How is tolerance to an allergen developed?

How is tolerance to an allergen developed?

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My question is mainly about how allergy shots work.

I did some basic research before posting here, however I could not find an explanation of what occurs at a cellular level.

Is it the persistance of the antigen which somehow induce immune tolerance?

The allergy shot in itself is a form of therapy called allergen immunotherapy (AIT). In it's essence, we're trying to get someone to develop immunologic tolerance to a given allergen such as pollen, okay! So how does it happen at the cellular level? (Assuming the treatment protocol is known)

Understanding The Mechanism Of Allergen Immunotherapy, as an article is kind of a broad overview. Thus there are phases to AIT that include early, intermediate and late phases. The process begins with a downregulation of mast cell and basophil activity, followed by induction of allergen specific Treg cells, a decrease in Th2 cells, and then a decrease in IgE production with an increase in IgG4/IgA.

Mechanistically, it doesn't look like it's well known how basophils and mast cells get regulated by AIT, but the theory is that the mechanism may resemble H2R (a histamine receptor) receptor activity during venom immunotherapy: H2R becomes highly upregulated after therapy start, and inhibits Fcε-R1 activation of mast cells and basophils, even in the presence of IgE (2, paywall on this one).

They provide an impressive table in Akdis & Akdis 2014 as to the role of immune cells in AIT:

So in the process of encountering the allergen, the immune system produces Treg cells as a result of dendritic cell antigen presentation. An inducible type of Treg called Tr1 is capable of abrogating the response of Th2 and Th1 cells through the secretion of TGF-ß and IL-10. They have a good table for this, too:

There's an effect in there due to TGF-ß exerting its effect on B cells that ends up inhibiting class switching to most other immunoglobulins except mucosal IgA. In conjunction with IL-4, IL-10 is capable of promoting the class switch of preceding B cells to IgG4. So the classes of Ig will largely become IgG4 and IgA in response to the allergen of interest. The B cells will also begin to produce their own IL-10, and in a way become a regulatory type of B cell, or Breg, that propagates the tolerogenic response.

And so the big conclusion: (1) the mast cells/basophils aren't as prone to causing anaphylaxis, (2) the effector cells specific for the allergen have actually shifted to populations of tolerogenic DCs, Tregs and Bregs, and (3) antibody production has shifted to IgG4/IgA from IgE. The net result is due to the repeated exposure to the allergen at some optimal concentration, but the key is they performed the treatment slow enough that the immune system had time to build up tolerance without going crazy. It's also likely that we don't know how long the system stays tolerant for after successful treatment.

It's much more complicated and if you can get past the paywall on source 2 there's really good, detailed info. I didn't want to go into a novel here, but let me know if you need clarification anywhere.

Immune Basis of Allergic Reactions to Food

Food allergies are diseases where the normal tolerance response to oral antigens is altered. Recent advances have begun to uncover mechanisms that mediate sensitization to food allergens and maintenance of the disease. Production of alarmins by epithelial cells triggers a cascade that leads to allergen-specific IgE synthesis. IL-9 has also been shown to play a role in mast cell recruitment and amplification of the allergic response. In recent years, increasing evidence suggests that sensitization to food allergens can be developed via nonoral routes, in particular the skin, thus leading to the "dual exposure hypothesis". Environmental factors such as diet or microbiota can shape the immune system to promote tolerance or sensitization to food antigens. While the mechanism of primary tolerance to food antigens is quite clear, that leading to permanent tolerance in food-allergic individuals through immunotherapy is still under study. Understanding the mechanisms by which oral tolerance is suppressed and sensitization develops will help to identify new targets to develop combined therapies for the treatment of food allergies.

Keywords: Allergen-specific immunotherapy Food allergy Microbiota Oral tolerance Skin sensitization.

How is tolerance to an allergen developed? - Biology

  • How Do Allergies Work?

  • Who Has Allergic Reactions?

The proteins found in pet dander, skin flakes, saliva and urine can cause an allergic reaction. Antihistamines can provide temporary relief but are not designed for long-term treatment. Allergists have specialized training to accurately diagnose allergies and develop treatment plans to help manage allergy symptoms.

Rhinitis, the condition of a constant runny nose, sneezing, and nasal stuffiness, can be allergic or non-allergic. Furthermore, there are two types of allergic rhinitis: Seasonal or Perennial.
1. Non-allergic Rhinitis

This condition differs from allergic rhinitis because the immune system is not involved. Although the cause is unknown, typical triggers can include a dry atmosphere, air pollution, alcohol, certain medications, spicy foods and strong emotions. The most effective approach is to avoid allergy symptom triggers, but decongestants, nasal sprays and antihistamines can allow some relief.

2. Perennial Allergic Rhinitis

In these cases, symptoms occur all year and are usually triggered by indoor allergens, such as mold, pet dander and dust.

3. Seasonal Allergic Rhinitis – “Hay Fever”
Hay fever is caused by pollen carried in the air, prevalent in the spring and fall. Allergic rhinitis causes inflammation in the nasal lining, which increases sensitivity to inhalants, so it makes sense that symptoms can be provoked by irritants such as smoke or strong odors, or changes in the temperature and humidity.

Plants commonly responsible for hay fever include trees such as pine, birch, cedar, hazel, willow and poplar, weeds such as ragweed and nettle, and grasses.

IFNβ inhibits the development of allergen tolerance and is conducive to the development of asthma on subsequent allergen exposure

Vanessa Fear, Tumour Immunology Group, M503, University of Western Australia, Harry Perkins Building North, Level 5 QQ Building, QEII Medical Centre, Monash Ave, Nedlands, WA 6009, Australia.

Inflammation Group, Telethon Kids Institute, School of Paediatrics and Child Health Research, University of Western Australia, Perth, WA, Australia

Inflammation Group, Telethon Kids Institute, School of Paediatrics and Child Health Research, University of Western Australia, Perth, WA, Australia

Inflammation Group, Telethon Kids Institute, School of Paediatrics and Child Health Research, University of Western Australia, Perth, WA, Australia

Burn Injury Research Unit, School of Surgery, University of Western Australia, Perth, WA, Australia

Tumour Immunology Group, School of Biomedical Sciences, University of Western Australia, Perth, WA, Australia

Vanessa Fear, Tumour Immunology Group, M503, University of Western Australia, Harry Perkins Building North, Level 5 QQ Building, QEII Medical Centre, Monash Ave, Nedlands, WA 6009, Australia.

Inflammation Group, Telethon Kids Institute, School of Paediatrics and Child Health Research, University of Western Australia, Perth, WA, Australia

Inflammation Group, Telethon Kids Institute, School of Paediatrics and Child Health Research, University of Western Australia, Perth, WA, Australia

Inflammation Group, Telethon Kids Institute, School of Paediatrics and Child Health Research, University of Western Australia, Perth, WA, Australia

Burn Injury Research Unit, School of Surgery, University of Western Australia, Perth, WA, Australia


Asthma is a chronic disease affecting up to 10% of the Australian population for which medical treatment is solely aimed at relief of symptoms rather than prevention of disease. Evidence from animal and human studies demonstrates a strong link between viral respiratory infections, atopy and the development of asthma. Type I IFNs include IFNα and IFNβ, with subtype expression tailored toward the specific viral infection. We hypothesized that exposure to type I IFNs and allergen may interfere with the healthy response to innocuous airway antigen exposure. In this study, we use an ovalbumin (OVA)-induced BALB/c model of experimental allergic airways disease, where pre-exposure of the airways to OVA is protective against allergen sensitization, leading to allergen tolerance. We investigated airways pre-exposure with OVA and type I IFNs on development of allergic airways disease. We demonstrate restoration of allergic airways disease on pre-exposure with allergen and IFNβ, and not IFNα. Dysfunction in tolerance led to changes in dendritic cell antigen capture/traffic, T-cell and B-cell responses. Furthermore, exposure to IFNβ with ongoing allergen exposure led to the development of hallmark asthma features, including OVA-specific IgE and airways eosinophilia. Data indicate a role for IFNβ in linking viral infection and allergy.

Induced Tolerance

Tolerance of Commensal Bacteria

The human large intestine (colon) contains an enormous (

10 14 ) population of microorganisms. (Our bodies consist of only

  • by synthesizing vitamins
  • by digesting polysaccharides for which we have no enzymes (providing an estimated 10% of the calories we acquire from our food)

Two tolerance-inducing mechanisms have been identified.

  • Stimulating the development of regulatory T cells (Treg) which provide protection against any inflammatory response that effector T cells might mount against the bacteria.
  • Enlisting the aid of a subset of innate lymphoid cells designated ILC3. ILC3 cells engulf bacterial antigens and process these into peptides nestled in the MHC class II molecules on their surface [Link]. These are presented to CD4 + T cells with the appropriate receptor (TCR). The interaction causes them to die (by apoptosis) rather than proliferate &mdash probably because of the lack of any co-stimulation ("signal two").

But still unanswered is how the immune response remains capable of responding to dangerous intestinal pathogens. Perhaps these elicit the necessary "signal two".

It turns out that not only do commensal bacteria in the intestine not trigger inflammation, but their presence is needed (at least in mice) to maintain a healthy colon.

  • Mice that are raised in a germfree environment [Link] or are treated with antibiotics to clean all the bacteria out of their colon are unhealthy and have GI tracts that are hypersensitive to injury. However, if they are given
      (from Gram-negative bacteria) or
  • lipoteichoic acid (from the peptidoglycan of Gram-positive bacteria)
    • lack TLR-2 or TLR-4 or
    • cannot signal through their TLRs [Link]
    • suggest that a continuous low level of activity of the innate immune system is essential to health &mdash even in the absence of pathogens
    • explain why deliberating feeding harmless bacteria ("probiotics") has proved beneficial to some human patients with a diseased colon
    • provide another reason for avoiding the indiscriminate use of antibiotics (which kill harmless bacteria as easily as pathogenic ones).

    Treating Allergies

    Allergists have struggled for years to find safe ways to tolerize allergic people to their allergens. This has usually involved giving a long series of injections of a special formulation of the allergen.

    • the active ingredient in poison ivy that triggers this cell-mediated immune response
    • allergens that trigger IgE-mediated allergic responses, such as
      • ragweed, grass, and tree pollens
      • insect stings
      • food allergens, e.g., peanuts and other nuts

      On close examination, though, it appears that what the treatments are doing is shifting the immune response from the harmful, unwanted one to a harmless one (e.g., from making IgE antibodies to making IgG instead). Thus what has been induced is deviation of the immune response rather than true tolerance. (This may also be the case for transplant tolerance.)

      Transplant Tolerance

      If ways could be found to induce genuine tolerance to allografts (organs transplanted from another person), this would enable the organ to resist rejection without the need for continuous use of immunosuppressive drugs.

      This photo, courtesy of the late Rupert B. Billingham (he died 16 November 2002), shows two adult white mice (strain A) that were tolerized to the cells of a black-coated strain (CBA) of mice when they were first born. Later, when adult, they were given skin grafts from the black mice. They retained these indefinitely without the need for any immunosuppression.

      Although this approach is not practical for humans, it did lay the groundwork for the first successful transplants (of kidneys) in humans. It also has inspired attempts to achieve graft tolerance in humans by pretreating the recipient with blood (rich in B cells) or bone marrow of the donor.

      In such cases (as well as Billingham's), it may be that tolerance of the graft is

      • created because the priming cells are unable to give a second signal to host T cells and
      • maintained by the continued survival in the recipient of these donor cells.

      Tolerance of the Fetus


      So far, the most effective preventive for IgE-mediated allergies is to inject the patient with gradually-increasing doses of the allergen itself. The goal is to shift the response of the immune system away from Th2 cells in favor of Th1 cells.

      Unfortunately, this therapy takes a long time and the results are too often disappointing.

      Clinical trials are now underway to test the safety and efficacy of a complex of ragweed pollen allergen with chemically-modified DNA. This complex binds to the immune receptor TLR-9 causing a shift of the immune response from Th2 to Th1 much more rapidly than desensitization by the allergen alone.

      How do your allergies develop?

      Worldwide, allergies are on the rise at an alarming rate. How do our bodies mistake otherwise harmless substances for potential dangers and cause the unpleasant, and sometimes even fatal, symptoms of allergy?

      Share on Pinterest Allergies affect millions of people worldwide, and the number is rising.

      From the mother anxiously watching for signs of wheezing the first time her child eats peanut butter to the retiree’s sudden reaction to shellfish, allergies can strike at any point during our lives.

      Hay fever affects 400 million individuals globally, with asthma affecting 300 million, food allergies between 200 and 250 million, and drug allergies affecting around 10 percent of the world’s population.

      The World Allergy Organization (WAO) warn that “the prevalence of allergic diseases worldwide is rising dramatically in both developed and developing countries.”

      Allergens, or molecules with the potential to cause allergy, are everywhere in our environment. They come in the form of tree pollen, food, mold, dust mites, snake or insect venom, and animals, such as cats, dogs, and cockroaches.

      When the body mistakes one of these substances as a threat and reacts with an immune response, we develop an allergy. Nobody is born with allergies. Instead, the 50 million people in the United States who suffer from allergies developed these only once their immune systems came into contact with the culprit.

      But how do our bodies mistake a friend for a foe? And what causes the symptoms that many are so familiar with?

      Allergy is defined as an inappropriate immune response to an otherwise harmless substance in the environment.

      Lisa A. Reynolds and B. Brett Finlay – both from the Michael Smith Laboratories at the University of British Columbia in Vancouver, Canada – explain in an article published in the journal Nature Reviews Immunology how the immune system reacts to foreign substances.

      Our immune cells are always on the lookout for dangers, such as bacteria, viruses, parasites, and toxic substances. When these molecules enter the body – through the lungs, mouth, intestine, or skin – the immune system can react by labeling them as either harmless or dangerous.

      Most of the time, our bodies accept or tolerate the presence of allergens.

      This is called a Type 1 immune response, and the cell type at the heart of this process is the regulatory T cell.

      That being said, in some individuals, the body’s immune cells see the allergen as a threat, and a pro-inflammatory response occurs as a result. This is called a Type 2 immune response, and a different class of T cell appears on the scene: T helper type 2 cells.

      These cells stimulate the production of immunoglobulin (Ig) E molecules in most allergies.

      The first exposure to an allergen that results in a Type 2 immune response is called allergic sensitization.

      Importantly, once the body has been sensitized, it maintains a lasting memory of the substance. And then, when it next comes into contact with the culprit, IgE molecules are primed to release a cascade of inflammatory players such as histamine, causing the unpleasant and potentially deadly symptoms of allergy.

      Allergies can manifest in several different ways, and everyone’s experience is unique. Our bodies can react by developing eczema (atopic dermatitis), hay fever (allergic rhinitis), allergic asthma, food allergies, or anaphylaxis, which is a severe and potentially deadly allergic reaction.

      Allergies are a lifetime companion, and treatment mostly revolves around the management of symptoms.

      But, as scientists are steadily getting to the bottom of what makes our immune system switch from Type 1 to Type 2 responses, there is a call to focus on preventing allergies from occurring in the first place.

      With 40 to 50 percent of schoolchildren worldwide sensitized to one or more allergens, preventing allergies in the future is likely to have a huge impact on global health.

      Mechanisms of immune tolerance to allergens: role of IL-10 and Tregs

      1 Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland. 2 Christine Kühne – Center for Allergy Research and Education (CK-CARE), Davos, Switzerland.

      Address correspondence to: Cezmi A. Akdis, Swiss Institute of Allergy and Asthma Research (SIAF), Obere Str. 22 CH-7270, Davos Platz, Switzerland. Phone: 41.81.410.08.48 E-mail: [email protected]

      1 Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland. 2 Christine Kühne – Center for Allergy Research and Education (CK-CARE), Davos, Switzerland.

      Address correspondence to: Cezmi A. Akdis, Swiss Institute of Allergy and Asthma Research (SIAF), Obere Str. 22 CH-7270, Davos Platz, Switzerland. Phone: 41.81.410.08.48 E-mail: [email protected]

      Published November 3, 2014 - More info

      During the past 20 years, major advances have been made in understanding the molecular and cellular mechanisms of allergen tolerance in humans. The demonstration of T cell tolerance, particularly that mediated by the immune-suppressive functions of IL-10, led to a major conceptual change in this area. Currently, the known essential components of allergen tolerance include the induction of allergen-specific regulatory subsets of T and B cells, the immune-suppressive function of secreted factors, such as IL-10 and TGF-β, the production of IgG4 isotype allergen–specific blocking antibodies, and decreased allergic inflammatory responses by mast cells, basophils, and eosinophils in inflamed tissues.

      Immune tolerance can develop against any immune-activating substance, and multiple mechanisms mediate this process. Deregulation of immune tolerance may lead to the development of allergies, asthma, tumors, chronic infections, rejection of transplanted organs, graft-versus-host disease, and many autoimmune diseases. Allergic diseases are characterized by the induction of a type 2 immune response that includes Th2 cells and type 2 innate lymphoid cells (ILC2s), together with the production of allergen-specific IgE antibodies and increased eosinophil numbers in the affected tissues and sometimes in peripheral blood ( 1 ). Although there are many different ways to treat allergic disease–associated symptoms, currently, the only long-term curative treatment is allergen-specific immunotherapy (AIT), which involves the administration of increasing doses of the causative allergen. Over time, AIT induces a state of allergen-specific immune tolerance. AIT has been performed for more than 100 years, though it has only been within the past two decades that the mechanisms that mediate the action of AIT have been slowly uncovered ( 2 ). After the discovery of Th1 and Th2 cells in 1986 ( 3 ), it was suggested that a Th2 response underlies the development of allergic diseases and that Th1 responses are predominant in infections and autoimmunity. Following these initial findings, the general dogma was that a switch toward a Th1 response would be required for the successful treatment of allergies by AIT, and a switch toward a Th2 response would be beneficial for the treatment of autoimmunity.

      In the mid-1990s, our group was working on the mechanisms of action of AIT in conventional and T cell epitope peptide immunotherapies ( 4 , 5 ). We were using honey bee venom allergy and its major allergen phospholipase A2 as a model to investigate antigen/allergen-specific immune response development in humans ( 4 ). In a 1996 article published in the JCI, we demonstrated that allergen-specific T cell tolerance was induced during the course of AIT ( 4 ). Two months after the beginning of venom immunotherapy, the proliferation of T cells specifically targeting phospholipase A2 and its T cell epitope peptides as well as the secretion of both Th2 (IL-4, IL-5, and IL-13) and Th1 (IL-2 and IFN-γ) cytokines were abolished. These data directly challenged the dogma that switching the balance between Th1 and Th2 responses is playing a role in treatment and suggested that the development of full T cell tolerance and suppression of both Th1 and Th2 subsets are taking place. As a control antigen, we demonstrated that tetanus toxoid–induced T cell proliferation and cytokine production remained unchanged following venom-specific AIT, demonstrating that the immune tolerance was specific to venom antigens and did not extend to other antigens. In addition, the state of T cell tolerance induced by AIT was altered in vitro by treatment with IL-2, IL-4, and IL-15. This was one of the first demonstrations that antigen-specific effector T cells have plasticity, suggesting that microenvironmental cytokines are important for determining success or failure in AIT ( 4 ). During these experiments, we were fortunate to be working with highly pure synthetic peptides and purified bee venom antigens collected in a sterile way. This enabled us to demonstrate immune tolerance, because any lipopolysaccharide contamination during collection and extraction of environmental allergens, such as house dust mites and pollens, would have led to results showing a skew from Th2 toward Th1.

      In hindsight, our research continued to elucidate the molecular and cellular mechanisms of T cell tolerance to allergens, and in our 1998 study published in the JCI, we demonstrated that human IL-10–producing Tregs (Tr1 cells) are linked to an antigen-specific suppressor function (Figure 1 and ref. 6 ). Intracytoplasmic cytokine staining of circulating lymphocytes revealed that IL-10 was initially produced by CD4 + CD25 + allergen–specific Tr1 cells and then by B cells and monocytes. These IL-10–secreting Tr1 cells were substantially increased as early as seven days after the start of bee venom AIT in allergic individuals. Following these initial findings, one major question was whether these Tr1 cells also develop during other types of AIT against different allergens. It took many years to demonstrate that Tr1 cells are generated in response to other immunotherapies such as sublingual immunotherapy, other allergens such as grass pollen and house dust mites, and peptide immunotherapies in allergy and autoimmune diseases ( 7 – 12 ). In addition, Tr1 cells were demonstrated to be present in high-dose exposure to allergen models, such as nonallergic beekeepers and cat owners ( 6 , 13 , 14 ).

      Mechanisms of allergen tolerance. The induction of allergen-specific Tregs, which switch from allergen-specific Th2 cells is one of the initial events in the development of allergen tolerance. The effector cells of allergic inflammation — mast cells, basophils, and eosinophils — are regulated by suppressive and regulatory functions of Tregs in several ways. Treg-secreted IL-10 and TGF-β suppress these cells. Tregs also suppress Th2 cells and their cytokines, preventing the provision of survival factors for these allergy effector cells. IL-10 and TGF-β suppress IgE production by B cells, and meanwhile, IL-10 induces IgG4. IL-10–producing regulatory B cells (Bregs) play a role in suppression of allergen-specific T cells and mainly switch to IgG4-producing plasma cells. H2R plays a role in the suppression of Th2 cells, inflammatory dendritic cells, and basophils.

      Studies during the past two decades have demonstrated that there are two broad subsets of CD3 + CD4 + Tregs. One subset is the naturally occurring thymus-derived CD4 + CD25 + FOXP3 + Tregs, also called natural Tregs (nTregs), and the other subset is the inducible Tregs (iTregs). Three main subsets of iTregs have been characterized: FOXP3-expressing iTregs, CD4 + FOXP3 - IL-10–producing Tr1 cells, and TGF-β–expressing Th3 cells. It has been repeatedly shown that all three subsets of iTregs coexist and overlap in many immune tolerance–related situations in humans. For example, antigen-specific CD4 + T cells that express IL-10, TGF-β, and FOXP3, or some combination of these markers, increase in nasal biopsies ( 12 , 15 – 17 ) and peripheral blood ( 7 – 9 ) in response to AIT at the healing phase.

      Tr1 cells have been shown to be important for the maintenance of a healthy immune response in different diseases, such as allergy, many autoimmune conditions, transplantation tolerance, and graft-versus-host disease in both humans and mice ( 13 , 18 – 26 ). Although IL-10 is the main cytokine produced by Tr1 cells, these cells also produce TGF-β and low-to-medium levels of IFN-γ and IL-5, but not IL-4 or IL-2 ( 27 , 28 ). It took almost a decade to demonstrate that human Tr1 cells suppress effector T cell responses by multiple mechanisms that depend on IL-10, TGF-β ( 7 ), PD-1, CTLA-4 ( 29 ), and histamine receptor 2 (H2R) ( 13 ).

      IL-10 has a potent immunosuppressive capacity that is crucial not only for the establishment of peripheral tolerance to allergens, but also in protecting the host from exaggerated inflammatory responses to pathogens as well as to autoimmune diseases ( 30 ). IL-10 directly inhibits T cells through suppression of CD28- and ICOS-dependent T cell costimulation ( 31 ). In addition, IL-10 inhibits the production of proinflammatory cytokines, chemokines, and chemokine receptors as well as the expression of MHC class II and costimulatory molecules CD80/CD86 on monocytes/macrophages and dendritic cells ( 30 ).

      In addition to T cell regulation, IL-10 secreted from Tr1 cells plays a major role in the induction of IgG4 and suppression of IgE ( 6 , 32 ). Moreover, it was recently demonstrated that IL-10–secreting B regulatory (Br1) cells essentially contribute to allergen tolerance (ref. 33 and Figure 1). Phospholipase A2–specific Br1 cells from nonallergic beekeepers and those that are induced after AIT showed increased expression of IL-10 with an antigen-specific suppressor capacity. A major finding of this study was that IgG4 production is specifically confined to Br1 cells. IgG4 represents a noninflammatory Ig isotype that does not activate complement and plays an IgE-blocking antibody role for the degranulation of mast cells and basophils ( 33 ).

      Specific Tr1 cells and immune tolerance development are essential for the induction and maintenance of healthy immune responses to allergens. The relationship between clinical allergen tolerance and immune tolerance has been observed by direct analysis of the affected tissues and skin during late-phase responses in humans who have undergone AIT with whole allergen and T cell epitope peptides as well as in individuals who have been exposed to naturally high doses of allergens. As of today, the concept that Tr1 cells mediate antigen-specific T cell tolerance has been demonstrated and generally accepted after the publication of several thousand studies on immune regulation.

      The authors’ laboratories are supported by grants from the Swiss National Foundation (320030_140772 and 310030_156823) and CK-CARE and from the European 7th Framework projects Mechanisms of the Development of Allergy (MeDALL) (261357) and Post-Infectious Immune Reprogramming and Its Association with Persistence and Chronicity of Respiratory Allergic Diseases (PREDICTA) (260895).

      Conflict of interest: The authors have declared that no conflict of interest exists.

      Reference information: J Clin Invest. 2014124(11):4678–4680. doi:10.1172/JCI78891.

      FcRn is mother’s milk to allergen tolerance

      In this issue Ohsaki et al. ( explain how breastfeeding can prevent the onset of food allergies in offspring by instructing T reg formation via neonatal Fc receptor (FcRn)–mediated transfer and uptake of allergen-containing IgG immune complexes (Ig-ICs) by gut dendritic cells (DCs).

      Allergy is characterized by the presence of serum IgE antibodies to common and harmless environmental and food allergens and can lead to allergic diseases like asthma, rhinitis, food allergy, and anaphylaxis. As allergy is highly prevalent is Western societies, and there seems to be no halt to the epidemic of food allergy, there is an urgent need for preventive strategies (Lambrecht and Hammad, 2017). Breastfeeding has long been shown to have protective effects on allergy development, yet protection seems to depend on whether the nursing mother is allergic or not and by extension whether the baby has high or low risk to develop disease (Munblit and Verhasselt, 2016). Yet other studies showed that breastfeeding can also promote allergies in babies, by allowing the transfer of allergens from the mother’s diet. Maternal allergen avoidance during breastfeeding has therefore been a common recommendation to prevent the onset of allergies in high-risk babies born to allergic parents. However, recent data suggest that early life allergen avoidance during the period of breastfeeding does not pay off and that certain food allergens should be introduced early in a diet to prevent food allergies (Du Toit et al., 2015). Given these controversies, in this issue, Ohsaki et al. studied whether and how maternal allergy to ovalbumin (OVA a major allergen in egg) or peanut affects the onset of allergy in their offspring. To induce allergy to foods, Ohsaki et al. (2018) sensitized mice via the epicutaneous route before and during pregnancy and during breastfeeding. When the offspring of these allergic mothers reached adulthood, they were also sensitized epicutaneously and given an oral challenge with allergen. Epicutaneous sensitization to food allergens is a highly relevant model, as peanut allergy in children often develops via a leaky skin barrier, and many food allergens like peanut are found in the household environment or as contaminants in baby skin lotions. The choice of OVA as a model allergen was also driven by the clinical observation that allergy to egg in early life is one of the strongest predictors of progression in the atopic march, the process by which children gradually develop severe allergic diseases like atopic dermatitis, rhinitis, and asthma. Remarkably, the offspring of allergic mothers was tolerant to food allergen challenge, whereas those born out of control nonallergic mothers developed signs of systemic anaphylaxis, a life-threatening form of food allergy. The tolerant offspring mice had developed allergen-specific Foxp3 + T reg cells that expanded in response to allergen exposure and suppressed anaphylaxis to food allergen challenge even in 3-mo-old offspring, when maternal-derived antibodies had long disappeared. Elegant setup of breeding and fostering of mice revealed that the protective T reg cells were induced mainly as a result of transfer of maternal allergen IgG immune complexes (Ig-ICs) via breastfeeding of the pups and less efficiently via direct transplacental transfer. Supplementation of lactating mice with allergen IgG1-IC was sufficient to confer protection in offspring. The neonatal Fc receptor FcRn is well known to mediate the transfer of Igs from mother to child via placenta and breastfeeding to suckling mice, implying a role of FcRn in mother and child. When only the offspring was deficient in FcRn, the induction of T reg cells and functional tolerance to food allergen offered by maternal allergen Ig-IC was abolished. Gut dendritic cells (DCs) express the FcRn receptor and were able to induce OVA-specific Foxp3 + T reg cells in response to exposure to breast milk–derived OVA Ig-ICs in vitro and ex vivo. Strikingly, mice lacking FcRn selectively in CD11c hi DCs were unable to mount T reg cells and tolerance to food allergens via maternal protection. Ohsaki et al. (2018) finally made an important translational leap and fed humanized FcRn transgenic mice with breast milk of healthy nonatopic mothers. This source of breast milk was rich in OVA-specific IgG4-IC. Although this experiment was performed by oral gavage in adult mice, human breast milk suppressed the salient features of food allergy, including systemic anaphylaxis, suggesting that the mouse findings of the study likely translate to the human situation.

      Breast milk has many beneficial effects on the progeny’s developing immune system, much more than passively protecting the offspring form infectious disease by passive transfer of maternal protective antibodies and influencing the composition of the infant gut microbiome and gut barrier function. Breastfeeding can shape the neonatal repertoire of T cells and B cells by transfer of free antigen, including such potent allergens like house dust mite and peanut. The current study is not the first to report that allergen Ig-ICs from an allergic mother protect the progeny against allergic disease via breastfeeding and FcRn and induction of Foxp3 + T reg cells (Mosconi et al., 2010 Nakata et al., 2010 Bernard et al., 2014). In the past it was found that TGFβ contained in breast milk could be decisive whether or not long-lasting T reg–mediated tolerance developed, but when Ig-ICs are present in breast milk, TGFβ does not seem to be required (Verhasselt et al., 2008). So where does the current study add novelty? In previous work, the role of FcRn was merely seen as a transfer receptor mediating the transepithelial uptake of allergen Ig-ICs from the lumen to the immune system’s DCs or macrophages, a known function of this receptor (Yoshida et al., 2004). However, in mice and humans, the FcRn is also expressed by DCs and macrophages (Guilliams et al., 2014), and it turns out increasingly that FcRn is crucial in determining the immunological outcome of an Ig-IC encounter (Stapleton et al., 2015). When IgG or and Ig-IC binds to activating Fc receptors on APCs, it is internalized in endosomes that undergo a gradual drop in pH. At a lower pH 6.5, the FcRn receptor has increased affinity for the constant domains of IgG. In the case of free IgG, this leads to recycling of the IgG to the cell membrane, followed by exocytosis, thus extending the half-life of IgG considerably. Binding of Ig-IC to FcRn and interaction with the invariant chain CD74 promote the routing of the Ig-IC to the MHCII-rich processing and loading compartment for presentation of peptides on MHCII to CD4 T cells (Qiao et al., 2008). It has also been shown that FcRn in DCs promotes the cross-presentation of Ig-IC by protecting antigens in an acidic endosomal environment and allowing transfer of undigested protein epitopes to the cytoplasm for further trimming by the proteasome (Baker et al., 2011). Ohsaki et al. (2018) suggest that FcRn might also act to promote tolerance, although the mechanism of such tolerance induction requires much more detailed analysis. It will be important to study which APCs among the CD11c targeted cells is mediating T reg tolerance in the gut. Various APCs can mediate food tolerance in the intestine of adult mice, but T reg formation seems to be particularly induced by macrophages closely collaborating with CD103 + conventional cDC1 (Mazzini et al., 2014). FcRn often does not work in isolation, but requires collaboration with activating or inhibitory Fc receptors for signaling and internalization of the Ig-ICs. Although the inhibitory Fc receptor FcγRIIb has a role in oral tolerance induction to common foods and is expressed by conventional DCs, it was shown that it was not required for tolerance induction by breast milk Ig-ICs in suckling mice (Samsom et al., 2005 Mosconi et al., 2010). Activating Fc receptors are therefore more likely candidates, but these are poorly expressed on conventional DCs, suggesting an important contribution of monocyte-derived cells and macrophages that highly express activating Fc receptors (Guilliams et al., 2014). Finally, the translational part of the study shows that ICs containing IgG4 and allergen confer protection from food allergy in adult mice in an FcRn-dependent manner. Induction of allergen-specific IgG4 is often seen in patients undergoing successful subcutaneous or sublingual allergen immunotherapy, or those who spontaneously tolerate high loads of allergen exposure like bee keepers and cat owners, likely also leading to formation of allergen Ig-ICs. It will be very important to study whether FcRn on DCs is involved in this particular state of tolerance to allergens. Studying the molecular details of the interaction of FcRn with IgG is certainly on the radar of drug companies who use this knowledge to improve the half-life of therapeutic antibodies that recycle via FcRn. It might therefore not be too long before we see therapeutic applications of tolerance promoting immune complexes that target FcRn.

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      Have you had the flu? Im not sure I would call that response measured. The immune system isnt conscious and responds in an almost mechanical way to challenge, with tissue damage and organ dysfunction often being the collateral damage to clearing what is perceived as an infection. The extent of of the damage to host tissue usually depends on the extent of the threat. For instance bacteria in the blood stream, even if the bacteria is not particularly harmful, will result in sepsis - widespread immune activation that progresses to loss of blood pressure, global edema, organ failure and death within hours. Viral sepsis can also occur.

      But the question about immune reaction to environmental antigens is a good one, and not one that biomedical science has a good answer for. The rate of allergies is on the rise, and correlates very well with industrialized living. A 70s french study found significantly higher rates of asthma in city raised children compared to rural children and since then this has been replicated in any number of ways. Clean living is definitely part of the problem, and it seems to have something to do with our microbiota and early childhood (children delivered by C-section, which are not immediately colonized by the mother's microbiome, have higher rates of allergies and asthma and the same goes for children who arent breastfed and therefore do not pick up bacteria from the mother's skin).

      Why specific allergies develop is also unclear. Every time we eat we introduce foreign substances into our bodies which the immune system tolerates. This is in part due to the requirement for multiple signals for immune activation, ie it is not enough for the immune system to encounter 'non-self', the encounter must also be accompanied by a signal that this is an infection - bacterial cell wall components, double stranded RNA (virus), evidence of tissue damage or cell death, and so on. The gut mucosa in particular is a 'tolerigenic' environment, rich in regulatory T cells, a type of immune cell that suppresses inappropriate immune responses and induces tolerance of antigens that don't appear to be dangerous. A few recent papers have hypothesized that food allergies (or other environmental allergies) are developed when a particularly immuno-stimulatory but otherwise benign antigen is encountered at the same time as something else that is causing tolerance to be broken.

      For instnce, if you eat pad thai, which contains eggs and peanuts, it is usually no problem. But if one day the eggs happen to be laced with invasive salmonella, then as you are processing your noodles the immune system will detect infection and the regulatory T cells will allow an immune response to mount in order to stop the bacteria. In this context, it is possible to develop a response against peanut antigen as well. Similarly, if you encounter some sort of pollen while dealing with a respiratory infection, you may develop allergy to the pollen.

      TLDR: there are mechanisms in place to prevent reaction to non-pathogenic antigens but these systems are weakened by industrialized living and can be broken if non-pathogenic antigen is encountered in the context of infection or injury.