Regulatory Immune Mechanisms in Tolerance to Food Allergy

Tolerance to food antigen manifests in the absence and/or suppression of antigen-specific immune responses locally in the gut but also systemically, a phenomenon known as oral tolerance. Oral tolerance is thought to originate in the gut-draining lymph nodes, which support the generation of FoxP3(+) regulatory T (Treg) cells. Here we use several mouse models to show that Treg cells, after their generation in lymph nodes, need to home to the gut to undergo local expansion to install oral tolerance. Proliferation of Treg cells in the intestine and production of interleukin-10 by gut-resident macrophages was blunted in mice deficient in the chemokine (C-X3-C motif) receptor 1 (CX3CR1). We propose a model of stepwise oral tolerance induction comprising the generation of Treg cells in the gut-draining lymph nodes, followed by migration into the gut and subsequent expansion of Treg cells driven by intestinal macrophages. Copyright © 2011 Elsevier Inc. All rights reserved.

Chemokine receptor CX3CR1+ dendritic cells (DCs) have been suggested to sample intestinal antigens by extending transepithelial dendrites into the gut lumen. Other studies identified CD103+ DCs in the mucosa, which, through their ability to synthesize retinoic acid (RA), appear to be capable of generating typical signatures of intestinal adaptive immune responses. We report that CD103 and CX3CR1 phenotypically and functionally characterize distinct subsets of lamina propria cells. In contrast to CD103+ DC, CX3CR1+ cells represent a nonmigratory gut-resident population with slow turnover rates and poor responses to FLT-3L and granulocyte/macrophage colony-stimulating factor. Direct visualization of cells in lymph vessels and flow cytometry of mouse intestinal lymph revealed that CD103+ DCs, but not CX3CR1-expressing cells, migrate into the gut draining mesenteric lymph nodes (LNs) under steady-state and inflammatory conditions. Moreover, CX3CR1+ cells displayed poor T cell stimulatory capacity in vitro and in vivo after direct injection of cells into intestinal lymphatics and appeared to be less efficient at generating RA compared with CD103+ DC. These findings indicate that selectively CD103+ DCs serve classical DC functions and initiate adaptive immune responses in local LNs, whereas CX3CR1+ populations might modulate immune responses directly in the mucosa and serve as first line barrier against invading enteropathogens.

Food allergy (FA) is an important atopic disease although its precise burden is unclear. This systematic review aimed to provide recent, up-to-date data on the incidence, prevalence, time trends, and risk and prognostic factors for FA in Europe. We searched four electronic databases, covering studies published from 1 January 2000 to 30 September 2012. Two independent reviewers appraised the studies and qualified the risk of bias using the Critical Appraisal Skills Programme tool. Seventy-five eligible articles (comprising 56 primary studies) were included in a narrative synthesis, and 30 studies in a random-effects meta-analysis. Most of the studies were graded as at moderate risk of bias. The pooled lifetime and point prevalence of self-reported FA were 17.3% (95% CI: 17.0-17.6) and 5.9% (95% CI: 5.7-6.1), respectively. The point prevalence of sensitization to ≥1 food as assessed by specific IgE was 10.1% (95% CI: 9.4-10.8) and skin prick test 2.7% (95% CI: 2.4-3.0), food challenge positivity 0.9% (95% CI: 0.8-1.1). While the incidence of FA appeared stable over time, there was some evidence that the prevalence may be increasing. There were no consistent risk or prognostic factors for the development or resolution of FA identified, but sex, age, country of residence, familial atopic history, and the presence of other allergic diseases seem to be important. Food allergy is a significant clinical problem in Europe. The evidence base in this area would benefit from additional studies using standardized, rigorous methodology; data are particularly required from Eastern and Southern Europe. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.