Before sensitization to one or more allergens can be discussed, it is essential to consider the definition of “allergen” itself. In a glossary issued by the European Academy of Allergy and Clinical Immunology’s Immunotherapy Task Force, Alvarez-Cuesta
et al. defined an allergen as “a protein or glycoprotein capable of binding immunoglobulin E (IgE)” [
13]. A biochemist would consider that an allergen is a protein (such as Der p 1 or Der p 2, the major allergens from
Dermatophagoides pteronyssinus) with a defined amino acid sequence and three-dimensional structure. Even then, the Der p 1 produced by
D. pteronyssinus is composed of several variant proteins with slight differences in the amino- acid sequence or with other small (post-translational) modifications [
14]. Ultimately, one must consider antigenic determinants or epitopes – unique, localized regions on the solvent-accessible surface of an antigen that are capable of eliciting an immune response (and subsequently binding IgE). This distinction explains why cross-sensitization and co-sensitization (as discussed below) have different molecular bases and frequencies of occurrence. In 2004, Ferreira
et al. proposed the definitions of “cross-reactivity”, “co-sensitization” and “co-recognition” [
15]. They noted that allergen cross-reactivity is essentially related to similar protein three-dimensional structures and occurs when IgE antibodies are originally raised against one allergen and then bind to a similar protein in another allergen; this is also referred to as “cross-sensitization” in the literature. In general, more than 70% amino acid sequence identity is required for cross-reactivity. The authors listed 28 major groups of cross-reactive proteins from various sources, and stated that the interaction of serum specific IgEs (ssIgEs) with a cross-reactive, homologous protein may or may not trigger allergic reactions, depending on host factors, the allergen in question and the nature of the exposure. In the case of pollen allergy, if the patient does not have clear clinical symptoms related to a specific pollen period, it is impossible to know which of the two or more cross-reactive proteins the patient was first exposed to. Hence, Ferreira
et al. suggested that the term “co-recognition” could define the great majority of IgE reactivity reactions in which the initial sensitizer is not known. They used the term “co-sensitization” to describe multiple, unrelated sensitizations to several structurally unrelated allergen groups. The structural basis of cross-reactivity was recently confirmed by Pfiffner
et al. [
16] in a micro-array study; 3,143 serum samples were tested to see whether they contained IgE that bound to any of 103 highly purified natural or recombinant allergens immobilized on the array. The researchers confirmed the previous cross-reactivity data from conventional IgE assays and reported predictions of cross-reactivity based on an iterative, motif detection algorithm. They hypothesized that cross-reaction (i.e. a single type of IgE binding to two or more related motifs) was more common than co-sensitization (i.e. separate IgEs each binding to different motifs). They also described a “hierarchy” of allergens within motif groups and speculated that this might influence the choice of AIT formulation. These observations also raised the issue of whether AIT should employ the most frequently cross-reacting allergen or an allergen that most stringently cross-reacted with other allergens.
The term “co-recognition” (for IgE reactivity reactions in which the initial sensitizer is not known) will typically apply to the particular case of panallergens [
17]. These are groups of evolutionarily conserved proteins found in many different plant genera and that present a very high degree of molecular homology. Essentially, each member of a panallergen family is co-recognized with each other member. The best-known panallergens are the profilin proteins, the polcalcin calcium transport proteins, the lipid transfer proteins and tropomyosin [
17]. Although these panallergens are not highly abundant, the high degree of homology can confound diagnoses. For example, the ssIgE against the profilin Phl p 12 in subjects with grass pollen allergy can also bind to Hev b 8 from latex extract – though this is not associated with clinically relevant latex allergy [
18]. Non-protein molecules can also induce IgE-driven cross-reactivity; cross-reactive carbohydrate determinants are glycoprotein-borne asparagine-linked oligosaccharides that can variously be found in insect venoms, plant pollens, mites, crustaceans and vegetables [
19].
Strictly, “polysensitization” means “more than one sensitization”, i.e. anything other than monosensitization. However, we note that de Jong
et al. proposed to use the term “paucisensitization” to describe 2 to 4 sensitizations and “polysensitization” to describe 5 or more sensitizations [
20]. Although this distinction may be relevant for certain clinical studies, only a small proportion of patients consulting allergists will be sensitized to 5 or more allergens, and we consider that “monosensitization” and “polysensitization” are sufficient for clinical use.
In summary, polysensitization can be divided into (i) cross-reactivity/cross-sensitization (the same IgE binds to several different allergens with common structural features) and (ii) co-sensitization (the simultaneous presence of different IgEs that bind to allergens that may not necessarily have common structural features). These relationships will be of importance when considering component-based diagnostics (CRD). Our definitions of polysensitization, paucisensitization, co-sensitization, co-recognition, cross-reactivity/cross-sensitization and polyallergy are given in Table
1.
Table 1
Summary of definitions
Polysensitization | Sensitization (as confirmed by SPTs or ssIgE assays) to two or more allergens |
Paucisensitization | Polysensitization (as confirmed by specific SPTs or ssIgE assays) to between two and four allergens. |
Co-sensitization, | IgE reactivity reactions in which multiple, unrelated sensitizations arise against structurally unrelated allergen groups. |
Cross-sensitization/cross-reactivity, | IgE reactivity reactions in which IgE antibodies are originally raised against one allergen and then bind to a similar protein in another allergen |
Co-recognition | A subset of cross-sensitization/cross-reactivity reactions in which the initial sensitizer is not known. |
Polyallergy | Clinically confirmed allergy (i.e. specific sensitization in SPTs or ssIgE assays and a causal relationship between symptoms and exposure to a specific allergen) to two or more allergens |