Mechanisms of immune tolerance relevant to food allergy
2011; Elsevier BV; Volume: 127; Issue: 3 Linguagem: Inglês
10.1016/j.jaci.2010.12.1116
ISSN1097-6825
AutoresBrian P. Vickery, Amy M. Scurlock, Stacie M. Jones, A. Wesley Burks,
Tópico(s)IL-33, ST2, and ILC Pathways
ResumoThe intestine has an unenviable task: to identify and respond to a constant barrage of environmental stimuli that can be both dangerous and beneficial. The proper execution of this task is central to the homeostasis of the host, and as a result, the gastrointestinal tract contains more lymphocytes than any other tissue compartment in the body, as well as unique antigen-presenting cells with specialized functions. When antigen is initially encountered through the gut, this system generates a robust T cell–mediated hyporesponsiveness called oral tolerance. Although seminal observations of oral tolerance were made a century ago, the relevant mechanisms are only beginning to be unraveled with the use of modern investigational techniques. Food allergy is among the clinical disorders that occur from a failure of this system, and therapies that seek to re-establish tolerance are currently under investigation. The intestine has an unenviable task: to identify and respond to a constant barrage of environmental stimuli that can be both dangerous and beneficial. The proper execution of this task is central to the homeostasis of the host, and as a result, the gastrointestinal tract contains more lymphocytes than any other tissue compartment in the body, as well as unique antigen-presenting cells with specialized functions. When antigen is initially encountered through the gut, this system generates a robust T cell–mediated hyporesponsiveness called oral tolerance. Although seminal observations of oral tolerance were made a century ago, the relevant mechanisms are only beginning to be unraveled with the use of modern investigational techniques. Food allergy is among the clinical disorders that occur from a failure of this system, and therapies that seek to re-establish tolerance are currently under investigation. Information for Category 1 CME CreditCredit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions.Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI Web site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted.Date of Original Release: March 2011. Credit may be obtained for these courses until February 28, 2013.Copyright Statement: Copyright © 2011-2013. All rights reserved.Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease.Target Audience: Physicians and researchers within the field of allergic disease.Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates these educational activities for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity.List of Design Committee Members: Brian P. Vickery, MD, Amy M. Scurlock, MD, Stacie M. Jones, MD, and A. Wesley Burks, MDActivity Objectives1.To describe ways in which the epithelial barrier is important in oral tolerance.2.To understand the ways in which antigen dose and timing affect oral tolerance.3.To define the roles of antigen-presenting cells and T cells in oral tolerance.4.To describe different types and functions of regulatory T (Treg) cells in the development of oral tolerance.Recognition of Commercial Support: This CME activity has not received external commercial support.Disclosure of Significant Relationships with Relevant CommercialCompanies/Organizations: B. P. Vickery has received research support from the National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases (NIAID), the Thrasher Research Fund, and Cephalon. A. M. Scurlock has received research support from the NIH. S. M. Jones has received research support from the National Peanut Board, NIH/NIAID, DYAX Corp, and the Food Allergy Initiative and is on the medical advisory board of the Food Allergy and Anaphylaxis Network (FAAN) and the steering committee of Sanofi-Aventis. A.W. Burks has consulted for ActoGeniX NV, Intelliject, McNeil Nutritionals, Novartis, Pfizer, and Schering-Plough; is a minority stockholder in Allertein and MastCell, Inc; has served on an advisory board for Dannon Co Probiotics and an expert panel for Nutricia; has received research support from the NIH, FAAN, and theWallace Research Foundation; has provided legal consultation or expert witness testimony on the topic of food allergy; and has served on the medical board of directors of FAAN.GlossaryANTIGEN-PRESENTING CELLS (APCS)Professional APCs are effective at endocytosing foreign antigens and displaying antigen to T cells in the context of MHC. Classically, macrophages, DCs, and B cells are professional APCs and express costimulatory molecules both constitutively and on stimulation. Nonprofessional APCs require stimulation before expression of MHC class II and include activated epithelial and endothelial cells.MUCIN OLIGOSACCHARIDESIntestinal mucins are primarily cell-surface mucins (MUC1, 3A, 3B, 4, 12, 13, and 17) that require glycosylation and sulfonation for proper assembly and function. Abnormalities in Muc1 and Muc2 are associated with gastritis, increased bacterial overgrowth, and colitis.NATURAL KILLER T (NKT)NKT cells are specialized αβ T cells that recognize glycolipid antigens that are CD1d restricted. The function of NKT cells in human allergic diseases is unclear.OCCLUDIN, CLAUDIN, AND JAM-Z01Tight junctions are important for organizing epithelial polarity and for epithelial integrity. Tight junction proteins include the transmembrane proteins occludins, claudins, junctional adhesion molecules (JAMs), and crumb. Some intestinal pathogens, including Helicobacter pylori and Shigella species, increase mucosal permeability by interfering with tight junction protein function and location.PEYER PATCHESOne part of the gut-associated lymphoid tissue (GALT), Peyer patches are lymphoid follicles that are found primarily in the distal small intestine. Peyer patches are located in the intestinal wall directly underneath microfold cells, where they are positioned to directly encounter soluble antigens from the lumen. Other parts of the GALT include lamina propria T and B cells, intraepithelial lymphocytes, and the MLNs.PLASMACYTOID DCsDC subsets include myeloid and plasmacytoid DCs. Plasmacytoid DCs express Toll-like receptors 7 and 9 and express IFN-α.RETINOIC ACIDNuclear steroid receptors, peroxisome proliferator-activated receptor (PPAR) and retinoic acid receptors (RARs), both bind RA, which is derived from vitamin A. In the intestinal tract dietary retinoic acid is an important cofactor used by DCs to promote the development of Foxp3+ Treg cells.REGULATORY T CELLSNatural Treg helper cells are thymically derived CD4+ cells that generally express TGF-β and Foxp3 and provide specific immunosuppression primarily to self-antigens. Adaptive Treg cells, also known as TR1 or TH3 cells, are CD4+ T cells that acquire functionally suppressive properties after exposure to exogenous antigens in the periphery.16s RIBOSOMAL RNABecause 16s Ribosomal RNA is unique among species, sequencing of these subunits from bacteria is the molecular platform for analyzing the variability and influence of the microbiome on organ-specific disease states (eg, the intestinal tract, oropharynx, and respiratory tract).THYMIC STROMAL LYMPHOPOEITIN (TSLP)TSLP is an IL-7–like cytokine expressed in activated epithelium, which promotes antigen presentation by DCs through the induction of second signal molecules, such as OX40, CD40, and CD80. These signals lead to the "inflammatory TH2" response and the development of allergic inflammation.γδ T CELLSγδ T cells recognize nonpeptide antigens that can be upregulated on cells because of stress and that resemble pathogen-associated molecular patterns/danger-associated molecular patterns. γδ T cells might be important in maintaining intestinal epithelial integrity because the lack of γδ T cells decreases tight junction protein phosphorylation (claudin and occludin) and loss of epithelial integrity with increased pathogen translocation.The Editors wish to acknowledge Seema Aceves, MD, PhD, for preparing this glossary. Credit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions. Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI Web site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted. Date of Original Release: March 2011. Credit may be obtained for these courses until February 28, 2013. Copyright Statement: Copyright © 2011-2013. All rights reserved. Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease. Target Audience: Physicians and researchers within the field of allergic disease. Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates these educational activities for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity. List of Design Committee Members: Brian P. Vickery, MD, Amy M. Scurlock, MD, Stacie M. Jones, MD, and A. Wesley Burks, MD Activity Objectives1.To describe ways in which the epithelial barrier is important in oral tolerance.2.To understand the ways in which antigen dose and timing affect oral tolerance.3.To define the roles of antigen-presenting cells and T cells in oral tolerance.4.To describe different types and functions of regulatory T (Treg) cells in the development of oral tolerance. Recognition of Commercial Support: This CME activity has not received external commercial support. Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations: B. P. Vickery has received research support from the National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases (NIAID), the Thrasher Research Fund, and Cephalon. A. M. Scurlock has received research support from the NIH. S. M. Jones has received research support from the National Peanut Board, NIH/NIAID, DYAX Corp, and the Food Allergy Initiative and is on the medical advisory board of the Food Allergy and Anaphylaxis Network (FAAN) and the steering committee of Sanofi-Aventis. A.W. Burks has consulted for ActoGeniX NV, Intelliject, McNeil Nutritionals, Novartis, Pfizer, and Schering-Plough; is a minority stockholder in Allertein and MastCell, Inc; has served on an advisory board for Dannon Co Probiotics and an expert panel for Nutricia; has received research support from the NIH, FAAN, and theWallace Research Foundation; has provided legal consultation or expert witness testimony on the topic of food allergy; and has served on the medical board of directors of FAAN. Professional APCs are effective at endocytosing foreign antigens and displaying antigen to T cells in the context of MHC. Classically, macrophages, DCs, and B cells are professional APCs and express costimulatory molecules both constitutively and on stimulation. Nonprofessional APCs require stimulation before expression of MHC class II and include activated epithelial and endothelial cells. Intestinal mucins are primarily cell-surface mucins (MUC1, 3A, 3B, 4, 12, 13, and 17) that require glycosylation and sulfonation for proper assembly and function. Abnormalities in Muc1 and Muc2 are associated with gastritis, increased bacterial overgrowth, and colitis. NKT cells are specialized αβ T cells that recognize glycolipid antigens that are CD1d restricted. The function of NKT cells in human allergic diseases is unclear. Tight junctions are important for organizing epithelial polarity and for epithelial integrity. Tight junction proteins include the transmembrane proteins occludins, claudins, junctional adhesion molecules (JAMs), and crumb. Some intestinal pathogens, including Helicobacter pylori and Shigella species, increase mucosal permeability by interfering with tight junction protein function and location. One part of the gut-associated lymphoid tissue (GALT), Peyer patches are lymphoid follicles that are found primarily in the distal small intestine. Peyer patches are located in the intestinal wall directly underneath microfold cells, where they are positioned to directly encounter soluble antigens from the lumen. Other parts of the GALT include lamina propria T and B cells, intraepithelial lymphocytes, and the MLNs. DC subsets include myeloid and plasmacytoid DCs. Plasmacytoid DCs express Toll-like receptors 7 and 9 and express IFN-α. Nuclear steroid receptors, peroxisome proliferator-activated receptor (PPAR) and retinoic acid receptors (RARs), both bind RA, which is derived from vitamin A. In the intestinal tract dietary retinoic acid is an important cofactor used by DCs to promote the development of Foxp3+ Treg cells. Natural Treg helper cells are thymically derived CD4+ cells that generally express TGF-β and Foxp3 and provide specific immunosuppression primarily to self-antigens. Adaptive Treg cells, also known as TR1 or TH3 cells, are CD4+ T cells that acquire functionally suppressive properties after exposure to exogenous antigens in the periphery. Because 16s Ribosomal RNA is unique among species, sequencing of these subunits from bacteria is the molecular platform for analyzing the variability and influence of the microbiome on organ-specific disease states (eg, the intestinal tract, oropharynx, and respiratory tract). TSLP is an IL-7–like cytokine expressed in activated epithelium, which promotes antigen presentation by DCs through the induction of second signal molecules, such as OX40, CD40, and CD80. These signals lead to the "inflammatory TH2" response and the development of allergic inflammation. γδ T cells recognize nonpeptide antigens that can be upregulated on cells because of stress and that resemble pathogen-associated molecular patterns/danger-associated molecular patterns. γδ T cells might be important in maintaining intestinal epithelial integrity because the lack of γδ T cells decreases tight junction protein phosphorylation (claudin and occludin) and loss of epithelial integrity with increased pathogen translocation. The Editors wish to acknowledge Seema Aceves, MD, PhD, for preparing this glossary. Food allergy, which is hypothesized to result from a defect in oral tolerance, is a common, serious, and growing problem in developed countries. Patients with food allergy have pathological immune responses to ingested food antigens and can rapidly experience harmful adverse symptoms on re-exposure. Although a recent meta-analysis identified variation in prevalence rates,1Chafen J.J.S. Newberry S.J. Riedl M.A. Bravata D.M. Maglione M. Suttorp M.J. et al.Diagnosing and managing common food allergies: a systematic review.JAMA. 2010; 303: 1848-1856Crossref PubMed Scopus (397) Google Scholar recent survey data from the Centers for Disease Control and Prevention indicate that the current prevalence of food allergy in US children is approximately 4%, an increase of almost 20% in the last decade.2Branum A.M. Lukacs S.L. Food allergy among children in the United States.Pediatrics. 2009; 124: 1549-1555Crossref PubMed Scopus (583) Google Scholar Increases in food allergy prevalence have also been observed in methodologically rigorous birth cohort studies, which use precise sampling techniques and well-defined outcome measures, suggesting that increasing prevalence is not simply caused by self-diagnosis or increased recognition of the disorder.3Venter C. Arshad S.H. Grundy J. Pereira B. Clayton C.B. Voigt K. et al.Time trends in the prevalence of peanut allergy: three cohorts of children from the same geographical location in the UK.Allergy. 2010; 65: 103-108Crossref PubMed Scopus (208) Google Scholar Similar trends in the prevalence of asthma, allergic rhinitis, and atopic dermatitis support the general concept that atopic diseases are increasingly common.4Gupta R. Sheikh A. Strachan D.P. Anderson H.R. Time trends in allergic disorders in the UK.Thorax. 2007; 62: 91-96Crossref PubMed Scopus (405) Google Scholar Interestingly, the likelihood that spontaneous clinical tolerance will develop in persons with food allergy varies depending on the allergen. In general, resolution of allergy to egg, milk, wheat, and soy can be expected, although sensitivity can persist into the second decade of life, which is longer than previously appreciated. In contrast, most patients allergic to peanut, tree nuts, and seafood will not outgrow their disease and must maintain strict elimination diets. The natural history of allergy to other important proteins, such as sesame and mustard, is largely unknown. In addition, current diagnostic testing for food allergy cannot predict a patient's risk for anaphylaxis or determine a subject's threshold dose to trigger symptoms. Therefore affected subjects and families must be constantly vigilant to avoid inadvertent exposure; however, accidental ingestions frequently occur even in the most cautious patients.5Sicherer S.H. Sampson H.A. Food allergy.J Allergy Clin Immunol. 2010; 125: S116-S125Abstract Full Text Full Text PDF PubMed Scopus (911) Google Scholar The inability to completely eliminate the possibility of anaphylaxis and the associated limitations in everyday activities are great sources of uncertainty and stress on affected families. Over time, health-related quality of life can be adversely affected; in some families the degree of impairment is similar to that seen with other serious chronic diseases of childhood, such as type 1 diabetes or ventilator-dependent chronic respiratory failure.6Cummings A.J. Knibb R.C. King R.M. Lucas J.S. The psychosocial impact of food allergy and food hypersensitivity in children, adolescents and their families: a review.Allergy. 2010; 65: 933-945Crossref PubMed Scopus (384) Google Scholar Although the effect of food allergies is substantial, their prevalence is remarkably low considering the complexities of the mucosal immune system. The gastrointestinal tract, which is the largest immunologic organ in the body, is constantly exposed to an enormous array of exogenous antigens, including commensal bacteria and ingested proteins.7Chehade M. Mayer L. Oral tolerance and its relation to food hypersensitivities.J Allergy Clin Immunol. 2005; 115: 3-12Abstract Full Text Full Text PDF PubMed Scopus (341) Google Scholar A single epithelial layer separates this antigenic load from the lymphocytes, antigen-presenting cells (APCs), stromal cells, and other immune cells in the lamina propria that together comprise the mucosa-associated lymphoid tissue (MALT). Within the MALT, unique populations of dendritic cells (DCs) interact with dietary antigens and determine the fate of the resulting adaptive response (ie, immunity vs tolerance).8Coombes J.L. Powrie F. Dendritic cells in intestinal immune regulation.Nat Rev Immunol. 2008; 8: 435-446Crossref PubMed Scopus (633) Google Scholar In this context immune tolerance is defined as the antigen-specific suppression of cellular or humoral immune responses. When the initial antigen exposure is mediated through the gastrointestinal tract, a robust T cell–mediated suppression develops called oral tolerance.9Faria A.M.C. Weiner H.L. Oral tolerance.Immunol Rev. 2005; 206: 232-259Crossref PubMed Scopus (625) Google Scholar This review will focus on the relationship between the component parts of the complex gastrointestinal mucosal immune system and IgE-mediated food allergy. Because most of the evidence with regard to immune tolerance to dietary antigens is derived from experimental animals, we will primarily discuss these model systems. Where possible, we will review the evidence for similar phenomena in human biology and the relevant applications for clinical medicine. After ingestion, dietary proteins undergo digestion by enzymes in the saliva and stomach, as well as by gastric acid. This processing results in reduced protein immunogenicity, likely through the destruction of conformational epitopes. However, specific biochemical properties common among different food groups confer resistance to this physical and chemical degradation, which collectively maintain the allergenicity of these proteins on reaching the small intestine (Table I). Additional factors that disrupt normal digestion, such as coadministration of antacids, have been shown in animal models to result in a breakdown in oral tolerance induction.10Untersmayr E. Jensen-Jarolim E. The role of protein digestibility and antacids on food allergy outcomes.J Allergy Clin Immunol. 2008; 121: 1301-1308Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar Other features of mucosal defense include a hydrophobic layer of mucin oligosaccharides, which trap antigen, and both constitutive (ie, human β-defensin 1) and inducible (LL-37 and human β-defensin 2 and 3) antimicrobial peptides.Table IBiochemical factors that promote allergenicityMolecular weight <70 kdGlycosylationResistance to thermal or chemical denaturationAbundance in food sourceLinear epitopesSolubility in water Open table in a new tab Secretory IgA has generally been considered to provide important tolerogenic function by binding to luminal antigens and preventing absorption (ie, "immune exclusion"), although its specific importance has been controversial.11Brandtzaeg P. Update on mucosal immunoglobulin A in gastrointestinal disease.Curr Opin Gastroenterol. 2010; 26: 554-563Crossref PubMed Scopus (97) Google Scholar A recent study showed that mice deficient in the receptor that secretes IgA and IgM into the intestinal lumen are hypersensitive to IgG-mediated anaphylaxis; nonetheless, they can be tolerized by an oral feed before systemic priming.12Karlsson M.R. Johansen F. Kahu H. Macpherson A. Brandtzaeg P. Hypersensitivity and oral tolerance in the absence of a secretory immune system.Allergy. 2010; 65: 561-570Crossref PubMed Scopus (51) Google Scholar In this model tolerance was transferrable by CD4+CD25+ splenocytes, suggesting that cellular mechanisms can compensate for an impaired immune exclusion mechanism. However, a recent case-control study from a larger placebo-controlled trial examining probiotics for allergy prevention in high-risk infants showed that the risk of atopy was inversely correlated with fecal IgA levels.13Kukkonen K. Kuitunen M. Haahtela T. Korpela R. Poussa T. Savilahti E. High intestinal IgA associates with reduced risk of IgE-associated allergic diseases.Pediatr Allergy Immunol. 2010; 21: 67-73Crossref PubMed Scopus (115) Google Scholar These data serve as one example of the complex and complementary forces that act to suppress immunity in the gut. Gastrointestinal epithelial dysfunction has been thought to contribute to food hypersensitivity through both increased sensitization caused by a leaky barrier and the heightened TH2 effector response that ensues. Epithelial junction complexes, also called adherens junctions, and tight junctions provide structural integrity to the gut barrier.14Dahan S. Roth-Walter F. Arnaboldi P. Agarwal S. Mayer L. Epithelia: lymphocyte interactions in the gut.Immunol Rev. 2007; 215: 243-253Crossref PubMed Scopus (104) Google Scholar However, this barrier is not completely formed at birth, and although not well understood, structural integrity might take time to fully develop.7Chehade M. Mayer L. Oral tolerance and its relation to food hypersensitivities.J Allergy Clin Immunol. 2005; 115: 3-12Abstract Full Text Full Text PDF PubMed Scopus (341) Google Scholar In mice the permeability of this barrier is further influenced by exposures to microbial pathogens, such as viruses, alcohol, nonsteroidal anti-inflammatory drugs, and other toxins, as well as cytokines (eg, IL-9), immune cells, and apoptotic pathways. These environmental exposures ultimately result in changes in gene expression and phosphorylation of tight junction proteins, such as occludins, claudins, and JAM-ZO1 proteins, which in turn are associated with changes in intestinal mast cells and allergic sensitization.15Forbes E.E. Groschwitz K. Abonia J.P. Brandt E.B. Cohen E. Blanchard C. et al.IL-9– and mast cell–mediated intestinal permeability predisposes to oral antigen hypersensitivity.J Exp Med. 2008; 205: 897-913Crossref PubMed Scopus (229) Google Scholar, 16Groschwitz K.R. Hogan S.P. Intestinal barrier function: molecular regulation and disease pathogenesis.J Allergy Clin Immunol. 2009; 124: 3-20Abstract Full Text Full Text PDF PubMed Scopus (1150) Google Scholar Interestingly, intestinal permeability was assessed in infants with food allergy by calculating the urinary ratio after ingestion of freely diffusible lactulose and normally unabsorbed mannitol.17Ventura M. Polimeno L. Amoruso A. Gatti F. Annoscia E. Marinaro M. et al.Intestinal permeability in patients with adverse reactions to food.Dig Liver Dis. 2006; 38: 732-736Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar Infants with food allergy were noted to have a lower ratio, indicating increased intestinal permeability, when compared with normal healthy young children. Investigators examined this ratio in children who had been on an allergen-free diet for at least 6 months and determined that intestinal permeability remained increased in children with food allergy, despite the absence of food allergen stimulation. Further evidence linking gastrointestinal epithelial barrier dysfunction and food allergy comes from studies in immunosuppressed patients after solid-organ transplantation who had food allergy while receiving systemic calcineurin inhibitors. Initially, investigators assumed this allergy was the result of transfer of sensitized donor lymphocytes. However, it is now theorized that medication-induced decreases in cellular ATP levels altered the integrity of junctional complexes, resulting in increased intestinal permeability.18Levy Y. Davidovits M. Cleper R. Shapiro R. New-onset post-transplantation food allergy in children—is it attributable only to the immunosuppressive protocol?.Pediatr Transplant. 2009; 13: 63-69Crossref PubMed Scopus (49) Google Scholar Mutations in the gene encoding filaggrin also lead to profound epidermal barrier dysfunction and are highly prevalent in patients with atopic dermatitis, which is in turn associated with an increased prevalence of food allergy. Acquired barrier defects associated with decreased filaggrin expression have been observed in the esophagi of patients with eosinophilic esophagitis and are thought to be secondary to IL-13.19Blanchard C. Stucke E.M. Burwinkel K. Caldwell J.M. Collins M.H. Ahrens A. et al.Coordinate interaction between IL-13 and epithelial differentiation cluster genes in eosinophilic esophagitis.J Immunol. 2010; 184: 4033-4041Crossref PubMed Scopus (237) Google Scholar However, no studies to date have examined the mechanistic relationship of filaggrin mutations to IgE priming in the gut or clinical food allergy.20van den Oord R. Sheikh A. Filaggrin gene defects and risk of developing allergic sensitisation and allergic disorders: systematic review and meta-analysis.BMJ. 2009; 339: b2243Crossref Scopus (379) Google Scholar Increasing evidence suggests that the mucosal epithelium is likely to be more involved in tolerance than simply by acting as a physical barrier. Epithelial cells are known to express MHC class II molecules on their basolateral membranes and thus might act as nonprofessional APCs, which do not express conventional costimulatory molecules, favoring anergy.21Hershberg R.M. Cho D.H. Youakim A. Bradley M.B. Lee J.S. Framson P.E. et al.Highly polarized HLA class II antigen processing and presentation by human intestinal epithelial cells.J Clin Invest. 1998; 102: 792-803Crossref PubMed Scopus (164) Google Scholar In addition, factors derived from the gut epithelium are generally believed to condition the DCs in the stroma, dampening immune responses and promoting gut homeostasis.22Iliev I.D. Matteoli G. Rescigno M. The yin and yang of intestinal epithelial cells in controlling dendritic cell function.J Exp Med. 2007; 204: 2253-2257Crossref PubMed Scopus (75) Google Scholar One such factor, constitutively expressed by the gut epithelium, is thymic stromal lymphopoetin (TSLP). TSLP is an IL-7–like cytokine that has been shown to activate expression of OX40 ligand on DCs and drive TH2 differentiation. Thus TSLP is a critical mediator of allergic inflammation in the lung and skin. By contrast, in the gut TSLP appears to play a regulatory role, limiting deleterious TH1 and TH17 inflammation in models of helminth infection and colitis.23Ziegler S.F. Artis D. Sensing the outside world: TSLP regulates barrier immunity.Nat Immunol. 2010; 11: 289-293Crossref PubMed Scopus (465) Google Scholar Although incompletely understood, this regulation can occur at the level of the DC, which expresses the TSLP receptor and has been shown to develop tolerogenic properties after TSLP exposure. Interestingly, regulatory responses to dietary allergens are evidently normal in TSLP receptor–deficient animals.24Blazquez A.B. Berin M.C. Gastrointestinal dendr
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