Natural Human Bet V 1-specific IgG Antibodies Recognize Non-conformational Epitopes Whereas IgE Reacts with Conformational Epitopes

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 IgG and IgG 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, IgG and IgG 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.

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References

Brazhnikov G, Smolnikov E, Litovkina A, Jiang T, Shatilov A, Tulaeva I . Natural human Bet v 1-specific IgG antibodies recognize non-conformational epitopes whereas IgE reacts with conformational epitopes. Allergy. 2023; 78(12):3136-3153. PMC: 10952721. DOI: 10.1111/all.15865. View

Akdis C, Blesken T, Wymann D, Akdis M, Blaser K . Differential regulation of human T cell cytokine patterns and IgE and IgG4 responses by conformational antigen variants. Eur J Immunol. 1998; 28(3):914-25. DOI: 10.1002/(SICI)1521-4141(199803)28:03<914::AID-IMMU914>3.0.CO;2-C. View

Shamji M, Kappen J, Akdis M, Jensen-Jarolim E, Knol E, Kleine-Tebbe J . Biomarkers for monitoring clinical efficacy of allergen immunotherapy for allergic rhinoconjunctivitis and allergic asthma: an EAACI Position Paper. Allergy. 2017; 72(8):1156-1173. DOI: 10.1111/all.13138. View

Ogulur I, Pat Y, Ardicli O, Barletta E, Cevhertas L, Fernandez-Santamaria R . Advances and highlights in biomarkers of allergic diseases. Allergy. 2021; 76(12):3659-3686. PMC: 9292545. DOI: 10.1111/all.15089. View

Shamji M, Singh I, Layhadi J, Ito C, Karamani A, Kouser L . Passive Prophylactic Administration with a Single Dose of Anti-Fel d 1 Monoclonal Antibodies REGN1908-1909 in Cat Allergen-induced Allergic Rhinitis: A Randomized, Double-Blind, Placebo-controlled Clinical Trial. Am J Respir Crit Care Med. 2021; 204(1):23-33. PMC: 8437124. DOI: 10.1164/rccm.202011-4107OC. View

Hales B, Chai L, Hazell L, Elliot C, Stone S, ONeil S . IgE and IgG binding patterns and T-cell recognition of Fel d 1 and non-Fel d 1 cat allergens. J Allergy Clin Immunol Pract. 2014; 1(6):656-65.e1-5. DOI: 10.1016/j.jaip.2013.08.008. View

Marsh D, Bias W, Hsu S, GOODFRIEND L . Association of the HL-A7 cross-reacting group with a specific reaginic antibody response in allergic man. Science. 1973; 179(4074):691-3. DOI: 10.1126/science.179.4074.691. View

Curin M, Huang H, Garmatiuk T, Gutfreund S, Resch-Marat Y, Chen K . IgE Epitopes of the House Dust Mite Allergen Der p 7 Are Mainly Discontinuous and Conformational. Front Immunol. 2021; 12:687294. PMC: 8241568. DOI: 10.3389/fimmu.2021.687294. View

Asher M, Keil U, Anderson H, Beasley R, Crane J, Martinez F . International Study of Asthma and Allergies in Childhood (ISAAC): rationale and methods. Eur Respir J. 1995; 8(3):483-91. DOI: 10.1183/09031936.95.08030483. View

10.

Focke M, Linhart B, Hartl A, Wiedermann U, Sperr W, Valent P . Non-anaphylactic surface-exposed peptides of the major birch pollen allergen, Bet v 1, for preventive vaccination. Clin Exp Allergy. 2004; 34(10):1525-33. DOI: 10.1111/j.1365-2222.2004.02081.x. View

11.

Cooke R, Barnard J, HEBALD S, STULL A . SEROLOGICAL EVIDENCE OF IMMUNITY WITH COEXISTING SENSITIZATION IN A TYPE OF HUMAN ALLERGY (HAY FEVER). J Exp Med. 2009; 62(6):733-50. PMC: 2133309. DOI: 10.1084/jem.62.6.733. View

12.

Lupinek C, Wollmann E, Baar A, Banerjee S, Breiteneder H, Broecker B . Advances in allergen-microarray technology for diagnosis and monitoring of allergy: the MeDALL allergen-chip. Methods. 2013; 66(1):106-19. PMC: 4687054. DOI: 10.1016/j.ymeth.2013.10.008. View

13.

Visco V, Dolecek C, Denepoux S, Le Mao J, Guret C, Rousset F . Human IgG monoclonal antibodies that modulate the binding of specific IgE to birch pollen Bet v 1. J Immunol. 1996; 157(2):956-62. View

14.

Laffer S, Vangelista L, Steinberger P, Kraft D, Pastore A, Valenta R . Molecular characterization of Bip 1, a monoclonal antibody that modulates IgE binding to birch pollen allergen, Bet v 1. J Immunol. 1996; 157(11):4953-62. View

15.

Neunkirchner A, Kratzer B, Kohler C, Smole U, Mager L, Schmetterer K . Genetic restriction of antigen-presentation dictates allergic sensitization and disease in humanized mice. EBioMedicine. 2018; 31:66-78. PMC: 6014064. DOI: 10.1016/j.ebiom.2018.04.001. View

16.

Larche M, Akdis C, Valenta R . Immunological mechanisms of allergen-specific immunotherapy. Nat Rev Immunol. 2006; 6(10):761-71. DOI: 10.1038/nri1934. View

17.

Campana R, Moritz K, Neubauer A, Huber H, Henning R, Brodie T . Epicutaneous allergen application preferentially boosts specific T cell responses in sensitized patients. Sci Rep. 2017; 7(1):11657. PMC: 5599525. DOI: 10.1038/s41598-017-10278-1. View

18.

Akdis C . Does the epithelial barrier hypothesis explain the increase in allergy, autoimmunity and other chronic conditions?. Nat Rev Immunol. 2021; 21(11):739-751. DOI: 10.1038/s41577-021-00538-7. View

19.

Elisyutina O, Lupinek C, Fedenko E, Litovkina A, Smolnikov E, Ilina N . IgE-reactivity profiles to allergen molecules in Russian children with and without symptoms of allergy revealed by micro-array analysis. Pediatr Allergy Immunol. 2020; 32(2):251-263. PMC: 7891667. DOI: 10.1111/pai.13354. View

20.

Huang H, Curin M, Banerjee S, Chen K, Garmatiuk T, Resch-Marat Y . A hypoallergenic peptide mix containing T cell epitopes of the clinically relevant house dust mite allergens. Allergy. 2019; 74(12):2461-2478. PMC: 7078969. DOI: 10.1111/all.13956. View