Pointner et al. Clin Transl Allergy (2020) 10:36 https://doi.org/10.1186/s13601-020-00341-y Clinical and Translational Allergy REVIEW Open Access Initiating pollen sensitization – complex source, complex mechanisms Lisa Pointner1, Athanasios Bethanis1, Michael Thaler1, Claudia Traidl‑Hofmann2,3, Stefanie Gilles2, Fatima Ferreira1* and Lorenz Aglas1* Abstract The mechanisms involved in the induction of allergic sensitization by pollen are not fully understood. Within the last few decades, fndings from epidemiological and experimental studies support the notion that allergic sensitization is not only dependent on the genetics of the host and environmental factors, but also on intrinsic features of the aller‑ genic source itself. In this review, we summarize the current concepts and newest advances in research focusing on the initial mechanisms inducing pollen sensitization. Pollen allergens are embedded in a complex and heterogeneous matrix composed of a myriad of bioactive molecules that are co‑delivered during the allergic sensitization. Surpris‑ ingly, several purifed allergens were shown to lack inherent sensitizing potential. Thus, growing evidence supports an essential role of pollen‑derived components co‑delivered with the allergens in the initiation of allergic sensitiza‑ tion. The pollen matrix, which is composed by intrinsic molecules (e.g. proteins, metabolites, lipids, carbohydrates) and extrinsic compounds (e.g. viruses, particles from air pollutants, pollen‑linked microbiome), provide a specifc context for the allergen and has been proposed as a determinant of Th2 polarization. In addition, the involvement of various pattern recognition receptors (PRRs), secreted alarmins, innate immune cells, and the dependency of DCs in driving pollen‑induced Th2 infammatory processes suggest that allergic sensitization to pollen most likely results from particular combinations of pollen‑specifc signals rather than from a common determinant of allergenicity. The exact identifcation and characterization of such pollen‑derived Th2‑polarizing molecules should provide mecha‑ nistic insights into Th2 polarization and pave the way for novel preventive and therapeutic strategies against pollen allergies. Keywords: Allergy, Pollen, Sensitization, Allergens, Th2 polarization, Alarmins, Adjuvants, IL‑4, Innate immunity, Dendritic cells Background where the humid milieu facilitates the release of soluble Worldwide, the sensitisation rate to pollen allergens is allergens and other co-delivered bioactive compounds around 40% and over 400 million people sufer from from the pollen matrix. Among wind-pollinated plants, allergic rhinitis symptoms caused by pollinosis [1–4]. the four plant families Oleaceae, Poaceae, Asteraceae Wind plays a key role in the induction of pollen sen- and Betulaceae represent the main sources of allergenic sitization enabling the direct contact of pollen with pollen in Europe [5, 6]. Up to now, 987 diferent aller- the human immune system at sites such as the upper gens have been ofcially described, of which 195 are respiratory tract, the ocular and oral mucosal surfaces, registered as plant-derived airborne allergens (https :// www.aller gen.org, 1st April 2020). Besides triggering seasonal rhinoconjunctivitis symptoms, a clinical con- *Correspondence: [email protected]; [email protected] 1 Department of Biosciences, University of Salzburg, Hellbrunnerstraße. dition also known as “hay fever”, pollen can also cause 34, 5020 Salzburg, Austria asthma, skin infammation, and even food allergies Full list of author information is available at the end of the article due to structural homology of food antigens to some © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/ zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Pointner et al. Clin Transl Allergy (2020) 10:36 Page 2 of 18 pollen allergens [7–14]. Te rising numbers of pollen- Factors contributing to allergic sensitization afected individuals, the variety of symptoms and the Allergy is generally considered a multifactorial disease, impact on the patients´ quality of life are making pollen but the individual factors and their respective contri- allergies a vast and serious socio-economic burden of bution to sensitization are not yet fully defned. Te Western civilization [15]. In this respect, it is of utmost prevalence of allergic diseases has been associated with importance to understand the underlying mechanisms a westernized lifestyle—the so-called hygiene hypoth- of sensitization to pollen allergens in order to develop esis—but also with environmental and genetic factors. innovative therapeutic strategies to efciently tackle Linkage analysis studies have already revealed allergy- pollinosis. Te scope of this review is to summarize relevant loci, while genome-wide association stud- the current concepts and newest advances in research ies hold the promise for new and reproducible genetic focusing on pollen sensitization. associations with allergic diseases [36]. However, given the multifactorial nature and heterogeneous manifesta- tion of allergic phenotypes, the integration of genetic Current concepts of allergic sensitization predisposition data into a coherent picture remains Exposure to environmental proteins does not normally challenging. trigger an immune response due to their non-pathogenic Te hygiene hypothesis by Strachan, which has been nature, yet allergic sensitization to pollen molecules is a redefned and updated over the years with the continu- global health problem. Allergies are thus considered type ous emergence of new data, presently postulates that 1 (IgE-mediated) hypersensitivity reactions to innocuous several variables associated with a westernized lifestyle, environmental antigens that is characterized by an imbal- such as diminished exposure to microbes, environmental anced immune response [16, 17]. changes, medication, diet, parasitic infections and oth- ers, infuence the susceptibility of the immune system to allergic diseases [37–40]. For instance, in contrast to life IgE‑mediated allergic immune response in urbanized cities and poor nutrition, growing up near In type 1 hypersensitivity reactions, antigen-presenting farms and fbre-rich nutrition were classed as benefcial cells (APCs), mainly dendritic cells (DCs), control the factors leading to immune tolerance [41]. While it is well diferentiation of naïve T helper cells into efector T known that environmental stimuli are directly linked to cells, such as T1 or T2 cells, depending on the nature epigenetic modifcations, the feld has been understudied and source of the antigen [17, 18]. Upon initial allergen in regard to allergic diseases [42]. In summary, experi- encounter, T2 polarization, a hallmark of allergic sen- mental and epidemiological fndings within the last few sitization, is triggered by interleukin 4 (IL-4) signalling decades support the view that the allergic sensitization and characterized by the secretion of T2-associated process is not solely dependent on the genetics of the cytokines (IL-4, IL-5 and IL-13) [19]. While IL-4 has a host and environmental factors, but also on intrinsic key role in the initiation of sensitization, IL-5 and IL-13 features of the allergenic source itself. In addition, epi- are relevant in later stages of the sensitization process genetic mechanisms might contribute to the initiation of as well as the efector phase. IL-5 is mainly involved in sensitization and maintenance of allergic diseases [43]. airway eosinophilia and hyperresponsiveness, whereas IL-13 mainly contributes to the maintenance of allergic disease by recruiting and activating various efector cells Initiation of sensitization by allergenic pollen to the site of allergic infammation [20, 21]. Upon activa- The activation of the innate immune system tion by T2 cytokines, B cells undergo class-switching to Besides the known adaptive immunity components produce antigen-specifc immunoglobulin E (IgE) anti- involved in allergic sensitization, a superordinate role can bodies, which prime mast cells and basophils by binding be allocated to the epithelium itself since it represents to its high afnity receptor FcεRI. Allergic sensitization is the primary contact site of the human body encounter- defned by the presence of allergen-specifc IgE. Upon re- ing the pollen. Whether sensitization to pollen-derived exposure, allergen-IgE cross-linking causes cell degranu- allergens occurs at the oral mucosa, the olfactory or cor- lation and release of infammatory mediators within neal epithelium is still a matter of debate;