A recent research project at the University Clinic for Dermatology, Allergology, and Venereology at the Medical University of Innsbruck, Austria (in German: Medizin Uni Innsbruck) has highlighted a new mechanism underlying certain allergic immune reactions. The Innsbruck team led by biologist Christine Heufler investigated lipocalins and was able to identify the formyl peptide receptor (FPR) 3 as the central player of this allergic reaction.
When it comes to activating the immune system against pathogens or allergens, the dendritic cells are at the forefront. The task of these immune cells is to sound the alarm by taking up and processing components (antigens) of the allergen and presenting them in a characteristic and recognizable form to the T cells. "Dendritic cells are highly specialized for the stimulation of T cell-dependent immune responses and decisively involved in the activation of helper T cells Th1 and Th2," says Christine Heufler, who has been researching the immunobiology of dendritic cells at the Innsbruck University Clinic for Dermatology, Allergology and Venereology (in German: Innsbrucker Univ.-Klinik für Dermatologie, Allergologie und Venerologie) for many years.
Although allergies are a major field of research, the molecular mechanism that leads to the activation of Th2 cells in response to allergens has so far remained undiscovered. Heufler and his team have now succeeded in elucidating this mechanism for a class of protein allergens - lipocalins - in cell culture and thus coming one step closer to a potential therapy option. The Journal of Allergy and Clinical Immunology reports on the far-reaching findings.
Lipocalins include most inhalation allergens of mammals, such as Can f 1 (or Canis familiaris allergen 1, produced by dogs) or Fel d 4 (Felis domesticus allergen 4, for cats), but also include human non-allergenic proteins such as lipocalin-1, which occurs in tear fluid. In cooperation with the lipocalin expert Bernhard Redl from the Innsbruck Biocenter, Austria, (in German: Innsbrucker Biozentrum), Beate Posch (part of Heufler's team) was able to show in a previous study that dendritic cells activate Th2 cells in response to allergenic lipocalins and Th1 cells activate Th2 cells in response to non-allergenic lipocalins. The interaction of dendritic cells with the allergen is therefore decisive for the type of immune response induced. "This work also provided a first indication that the formyl peptide receptor (FPR) 3 could play an outstanding role in this," said Heufler.
In the current research work, the function of the FPR3 was analyzed in more detail. The researchers found that the degradation of allergenic lipocalins in dendritic cells leads to the formation of peptides that bind to FPR3, whereas the peptides that are formed during the degradation of non-allergenic lipocalins do not bind to the receptor. Binding to the receptor inhibits the production of the messenger Interleukin-12 in the dendritic cell. The absence of IL12 during the activation phase of T-helper cells prevents the development of Th1 and leads to the activation of Th2 cells and thus to allergic reactions. "With this reaction chain of allergen uptake, production of FPR3-binding peptides in the dendritic cell, blockade of IL12 production and development of Th2 cells, we could for the first time demonstrate the development of lipocalin-specific allergic reactions," confirms first author Dominik Klaver.
In the next step, the researchers manipulated FPR3 in allergen-treated dendritic cells and were thus able to visualize the therapeutic target of the receptor. "By gene silencing or the addition of an antagonist, the function of the receptor can be switched off, so that we could see that the development of Th2 cells is actually prevented. Instead, T-helper cells that produce the anti-inflammatory cytokine IL10 and thus hinder the immune response mature - the desired reaction in allergies," said Christine Heufler, a biologist.
Peptides from allergenic lipocalins bind to formyl peptide receptor 3 in human dendritic cells to mediate Th2 immunity. Klaver D, Posch B, Geisler A, Herrmann M, Reider N, Heufler C. J Allergy Clin Immunol. 2019 Jul 19th [Epub ahead of print]