The importance of iron in birch allergies

Seasonal allergies affect millions of people every year, causing itching, sneezing and runny noses. While many of the molecules responsible for provoking allergic reactions have been identified, the way these molecules sensitize our immune systems and cause allergic reactions has remained mysterious. However, Franziska Roth–Walter and colleagues at both the Technical University of Madrid and the Medical University of Vienna have begun to shed some light on this mystery.

Trees  

In their recent publication in the Journal of Biological Chemistry, they identified the mechanism behind sensitization to Bet v 1, the major allergen in birch pollen.

While all people are constantly exposed to pollens, only those with a sensitized immune system become symptomatic. Sensitization occurs upon an initial exposure to the pollen. This exposure activates special immune cells called B cells. The B cells produce specific immunoglobulin E antibodies that attach themselves to mast cells, which are immune cells that mediate the inflammatory response.

Upon a second exposure, the immunoglobulin E antibodies exclusively recognize the allergen. This recognition results in the destruction of the mast cell and the release of its stores of histamine and other powerful chemicals into the surrounding cells, ultimately leading to the onset of allergy symptoms.

The birch tree is just one of many types of plants to which people commonly develop allergies. Interestingly, in birch tree pollen, a single protein, Bet v 1, is responsible for binding immunoglobulin E and initiating the allergic response. Even though Bet v 1 was first identified in 1989 and has been the subject of numerous studies, it is still not clear how people become sensitized to this protein.

Roth–Walter and colleagues decided to look into how Bet v 1 causes sensitization by comparing the structure of Bet v 1 to that of human lipocalin 2, or LCN2, a member of the lipocalin protein family, which contains many known allergens.

Comparison of the structures of Bet v 1 and LCN2 revealed that both proteins have a hydrophobic pocket surrounded by a similar core structure. The hydrophobic pocket characteristic of the lipocalin family acts as a binding site for small, iron-chelating molecules. Additionally, docking analysis of the Bet v 1 protein and its possible ligands suggests that Bet v 1, like LCN2, has a strong affinity for iron-catecholates.

Interestingly, the presence or absence of iron in LCN2 determines whether LCN2 can initiate an immune response. As Bet v 1 is structurally and biochemically similar to LCN2, Roth–Walter and colleagues compared the immune response after exposure to apo-Bet v 1 (noniron bound) and holo-Bet v 1 (iron bound). Significantly, as with LCN2, exposure to apo-Bet v 1 resulted in an immune response and the production of immunoglobulin E antibodies, whereas exposure to holo-Bet v 1 inhibited the immune response. Therefore, the presence or absence of iron dictates whether Bet v 1 instigates an immune response.

This result suggests that under normal cellular conditions, when iron is more abundant, Bet v 1 is immune suppressive. However, when immune cells are challenged by infection or inflammation, iron stores are depleted. Under those conditions, Bet v 1 is present in the apo-, or noniron-bound, form, which results in the activation of B cells, production of immunoglobulin E antibodies and sensitization. Thus, the presence or absence of iron in the immune cells is a critical determinant of the allergenicity of Bet v 1 and potentially other lipocalin proteins.

Photo of Kathleen McCannKathleen McCann (Kathleen.mccann
@yale.edu) is a graduate student in the genetics department at Yale University.