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Review
. 2017 Apr:30:12-27.
doi: 10.1016/j.smim.2017.07.007. Epub 2017 Aug 12.

Murine models for mucosal tolerance in allergy

Ursula Smole  1 , Irma Schabussova  2 , Winfried F Pickl  3 , Ursula Wiedermann  4
Affiliations
Review

Murine models for mucosal tolerance in allergy

Ursula Smole et al. Semin Immunol. 2017 Apr.

Abstract

Immunity is established by a fine balance to discriminate between self and non-self. In addition, mucosal surfaces have the unique ability to establish and maintain a state of tolerance also against non-self constituents such as those represented by the large numbers of commensals populating mucosal surfaces and food-derived or air-borne antigens. Recent years have seen a dramatic expansion in our understanding of the basic mechanisms and the involved cellular and molecular players orchestrating mucosal tolerance. As a direct outgrowth, promising prophylactic and therapeutic models for mucosal tolerance induction against usually innocuous antigens (derived from food and aeroallergen sources) have been developed. A major theme in the past years was the introduction of improved formulations and novel adjuvants into such allergy vaccines. This review article describes basic mechanisms of mucosal tolerance induction and contrasts the peculiarities but also the interdependence of the gut and respiratory tract associated lymphoid tissues in that context. Particular emphasis is put on delineating the current prophylactic and therapeutic strategies to study and improve mucosal tolerance induction in allergy.

Keywords: Allergy; Animal models; BALT; Commensals; GALT; Mucosal tolerance; NALT; Regulatory T cells.

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Figures

Fig. 1
Fig. 1. Maintenance of immune tolerance in the airways (upper panel) and the gut (lower panel).
Under homeostatic conditions, tolerogenic immune responses are created by factors released from airway and gut epithelial cells (cytokines, chemokines, vitamin metabolites, etc) upon triggering of pattern recognition receptors (PRR) by environmental antigens, food and commensals. Shown are the critical mediators that contribute to the priming and differentiation of antigen presenting cells and lymphocytes. Apart from epithelial-derived mediators, these also include metabolites directly derived from commensals (e.g., SCFAs). Moreover, pathways of transepithelial antigen transfer, which include uptake by CD103+ DC, macrophages and M cells but also diffusion through tight junctions and transcellular routes, are depicted. Upon CCR7-dependent migration to draining lymph nodes, CD103+ DC instruct naïve CD4+ T cells to differentiate into Treg, which is dependent on a TGF-β and RA rich milieu created by both DC and LN resident stromal cells. In the periphery, Tregs get further expanded under the influence of IL-10, IDO and RA, and exert their regulatory function (Teff suppression and apoptosis). In addition, gut-derived antigens might also reach the liver, where they become presented (liver DCs, Kupffer cells) and lead to Treg priming. A fraction of gut-resident antigens is directly bound (neutralized) by secretory IgA elaborated by the large number of gut-resident B cells, many of them organized in Peyer’s patches found in the small intestine. Similarly organized structures can be found in the upper and lower airways (iNALT and iBALT). Once induced, those can be recognized as highly organized structures consisting of B cell- and T cell-rich zones, interspersed with follicular (FDC) and conventional DCs and typically associated with HEV. The airways are protected by sIgA and in addition the lower airways are patrolled by alveolar macrophages (AMϕ). FDC, follicular dendritic cells; HEV, high endothelial venules; iBALT, induced bronchial associated lymphoid tissue; IDO, indoleamine 2,3-dioxygenase; iNALT, induced nasal associated lymphoid tissue; PRR, pattern recognition receptor; RA, retinoic acid; SCFA, short chain fatty acid; sIgA, secretory IgA; Teff, T effector cells; Treg, T regulatory cells.
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