Introduction
The fungal kingdom comprises ubiquitous heterotrophic eukaryotes, specialized in the decomposition of organic material and recycling (1) and with possible symbiosis interactions among fungi or with other organisms, e.g. with algi in lichens or with plants in mycorrhiza. The systematic in fungi is complex, but recent genomic technologies have allowed to improve their phylogenetic tree. Some of them are macroscopic, e.g. edible mushrooms, while others belong to microorganisms (1) and are the focus of this review. Their ubiquity and diversity reflect those of the living world: spores of several fungal species have been detected from samples collected in arctic or desert areas (2), and the number of fungal species has been estimated at 3,8 million (3), being today much of them still unknown. Humans are thus exposed to fungi each day during their entire lifetime.
Fungi evolved to feed on virtually every complex molecule in any ecological niche, reducing it to simple units able to re-enter the nutrition chains. In doing so, fungi selected an evolutionary pathway characterized by complexity and mobility, through the efficient use of multiple developmental stages and enzyme secretion in the environment. Fungi do not ingest the organisms they are feeding upon, but release lytic enzymes able to process macromolecules into small nutrients. Ingested nutrients allow fungal growth and the production of mobile, airborne forms conveyed to new locations. Leftovers like secreted components and previous developmental forms persist in the environment, explaining the ubiquity and abundance of fungal components.
Although fungi bear pathogen-associated molecular patterns (PAMPs), ligands for innate immune pattern recognition receptors (PRRs), most interactions between fungi and the human host do not result in disease. Instead, a fungal disease usually manifests in susceptible hosts. Infection is associated with immune deficiency, while hypersensitivity occurs mainly in atopic patients (4,5). Some papers have shown that, depending on the ability of a given fungus to grow at human body temperature (thermotolerant fungus able to grow in the airways resulting in fungal colonization) or not (mesophilic), the pathogenic threat posed to the human host is either both infectious and allergic, or allergic only. Typical examples of medically important thermotolerant fungi areAspergillus fumigatus and Candida albicans , whileAlternaria alternata and Cladosporium herbarum are typically mesophilic (6).
The third form of the fungi-related disease is caused by mycotoxins, small molecules produced by fungi as means to secure their feeding environment. Mycotoxins are potentially harmful when they are ingested from contaminated stored foods. As opposed to diseases related to airborne fungal forms, mycotoxin exposure other than through ingestion is not considered causal for mycotoxin-related diseases (7).
However, fungal antigens are characterized by intra-kingdom specificity, with a relation between the fungal systematics and IgE sensitization pattern (7). Many fungal proteins have evolved for specific functions associated with heterotroph nutrition. The degree of homology reflects phylogenetic distance (8). There is extensive cross-recognition of fungal antigens, contributing to clinical cross-reactivity manifested as hypersensitivity symptoms related to exposure to various fungi, and biological cross-reactivity when skin or laboratory tests are performed for fungi-specific immunoglobulins. Cross-reactivity between fungi and organisms from other domains of life is limited. A prominent exception is chitin, a carbohydrate component of the fungal cell wall, but also of insect and arachnid (house dust mites, crustaceans) exoskeleton (7,9). However, other examples of medically relevant cross-reactivity exist,e.g . between the skin fungus Malassezia (M.) sympodialisand human host proteins (10).
Fungal taxonomy is complex and still evolving, but the main allergenic genera and species belong to three of the ten fungal phyla currently described: Ascomycota (comprising Candida, Alternaria, Aspergillus, Penicillium, Trichophyton , among other genera),Basidiomycota (e.g . Rhodotorula, Ustilago ), andMucoromycota (classified until recently as part of the former phylum Zygomycota) (e.g . Mucor ) (11,12) (Table 1 ). Inside each phylum, phylogenetic relationship explains allergen cross-reactivity at the level of genera and species (8). The following sections bring further detail to these topics.