Trained immunity and allergy: State of the art and future perspectives
Authors: Lizzy Wanka, Uta Jappe
Journal: Allergy (2020)

To the Editor, Allergic diseases have become a global challenge during the last decades. Therefore, much effort has gone into understanding the mechanisms of allergy and improving diagnostic measures and treatment efficacy (precision medicine). Recently, the mechanistic understanding of immunity and its characteristics was considerably renewed by the upcoming research field of "trained immunity," where the classical principle that only the adaptive immune system is able to build up a memory to reinfection with pathogens was re-thought.1 Netea et al defined "trained immunity" as a reaction to a pathogenic insult ("first hit"), including environmental factors, microbial proteins, and allergens, with subsequent epigenetic, metabolic, and functional reprogramming of innate immune cells, resulting in a nonspecific, modulated response to secondary stimuli ("second hit"). The concept of an innate immune memory explains why an "immunological memory" is even observed in plants and invertebrates, organisms lacking adaptive immunity.1, 2 As described several times for the tuberculosis vaccine bacillus Calmette-Guérin (BCG), trained immunity also explains cross-protection, a heightened response to a second infection, whereby it is independent whether this occurs to the same pathogen or a different one.1, 2 This nonspecific immune response seems unlikely for the classical highly specific allergic response; however, helminth3 and virus infections4 have been shown to affect both tolerance and the increased risk of reactions to allergens. Figure 1 displays an overview on the different aspects of trained immunity and where this concept is linked to allergy. Both a systemic and a local trained immunity exist: Systemic trained immunity is induced at the level of bone marrow progenitor cells due to stimulation of these cells with BCG or the microbial β-glucan. The trained progenitor cells mature to monocytes and differentiate to trained effector cells such as macrophages or NK cells at their respective place of action.2 In contrast, local training of differentiated effector cells takes place in the peripheral tissue. Here, epithelial cells form the first line of defense, but this barrier can be overcome/activated by allergens and microbial products and is key to allergenic sensitization. Several allergens possess proteolytic activity and are able to cleave tight junctions and consequently provide a way through the epithelial layer.5 Der p 2 mimics the myeloid differentiation protein-2 by binding LPS, which stimulates the Toll-like receptor 4 at the surface of epithelial cells and induces an TH2-like inflammation.5 The paradigm that an allergen alone cannot overcome the epithelial barrier without enzymatic function or adjuvants was overthrown by the demonstration that grass pollen allergens were taken up by airway epithelial cells and were transported as intact allergens through the epithelium.5 Besides allergens, also microbial products can overcome/activate the epithelium, for example β-glucan for which trained immunity effects have explicitly been observed.1, 2 Whether this activation of epithelial cells already fits the trained immunity characteristic of a change in cell function will be part of future research. Finally, environmental factors or respiratory diseases can increase the permeability of the epithelial barrier for allergens.5 The presence of a broad range of cytokines, chemokines, allergens, and microbial products mediates complex cellular processes with innate and adaptive immune cells. The cytokines thymic stromal lymphopoietin (TSLP), IL-25, and IL-33 were shown to induce trained immunity6 and are also involved in the development of allergic responses. TSLP and IL-33 are important for the activation of group 2 innate lymphoid cells (ILC2s) which secrete IL-4, IL-5, and IL-13. IL-4 triggers the TH2 immune response, and IL-5 is involved in the activation of B cells and mediates eosinophilia, whereas IL-13 induces mucus secretion and airway hyperreactivity. ILC2s were found to be sufficient to induce asthma-like pathological changes even in the absence of adaptive immune cells, and trained ILC2s show enhanced secretion of TH2-type cytokines after re-stimulation.7 Thus, ILC2s may have an enormous impact on the development of allergy, and TH2-type allergic airway inflammation can develop independently of adaptive immunity. A second example therefore is the activation of an invariant NKT cell subpopulation after viral infection, subsequently recruiting and activating lung macrophages, expressing IL-13 and its receptor. This creates a positive feedback loop which results in a persistent expression of IL-13, causing chronic mucous cell metaplasia and airway hyperreactivity.8 The persistent expression of cytokines displays no trained immunity effect by definition but leads to chronification of the inflammation process. A new link between the two immune systems where the adaptive immune system activates the innate immune memory was described after a viral infection, inducing trained alveolar macrophages with changed metabolism and anti-microbial responsiveness.9 The education of these macrophages required activated CD8+ T cells and the release of interferon γ. This and other described effects of trained immunity are mediated through modulation of transcription factors and metabolic as well as epigenetic reprogramming of cells in contrast to gene rearrangement and proliferation of antigen-specific lymphocyte clones, forming the base for adaptive immune memory.1 Altogether, Figure 1 illustrates that there are innate immune cells which developed a memory effect without having changed their original function or which modulate/are modulated by the adaptive immune system and thus are not part of the trained immunity concept even when they differ considerably from the classical understanding of innate immune responses. Little is known about the existence or mechanisms of allergic trained immunity but pathological outcomes of trained immunity were already shown for inflammatory and neurodegenerative diseases,2 and there is some evidence that this research field will reveal several well-guarded secrets about allergenic processes. Most likely, the allergic response is a highly regulated and complex mechanism with members of both, the innate and adaptive immune system, and this link is maybe also the key feature of very potent allergens. However, since an association between infections and allergy has been known for quite some time, it is most plausible that phenomena of innate immune memory observed for infections are also active in the development of allergy. First, in vitro studies could show how different innate immune cells react to allergen stimulation after training with pathogens and in vivo experiments with allergic mouse models after stimulation with pathogens/vaccines might support these investigations. Prof. Jappe reports grants and personal fees from Federal Ministry of Education and Science, German Center for Lung Research, during the conduct of the study. The authors gratefully acknowledge the funding of the Federal Ministry of Education and Research [German Center for Lung Research (DZL)]. 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