Bacteria-Induced Type 2 Immunity in Host Defense and Disease

So-called type 2 immune responses fulfill critical functions in wound healing and host defense against parasites. However, such immune responses also play a key role in allergic diseases. Allergic individuals have developed a type 2 immune response and specific immunoglobulin E (IgE) antibodies against apparently harmless environmental proteins (known as allergens). Subsequent contact with the allergen activates mast cells (MCs) via surface-bound IgE antibodies. MCs immediately respond to this stimulus with rapid release of compounds that cause allergic symptoms and, in extreme cases, anaphylaxis. Despite this powerful, even deadly potential of IgEs and MCs, the physiologic functions of this allergy module of immunity remain enigmatic. We recently showed that IgE antibodies and IgE effector cells play a critical role in type 2 immune responses that protect mice against bee and snake venoms. These results confirmed the controversial toxin hypothesis, which suggests that allergic reactions represent an important component of the host defense against noxious substances, such as toxins and venoms. IgE antibodies are not only produced in response to parasites, allergens or venoms but also during infections with certain toxin-producing bacteria. It is suggested that infections with such pathogens can increase incidence and severity of atopic diseases, such as atopic dermatitis or asthma. On a different note, antibiotics-resistant bacteria also represent a major global health problem due to the lack of effective treatment strategies and vaccines. In this project we tackle different challenges in type 2 immunity, host defense and vaccination by addressing the following questions: (1) What are the host- and pathogen components involved in type 2 immunity and IgE development upon infection with toxin-producing bacteria? (2) Can the powerful allergy module contribute to immune defense against such pathogens and could this be exploited for vaccination approaches? (3) Does bacterial skin infection influence the development of allergic asthma? We apply experimental models of bacterial infection and allergic asthma in order to address these questions. With millions of people worldwide affected by allergies and infections with antibiotic-resistant bacteria, our project has the potential to simultaneously provide critically required novel insight and treatment directions for two global health problems.

So called type 2 immune responses fulfill critical functions in wound healing and host defense against parasites. However, such immune responses also play a key role in allergic diseases. Allergic individuals have developed a type 2 immune response and specific immunoglobulin E (IgE) antibodies against apparently harmless environmental proteins (known as allergens). Subsequent contact with the allergen activates mast cells (MCs) via surface bound IgE antibodies. MCs immediately respond to this stimulus with rapid release of compounds that cause allergic symptoms and, in extreme cases, anaphylaxis. Despite this powerful, even deadly potential of IgEs and MCs, the physiologic function of this allergy module of immunity is enigmatic. We recently showed that IgE antibodies and IgE effector cells play a critical role in type 2 immune responses that protect mice against bee and snake venoms. These results confirmed the controversial toxin hypothesis, which suggests that allergic reactions represent an important component of the host defense against noxious substances, such as toxins and venoms. IgE antibodies are not only produced in response to parasites, allergens or venoms but also during infections with certain toxin-producing bacteria. It is suggested that infections with such pathogens can increase incidence and severity of allergic diseases, such as atopic dermatitis or asthma. In this project we intended to investigate the mechanisms of type 2 immunity upon bacterial infection and their importance for host defense and development of allergies. We found that skin infection with pathogenic bacteria induces IgE antibodies which recognize the bacteria. On the one hand, this immune response increased the protection against severe bacterial infection. IgE antibodies and mast cells turned out to be important for this protective effect. This means that one biological function of allergic immune responses could be immune defense against bacteria. On the other hand, the initial skin infection also led to increased risk of allergy development and more severe symptoms when allergens were are applied at the same site as the bacteria. While this part of the study is still ongoing, it seems that this effect on allergy development was mediated by a direct effect of the infection on a specific immune cell population in the bone marrow. These results indicate that allergic immune responses can fulfill beneficial biological functions that might warrant their conservation throughout evolution. However, our study also highlights the requirement for delicately balanced type 2 immunity: when confronted exclusively with a biological threat, such as a bacterial pathogen, IgE antibodies and effector cells fulfill a beneficial role and are even protective. However, when "distracted" by concomitant exposure to harmless allergens, the same immune response is misdirected and can transform into a detrimental immune response resulting in allergy.