5.2.1 Quick Review… What Is an Antigen? And What Is an Allergen?

An antigen is a substance, most commonly a protein or polysaccharide, that causes the body to produce an antibody. The part of the antigen that is recognized by the body’s immune system is the epitope. The paratope is the part of the antibody that recognizes the antigen epitope. The epitope-paratope configuration that occurs upon antigen-antibody recognition is a unique three-dimensional lock-and-key formation. Of note, some epitopes from different antigens may be sufficiently similar in structure to bind the same antibody paratope; this results in cross-reactivity. An allergen is antigen that specifically triggers the allergic cascade; an allergen epitope binds paratopes on immunoglobulin E (IgE) molecules.

5.2.2 Tell Me a Bit More About Allergens… Please?

Substances containing allergenic proteins and polysaccharides are frequently complex biological constructs (e.g., pollen spores), and they often contain multiple proteins with varied epitopes. Certain allergens are identified as more important than the others. A major allergen is an antigenic fraction to which at least 50% of patients are sensitive per in vitro or in vivo testing. A minor allergen causes less than 50% of patients to react. For example, the major allergen in cat dander extract is Fel d 1, but the extract can contain multiple minor allergens as well. Understandably, patients will vary in their reactivity to major and minor allergens. Multiple major allergens have been identified and are noted throughout this and other inhalant allergen chapters.

A vial of allergen extract contains multiple components including the major and minor allergens themselves, as well as inert proteins and extract solution. Most nonstandardized extracts are preserved in a 50% glycerin solution ± 0.4% phenol. Extracts will deteriorate over time with a typical shelf life of ≤ 3 years at 4 °C.

5.2.3 What Are Standardized and Nonstandardized Allergen Extracts?

For the most part, allergy extracts have been only roughly quantified, although more strict standardization is evolving. Nonstandardized quantification schemes include allergen units (Noon units, 1 unit of pollen toxin from 1,000th part of 1 mg Phleum pollen), protein nitrogen units (PNU, 0.01 µg of phosphotungstic acid-precipitable protein nitrogen), and weight per volume (W/V). The last method is the most commonly used method: the weight (grams) of dry allergen in a volume (100 mL) of solution. Bioequivalence will be roughly maintained within a company through consistent manufacturing, but significant variation will exist between manufacturers.

Standardized extracts date back to 1981 and are extracts which have been tested to be equivalent to a recognized reference. The Food and Drug Administration (FDA) produces a reference standard and manufacturers compare their product lot with this standard. If a sample’s activity is between 70% and 140% of the reference standard then the lot passes and is designated the same bioequivalent allergy unit (BAU) concentration as the standard. Multiple standardization methods exist. Grass allergens are standardized via radioallergosorbent (RAST) or enzyme-linked immunosorbent assay (ELISA) inhibition. Standards for dust mite are referenced using three fold dilutions, similar to the five-fold dilutions used for intradermal dilutional testing, although erythema size, not wheal, is measured. Cat is standardized by assaying major allergen content (Fel d 1). If a standardized allergen exists, then it is best to use the standardized allergen instead of its W/V quantified option; the bioactivity across lots and manufacturers is more consistent and hence safer. Standardized extracts are quantified in allergy units (AU) for dust mites, BAUs for some allergens (e.g., cat, grasses), or major allergen content in micrograms (e.g., short ragweed Amb a1). Some of the current standardized allergens licensed within the United States are discussed throughout this and other inhalant allergen chapters.

5.2.4 What Is Cross-Reactivity?

Cross-reactivity is a concept that must be understood to fully appreciate the complexities of allergy management. As many plants share a common evolutionary history, their allergens (and epitopes) will be conserved or minimally changed between species. Cross-reactivity increases with the closeness of the biologic relationship: order → family → (tribe within a family) → genus → species (the latter are most closely related). Cross-reactivity between intimately related species is common. Hence the body may react to two different pollinating species of plant interchangeably as the “lock and key” of antigen to IgE (epitope to paratope) molecule is similar. When an individual reacts similarly to different species, these species are described as being cross-reactive. In general, grasses tend to have the most cross-reactivity, weeds to a lesser degree, and trees possess the least cross-reactivity. Cross-reactivity can also occur between unrelated inhalants, and between foods and inhalants, if they happen to contain similar epitopes. An example is orally ingested apples and inhaled birch pollen that contain similar epitopes; a birch-sensitive patient can develop oral itching/swelling (oral allergy syndrome) from eating apples.