Today, in vivo allergy diagnosis and allergen-specific immunotherapy (AIT) are still based on allergen extracts obtained from natural allergen sources. Several studies analyzing the composition of natural allergen extracts have shown severe problems regarding their quality such as the presence of undefined nonallergenic materials, contaminants as well as high variabilities regarding contents and biological activity of individual allergens. Despite the increasing availability of sophisticated analytical technologies, these problems cannot be overcome because they are inherent to allergen sources and methods of extract production. For in vitro allergy diagnosis problems related to natural allergen extracts have been largely overcome by the implementation of recombinant allergen molecules that are defined regarding purity and biological activity. However, no such advances have been made for allergen preparations to be used in vivo for diagnosis and therapy. No clinical studies have been performed for allergen extracts available for in vivo allergy diagnosis that document safety, sensitivity, and specificity of the products. Only for very few therapeutic allergen extracts state-of-the-art clinical studies have been performed that provide evidence for safety and efficacy. In this article, we discuss problems related to the inconsistent quality of products based on natural allergen extracts and share our observations that most of the products available for in vivo diagnosis and AIT do not meet the international standards for medicinal products. We argue that a replacement of natural allergen extracts by defined recombinantly produced allergen molecules and/or mixtures thereof may be the only way to guarantee the supply of clinicians with state-of-the-art medicinal products for in vivo diagnosis and treatment of allergic patients in the future.

Purpose of review: More than 30 years ago, the first molecular structures of allergens were elucidated and defined recombinant allergens became available. We review the state of the art regarding molecular AIT with the goal to understand why progress in this field has been slow, although there is huge potential for treatment and allergen-specific prevention.Recent findings: On the basis of allergen structures, several AIT strategies have been developed and were advanced into clinical evaluation. In clinical AIT trials, promising results were obtained with recombinant and synthetic allergen derivatives inducing allergen-specific IgG antibodies, which interfered with allergen recognition by IgE whereas clinical efficacy could not yet be demonstrated for approaches targeting only allergen-specific T-cell responses. Available data suggest that molecular AIT strategies have many advantages over allergen extract-based AIT.Summary: Clinical studies indicate that recombinant allergen-based AIT vaccines, which are superior to existing allergen extract-based AIT can be developed for respiratory, food and venom allergy. Allergen-specific preventive strategies based on recombinant allergen-based vaccine approaches and induction of T-cell tolerance are on the horizon and hold promise that allergy can be prevented. However, progress is limited by lack of resources needed for clinical studies, which are necessary for the development of these innovative strategies.

Immunoglobulin E (IgE)-associated allergy is the most common immunologically-mediated hypersensensitivity disease. It is based on the production of IgE antibodies and T cell responses against per se innocuous antigens (i.e., allergens) and subsequent allergen-induced inflammation in genetically pre-disposed individuals. While allergen exposure in sensitized subjects mainly boosts IgE production and T cell activation, successful allergen-specific immunotherapy (AIT) induces the production of allergen-specific IgG antibodies and reduces T cell activity. Under both circumstances, the resulting allergen-antibody complexes play a major role in modulating secondary allergen-specific immune responses: Allergen-IgE complexes induce mast cell and basophil activation and perpetuate allergen-specific T cell responses via presentation of allergen by allergen presenting cells to T cells, a process called IgE-facilitated antigen presentation (FAP). In addition, they may induce activation of IgE memory B cells. Allergen-induced production of specific IgGs usually exerts ameliorating effects but under certain circumstances may also contribute to exacerbation. Allergen-specific IgG antibodies induced by AIT which compete with IgE for allergen binding (i.e., blocking IgG) inhibit formation of IgE-allergen complexes and reduce activation of effector cells, B cells and indirectly T cells as FAP is prevented. Experimental data provide evidence that by binding of allergen-specific IgG to epitopes different from those recognized by IgE, allergen-specific IgG may enhance IgE-mediated activation of mast cells, basophils and allergen-specific IgE⁺ B cells. In this review we provide an overview about the role of allergen-specific antibodies in regulating secondary allergen-specific immune responses.

Background: The nature of epitopes on Bet v 1 recognized by natural IgG antibodies of birch pollen allergic patients and birch pollen‐exposed but non‐sensitized subjects has not been studied in detail.Objective: To investigate IgE and IgG recognition of Bet v 1 and to study the effects of natural Bet v 1‐specific IgG antibodies on IgE recognition of Bet v 1 and Bet v 1‐induced basophil activation.Methods: Sera from birch pollen allergic patients (BPA, n = 76), allergic patients without birch pollen allergy (NBPA, n = 40) and non‐allergic individuals (NA, n = 48) were tested for IgE, IgG as well as IgG₁ and IgG₄ reactivity to folded recombinant Bet v 1, two unfolded recombinant Bet v 1 fragments comprising the N‐terminal (F1) and C‐terminal half of Bet v 1 (F2) and unfolded peptides spanning the corresponding sequences of Bet v 1 and the apple allergen Mal d 1 by ELISA or micro‐array analysis. The ability of Bet v 1‐specific serum antibodies from non‐allergic subjects to inhibit allergic patients IgE or IgG binding to rBet v 1 or to unfolded Bet v 1‐derivatives was assessed by competition ELISAs. Furthermore, the ability of serum antibodies from allergic and non‐allergic subjects to modulate Bet v 1‐induced basophil activation was investigated using rat basophilic leukaemia cells expressing the human FcεRI which had been loaded with IgE from BPA patients.Results: IgE antibodies from BPA patients react almost exclusively with conformational epitopes whereas IgG, IgG₁ and IgG₄ antibodies from BPA, NBPA and NA subjects recognize mainly unfolded and sequential epitopes. IgG competition studies show that IgG specific for unfolded/sequential Bet v 1 epitopes is not inhibited by folded Bet v 1 and hence the latter seem to represent cryptic epitopes. IgG reactivity to Bet v 1 peptides did not correlate with IgG reactivity to the corresponding Mal d 1 peptides and therefore does not seem to be a result of primary sensitization to PR10 allergen‐containing food. Natural Bet v 1‐specific IgG antibodies inhibited IgE binding to Bet v 1 only poorly and could even enhance Bet v 1‐specific basophil activation.Conclusion: IgE and IgG antibodies from BPA patients and birch pollen‐exposed non‐sensitized subjects recognize different epitopes. These findings explain why natural allergen‐specific IgG do not protect against allergic symptoms and suggest that allergen‐specific IgE and IgG have different clonal origin.

Scombroid food poisoning (SFP) is a foodborne disease that develops after consumption of fresh fish and, rarely, seafood that has fine organoleptic characteristics but contains a large amount of exogenous histamine. SFP, like other food pseudo-allergic reactions (FPA), is a disorder that is clinically identical to allergic reactions type I, but there are many differences in their pathogenesis. To date, SFP has been widespread throughout the world and is an urgent problem, although exact epidemiological data on incidence varies greatly. The need to distinguish SFP from true IgE-associated allergy to fish and seafood is one of the most difficult examples of the differential diagnosis of allergic conditions. The most important difference is the absence of an IgE response in SFP. The pathogenesis of SFP includes a complex system of interactions between the body and chemical triggers such as exogenous histamine, other biogenic amines, cis-urocanic acid, salicylates, and other histamine liberators. Because of the wide range of molecular pathways involved in this process, it is critical to understand their differences. This may help predict and prevent poor outcomes in patients and contribute to the development of adequate hygienic rules and regulations for seafood product safety. Despite the vast and lengthy history of research on SFP mechanisms, there are still many blank spots in our understanding of this condition. The goals of this review are to differentiate various molecular mechanisms of SFP and describe methods of hygienic regulation of some biogenic amines that influence the concentration of histamine in the human body and play an important role in the mechanism of SFP.