Genetic Quirk Promotes Allergies

Interview with Dr. Pam Guerrerio

Allergic reactions happen when the immune system reacts to a substance that should be ignored. This can range from a slight rash when sitting on the grass, to anaphylaxis after eating a nut. 

About 10% in the UK population say they have one or more allergies, but could we have a new way of treating them?

Currently, hayfever and mild allergies to animals are managed with antihistamines, but the root of the problem, scientists at Johns Hopkins University have shown, could be how cells respond to a specific chemical signal called TGFβ.

The paper, published last week in Science and Translational Medicine, examines the link between allergies and TGFβ. TGFβ has been associated with many roles in the body: it's in the same family as insulin and is known to be involved in tissue growth and development, but TGFβ also controls the behaviour of immune cells known as  "Tregs" or regulatory T cells.These, in turn, coordinate the production by other immune cells of inflammatory signals called cytokines.

There are some humans who lack TGFβ signalling. These people suffer from a disease known as Loey-Dietz Syndrome (LDS), caused by a genetic mutation in the gene coding for their TGFβ receptors, making them less sensitive.

LDS patients usually have craniofacial, skeletal, developmental problems and spiralled or twisted arteries; but, intriguingly, sufferers also have a higher than average chance of developing asthma (48% of LDS patients have asthma compared to 8% in the general population), eczema (38% compared to 11%) and food allergies.

The John's Hopkins team suspects that the lack of TGFβ signals in these patients is what gives them their predisposition to allergies. This is not a feature only seen with LDS patient. Otherwise healthy children with allergies have also been shown to have elevated levels of TGFβ.

Although we don't know precisely how the pathway works, we do know that the interaction between TGFβ and the Treg cells is very involved. It is thought that if TGFβ production could be dampened that this would bring the Treg cells under control, stopping their over sensitively to antigens.

A drug currently proscribed for high blood pressure, Losartan, has been shown to reduce levels of TGFβ and could potentially be used to treat allergies. Studies are already underway in mice to see how effective it is, but because Losartan has already been approved for use in humans by the Food and Drug Administration (FDA) it could be made available as a treatment for allergies relatively soon if it's seen to be effective.

Dr. Pam Guerrerio, who led the study, said "we can learn a lot from these rare genetic disorders" This new information gives us greater understanding of how our bodies work and we can begin to elucidate the pathways involved, developing novel treatments that exploit them.

Antihistamines are effective, in most cases, at blocking the histamines that cause the allergic reaction, but in the future we might be able to stop the cascade of chemicals further up stream.

Antihistamines don't help every allergy, food allergies for example are rarely helped, but by targeting new drugs earlier in the pathway we may see better results.

The scientists involved "are hopeful that this is a key pathway to target because it seems to be sufficient to cause allergy"

It is not completely clear what the mechanism of action is, but it is involved with our response to allergens. The team now have two areas to look at: the exact pathway of TGFβ, and the development of allergies and potential therapies.

Further research in this area could produce drugs that alter this level of cell communication, stopping random responses to mundane antigens.