Tuesday, 1 April 2014

Oh Immune System, You're Just Overreacting...

Your immune system is constantly working to protect you from the onslaught of bacteria, viruses and parasites that would otherwise invade your body and potentially cause disease. Ordinarily the immune system works tirelessly without us even knowing; it is only when something creeps through the defences do we actually notice our immune system. Typically only to curse it as we struggle through a work day with a full blown cold.

Not surprisingly perhaps, when our only reactions towards it are negative, the immune system can be oversensitive and respond to harmless everyday substances as if they were harmful. These substances can range from pollen to food substances to latex to penicillin, almost any substance the body encounters on a day to day basis. When the immune system next encounters the substance, it launches a full blown attack, think taking on an ant with a rocket launcher, and you won’t be far wrong.

This overkill tactic results in an allergic reaction.

It is already known the immune response initiated by an allergen differs to an ordinary immune response. When the immune barriers are breached, by a bacterium or a virus for example, cells are on hand to ingest the foreign particles and present them to the immune system. The immune system activates the correct white blood cells which start producing specific antibodies against these particles. Antibodies act as a homing system, marking the foreign particles for destruction by other immune cells. After the foreign body is dealt with the antibodies linger in the body, and are able to quickly activate the immune system if the foreign particle is encountered again.

An antibody that encounters an allergen, a substance that causes an allergy, activates a particular type of white blood cell called a mast cell. Mast cells are important in wound healing and defending against infectious agents, but are most renowned for their role in allergic reactions. Mast cells respond to allergens via a specific receptor on their cell surface, FcεRI. An antibody with an allergen binds to FcεRI and activates a downstream signalling pathway, causing the primed mast cells to release powerful signalling molecules, including histamine. These can act on the other cells within the body resulting in the characteristic symptoms of an allergic reaction.

But an allergic reaction can range from mild hayfever or a slight rash to life-threatening anaphylactic shock, so what could cause these massive discrepancies?

The response of mast cells to an allergen is now thought to be dictated by how tightly the antibody binds to the allergen, and that the strength of binding is actually detected by the FcεRI receptor. This mechanism of action has been seen in other cells; for example, yeast cells use the presence of pheromones to control their growth. The yeast cells possess receptors which recognise the pheromones and change the cell’s growth patterns depending on the levels of pheromones present in the environment. Similarly to the yeast, mast cells are thought to change their behaviour via the FcεRI receptor in response to high-affinity, tight binding of the allergen to the antibody, or low-affinity, loose binding of the allergen to the antibody, stimulation.

There are some antibodies able to bind their targets more strongly than others, generating these differences in affinity. Binding affinity influences how rapidly the antibody moves away from the FcεRI receptor, therefore antibodies with a low target affinity, dissociate away faster from the FcεRI receptor whereas antibodies with a high affinity stick around for much longer. If the antibody lingers around the FcεRI receptor it is able to keep stimulating the receptor, this translates to a greater response from the mast cell.

This was demonstrated by a team of scientists in the US by stimulating mast cells with chemicals. These chemicals bind to the same antibody but at different affinities thus changing the stimulation the FcεRI receptor receives. These chemicals actually activated different signalling pathways within the mast cell despite the stimulation initiating in the same receptor. The end response of the mast cell differed between the chemicals depending on the pathway activated. This was also evident when the team tried a similar study using mice where the mast cells again showed a differing response dependent on the affinity of the antibody to the chemical.

The change in mast cell response gives an idea into how the affinity of the antibody may change the allergic reaction experienced by an individual. However, other cells in the immune system possess receptors similar to the FcεRI receptor therefore these results may well extend beyond allergy studies. The understanding of how our immune system works is critical for us to develop new ideas and therapeutics allowing better management strategies and treatment options. 

References:

Suzuki et al. 2014. Molecular Editing of Cellular Responses by the High-Affinity Receptor for IgE https://www.sciencemag.org/content/343/6174/1021.full


Marc Daëron. 2014. Signaling Shifts in Allergy Responses

https://www.sciencemag.org/content/343/6174/982.full


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