by concurrent parasitic infection. Here, in mice with concurrent helminth infection, helicobacter-associated gastric atrophy was reduced considerably despite chronic inflammation and high helicobacter colonization. This correlated with a substantial reduction in mRNA for cytokines and chemokines associated with a gastric inflammatory response of type 1 T-helper cells. Thus, concurrent enteric helminth infection can attenuate gastric atrophy, a premalignant lesion.

Man the barrier! strategic defences in the intestinal mucosa

Immunologists typically study the immune responses induced in the spleen or peripheral lymph nodes after parenteral immunization with antigen and poorly defined experimental adjuvants. However, most antigens enter the body through mucosal surfaces. It is now clear that the microenvironment in these mucosal barriers has a marked influence on the immune response that ultimately ensues. Nowhere is the microenvironment more influential than in the gut-associated lymphoid tissue (GALT). The GALT must constantly distinguish harmless antigens that are present in food or on commensal bacteria from pathogenic assault by microbes. It is perhaps not surprising, then, that the GALT contains more lymphocytes than all of the secondary lymphoid organs combined.

Toll-Like Receptor 4 Signaling by Intestinal Microbes Influences Susceptibility to Food Allergy

The mechanisms by which signaling by the innate immune system controls susceptibility to allergy are poorly understood. In this report, we show that intragastric administration of a food allergen with a mucosal adjuvant induces allergen-specific IgE, elevated plasma histamine levels, and anaphylactic symptoms in three different strains of mice lacking a functional receptor for bacterial LPS (Toll-like receptor 4 (TLR4)), but not in MHC-matched or congenic controls. Susceptibility to allergy correlates with a Th2-biased cytokine response in both the mucosal (mesenteric lymph node and Peyer’s patch) and systemic (spleen) tissues of TLR4-mutant or -deficient mice. TLR4-mutant mice are not inherently impaired in their ability to regulate Th1 cytokine production because they respond to stimulation via TLR9. Coadministration of CpG oligodeoxynucleotides during sensitization of TLR4-mutant mice with allergen plus CT abrogates anaphylactic symptoms and Ag-specific IgE, and results in a Th1-polarized cytokine response. When the composition of the bacterial flora is reduced and altered by antibiotic administration (beginning at 2 wk of age), TLR4 wild-type mice become as susceptible to the induction of allergy as their TLR4-mutant counterparts. Both allergen-specific IgE and Th2 cytokine responses are reduced in antibiotic-treated mice in which the flora has been allowed to repopulate. Taken together, our results suggest that TLR4-dependent signals provided by the intestinal commensal flora inhibit the development of allergic responses to food Ags.

An Enteric Helminth Infection Protects Against an Allergic Response to Dietary Antigen

Although helminths induce a polarized Th2 response they have been shown, in clinical studies, to confer protection against allergies. To elucidate the basis for this paradox, we have examined the influence of an enteric helminth infection on a model of food allergy. Upon Ag challenge, mice fed peanut (PN) extract plus the mucosal adjuvant cholera toxin (CT) produced PN-specific IgE that correlated with systemic anaphylactic symptoms and elevated plasma histamine. PN-specific IgE was not induced in helminth-infected mice fed PN without CT. Moreover, when PN plus CT was fed to helminth-infected mice, both PN-specific IgE and anaphylactic symptoms were greatly diminished. The down-regulation of PN-specific IgE was associated with a marked reduction in the secretion of IL-13 by PN-specific T cells. When helminth-infected PN plus CT-sensitized mice were treated with neutralizing Abs to IL-10, the PN-specific IgE response and anaphylactic symptoms were similar to, or greater than, those seen in mice that receive PN and CT alone. Taken together, these results suggest that helminth-dependent protection against allergic disease involves immunoregulatory mechanisms that block production of allergen-specific IgE.

Mucosal immunity and allergic responses: lack of regulation and/or lack of microbial stimulation?

Summary:  Allergic hyperreactivity is defined as an exaggerated immune response [typically immunoglobulin E (IgE) but also non‐IgE mediated] toward harmless antigenic stimuli. The prevalence of allergic disease has increased dramatically during the last 20 years, especially in developed countries. Both genetic and environmental factors contribute to susceptibility to allergy. Evidence has emerged supporting the hypothesis that a reduction in antigenic stimulation brought about by widespread vaccination, improvements in standards of hygiene, and extensive use of antibiotics has contributed to the dysregulation of T‐helper 2 cell (Th2) type responsiveness that typifies allergy. Regulation of the inherently Th2‐biased mucosal immune response is crucial both to the maintenance of homeostasis at this strategic defensive barrier and to the prevention of allergic disease. The ability of Th1 responses to counter‐regulate Th2 reactivity is well characterized. More recently, interest has centered on regulatory T cells, which can suppress both Th1 and Th2 cells through the secretion of immunosuppressive cytokines such as interleukin‐10 and transforming growth factor‐β. In this review, we discuss the basic cellular mechanisms of allergic diseases at mucosal surfaces, focusing on allergic responses to food, before examining newer work that suggests the induction of allergic hyperreactivity is due to a deficient immunoregulatory network, a lack of microbial stimulation, or both.

Control freaks: immune regulatory cells

The “Immune Regulatory Networks” meeting in Boston gathered scientists with a passion for regulatory T cells to discuss the latest information on an increasingly important subject.

Preventing Intolerance: The Induction of Nonresponsiveness to Dietary and Microbial Antigens in the Intestinal Mucosa

The gut-associated lymphoid tissue (GALT) is constantly exposed to a variety of Ags and must therefore decipher a large number of distinct signals at all times. Responding correctly to each set of signals is crucial. When the GALT receives signals from the intestinal flora or food Ags, it must induce a state of nonresponsiveness (mucosal tolerance). In contrast, when pathogenic bacteria invade the intestinal mucosa, it is necessary to elicit strong T and B cell responses. The GALT is therefore in the position of constantly fighting intolerance to food and the commensal flora while effectively battling infectious microbes. Determining precisely which type of response to generate in each case is key to the prevention of immune dysregulation and tissue damage.

Mucosal antigen presentation and the control of tolerance and immunity

The authors were the program organizers for the meeting, which was sponsored by the Center for the Study of Inflammatory Bowel Disease at Massachusetts General Hospital, Boston, MA, USA. Additional support was provided through unrestricted educational grants from Amgen Inc., Biogen Inc., Celgene Corp. and Immunex Corp.

Enteric Infection Acts as an Adjuvant for the Response to a Model Food Antigen

Oral administration of soluble protein Ags typically induces Ag-specific systemic nonresponsiveness. However, we have found that feeding a model food protein, OVA, to helminth-infected mice primes for a systemic OVA-specific Th2 response. In this report we show that, in addition to creating a Th2-priming cytokine environment, helminth infection up-regulates costimulatory molecule expression on mucosal, but not peripheral, APCs. To examine the consequences of mucosal infection for the T cell response to orally administered Ag, we adoptively transferred transgenic, OVA-specific, T cells into normal mice. We found that helminth infection enhances the expansion and survival of transgenic T cells induced by Ag feeding. Transfer of 5,6-carboxyfluorescein diacetate succinimidyl ester-labeled donor cells showed that T cell proliferation in response to Ag feeding takes place primarily in the mesenteric lymph nodes. Upon subsequent peripheral exposure to Ag in adjuvant, the proliferative capacity of the transferred transgenic T cells was reduced in noninfected mice that had been fed OVA. Helminth infection abrogated this reduction in proliferative capacity. Our data suggests that enteric infection can act as an adjuvant for the response to dietary Ags and has implications for allergic responses to food and the efficacy of oral vaccination.

Strain-specific TCR repertoire selection of IL-4-producing Thy-1dull γ δ thymocytes

Thy‐1dull γ δ thymocytes constitute an unusual subset of mature TCRγ δ cells which share with NK T cells the expression of cell surface markers usually associated with activated or memory cells and the simultaneous production of high levels of IL‐4 and IFN‐γ upon activation. In DBA / 2 mice, Thy‐1dull γ δ thymocytes express a restricted repertoire of TCR that are composed of the Vγ1 gene product mainly associated with Vδ6.4 chains exhibiting very limited junctional sequence diversity. In this study we have characterized this γ δ T cell population in different strains of mice and show that Thy‐1dull γ δ thymocytes are present in every strain tested, albeit at different frequencies. Moreover IL‐4 production by γ δ thymocytes is mainly confined to the Thy‐1dull γ δ population in every strain tested. Finally, the repertoire of TCR expressed by Thy‐1dull γ δ thymocytes varies in different strain of mice, although a biased expression of Vγ1 and Vδ6 chains was observed in all strains studied. However, the extent of junctional diversity of the Vγ1 and Vδ6 chains expressed by Thy‐1dull γ δ thymocytes varied from oligoclonal in DBA / 2 mice to polyclonal in FVB / N mice. Thy‐1dull γ δ thymocytes from mouse strains such as C3H / HeJ and BALB / c contain cells with diverse Vδ6(D)Jδ junctions together with cells with relatively homogeneous Vδ6(D)Jδ junctions, similar to those found in DBA / 2. Thus, the Thy‐1dull γ δ population appears to contain two subsets of cells which differ in the diversity of their TCR.