Date of Award

Spring 2020

Document Type

Open Access Dissertation

Department

Chemistry and Biochemistry

First Advisor

Maksymilian Chruszcz

Abstract

Group 1 and 2 house dust mites (HDM) allergens elicit IgE response in more than 80% of sensitized individuals. These allergens affect 10-30% of the world’s population. Prolonged inhalation of low doses of allergens (microgram amounts inhaled over months or years) by genetically predisposed individuals leads to the induction of a Th2-type immune response induced by allergen-specific immunoglobulin E (IgE) produced by plasma cells resulting in allergic diseases like asthma, atopic dermatitis, and rhinitis. Group 1 and 2 HDM allergens, in particular, are associated with the development of the aforementioned allergic diseases. The goal of this research was to characterize properties of Group 1 and 2 HDM allergens related to their structure, function, and interactions with monoclonal antibodies (mAbs). Structural studies, specifically X-ray crystallography, were used to identify important residues responsible for antigen-antibody interactions. Protein characterization and analysis of the antigenic surface of these allergens enabled the design of allergen mutants with defined three-dimensional structure, reduced IgE reactivity, and retained T cell epitopes for production of hypoallergens to be utilized in HDM allergy immunotherapy.

Another family of allergens studied in this research were profilins. This family shares high amino acid sequence identities and similarities even between distantly related members. This sequence homology can lead to IgE cross-reactivity resulting in pollen-food syndrome. Details on protein production, thermal stability, and allergen sensitization studies in patients with pollen-food syndrome are presented herein. Understanding the vi immunological, molecular, and structural properties of profilins will demystify the clinical importance of profilins in pollen-food syndrome.

Lastly, in this research, a new robust way of predicting IgE cross-reactivity between two allergens belonging to the same protein family was developed. The A-RISC index (Allergens’–Relative Identity, Similarity and Cross-reactivity) results in a single numerical value which enables the likelihood of IgE cross-reactivity to be grouped into four categories: high, medium-high, medium-low and low. The proposed approach can facilitate analysis in component-resolved allergy diagnostics, generate avoidance guidelines for allergic individuals, and assist with the design of immunotherapy. This research will facilitate future immunotherapy, vaccine design and component-resolved allergy diagnostics in not only profilins and HDM allergies, but in all other relevant types of allergies.

Available for download on Friday, March 26, 2021

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Chemistry Commons

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