Unraveling a novel type of severe food allergy

Allergy belongs to the chronic inflammatory diseases affecting up to 30% of the population in westernized countries where food allergy has become a substantial and evolving public health issue. In the last decade, a novel type of food allergy presenting with severe allergic reactions several hours after consumption of red meat has been described. The response is caused by IgE antibodies directed against the carbohydrate epitope galactose-α-1,3-galactose (α-Gal) found in mammalian meat.

The overall aim of this thesis was to generate new insight into the red meat allergy syndrome, scrutinizing the humoral response to α-Gal and other glycans, as well as the impact of tick bites as the sensitization route. Moreover, the influence of thermal processing on the allergenicity of beef proteins was addressed and finally the involvement of immune cells was investigated.

We showed for the first time that the α-Gal epitope is present in the European tick Ixodes ricinus, supporting previous data reporting a strong relationship between tick bites for the production of IgE to α-Gal and subsequent development of red meat allergy. All studied patients described urticaria as the dominant symptom following consumption of red meat and around half of the patients had experienced anaphylactic reactions, emphasising the severity of this novel type of food allergy. After having characterized the patients an immunoproteomic approach was utilised and seven novel α-Gal-containing beef proteins that bound IgE from red meat allergic patients were identified, where four of these proteins were stable to thermal processing. Furthermore, we showed that their IgE antibodies did not recognize the other major mammalian carbohydrate, N-glycolylneuraminic acid, or common cross-reactive carbohydrate determinants from plants and venoms. In addition, we demonstrated that these patients had a selective IgE reactivity against the α-Gal glycan structure unrelated to the whole glycoprotein. Finally we investigated the α-Gal uptake with the model α-Gal-containing antigen bovine thyroglobulin and showed that it was actively internalized by human immature monocyte derived dendritic cells in a dose and time-dependent manner. The similarity in internalization kinetics between the human and bovine thyroglobulin indicated an α-Gal- independent mechanism, presumably via macropinocytosis. After endosomal processing it was possible to specifically detect α-Gal expression on the plasma membrane derived only from bovine thyroglobulin.

The work in this thesis has contributed to increased understanding of the role of IgE antibodies to α-Gal, the allergenicity of α-Gal-containing beef proteins after thermal processing, the importance of tick bites as the primary sensitization pathway and the involvement of immune cells in this delayed allergic response. Such knowledge is vital for the improvement of current treatment strategies. However, a deeper understanding about the mechanisms behind red meat allergy syndrome is needed and warrants further studies.

List of scientific papers

I. C. Hamsten, M. Starkhammar, T.A.T. Tran, M. Johansson, U. Bengtsson, G. Ahlén, M. Sällberg, H. Grönlund & M. van Hage. ”Identification of galactose-α-1,3- galactose in the gastrointestinal tract of the tick Ixodes ricinus; possible relationship with red meat allergy.” Allergy 2013 Apr; 68(4):549-52.
https://doi.org/10.1111/all.12128

II. Carl Hamsten, Thi Anh T. Tran, Maria Starkhammar, Annelie Brauner, Scott P. Commins, Thomas A. E. Platts-Mills, Marianne van Hage. “Red meat allergy in Sweden: Association with tick sensitization and B-negative blood groups.” J Allergy Clin Immunol 2013 Dec; 132(6):1431-1434.e6.
https://doi.org/10.1016/j.jaci.2013.07.050

III. D. Apostolovic, T.A.T. Tran, C. Hamsten, M. Starkhammar, T. Cirkovic Velickovic & M. van Hage. “Immunoproteomics of processed beef proteins reveal novel galactose-α-1,3-galactose-containing allergens”. Allergy 2014 Oct; 6(10): 1308-15.
https://doi.org/10.1111/all.12462

IV. D. Apostolovic, T.A.T. Tran, S. Sánchez-Vidaurre, T. Cirkovic Velickovic, M. Starkhammar, C. Hamsten & M. van Hage. ”Red meat allergic patients have a selective IgE response to the α-Gal glycan.” Allergy 2015 Nov; 70(11):1497-500.
https://doi.org/10.1111/all.12695

V. Thi Anh Thu Tran, Jeanette Grundström, Maja Krstic, Vladana Vukojević, Danijela Apostolovic, Carl Hamsten, Guro Gafvelin & Marianne van Hage. ”In vitro uptake of α-Gal containing proteins by human monocyte derived dendritic cells”. [Manuscript]