Scientists Identify Genetic Basis Of Allergies: Treatments Could Soon Target Genes, Not Symptoms
Allergies plague people of all ages for at least six months of each year. Often, little can be done to treat allergies, and instead people take steps to soothe symptoms. However, a new study identifies a fault in one's genetic code that can lead to allergic reactions.
Allergic diseases tend to run in families, or be inherited, but specific genes and pathways that drive these disorders have not yet been identified. Identification of common diseases and disorders as having a genetic basis is often promising. Genetic disorders are sometimes more easily treated than others, as scientists know where to target drugs and what exactly is causing the issue or symptoms.
In a new study, researchers focused on transforming growth factor-β (TGFβ). TGFβ is known to help immune cells, called T cells, grow and mature. T cells are responsible for the body's immune response; they have the ability to recognize disease-causing agents and launch an immune response. Mediated by other immune cells, they can reduce an immune response and directly act to destroy cells being altered by disease-causing agents, called pathogens. As T cells mature, they gain the ability to recognize these pathogens and are instrumental for proper immune function.
Scientists have deduced that issues in TGFβ will lead to issues in the immune system and allergies. An allergy is simply an overreaction of one's immune system, leading to higher than usual levels of inflammation from an overblown immune response.
In the study, 58 patients with Loeys-Dietz syndrome (LDS), a genetic disease established to have mutated TGFβ genes, leading them to suffer from allergic diseases at much higher rates than the general population. Thirty-one percent had a history of food allergies, and 45 percent had asthma, and many had a history of eczema and nasal allergies. Through blood testing, researchers found that patients with LDS had significant amounts of T cells that were specialized to turn off the effect of T cells. Upon closer inspection, they found that an overexpression of TGFβ caused the increase in T cells.
The increase in molecules that turn off an immune response tends to create an allergic reaction. This is, admittedly, counterintuitive, since one would ordinarily think that greater immune responses lead to better immunity. But if an immune response is squelched at an inappropriate time, as it would be if there were excess T cells dampening an immune response, then inflammation from the infection that originally caused the immune response can persist. Persistent inflammation leads to allergic responses one typically sees in allergy season: reddening of an area, fever, itching, watery eyes, and a runny nose. These symptoms can become debilitating if the immune response that would ultimately make all of this go away is hindered by an excess of T cells, caused by the genetic change to TGFβ. Elevated TGFβ signaling promptsthe immune system to react to harmless substances, such as dust or foods.
"Disruption in TGFβ signaling does not simply nudge immune cells to misbehave but appears to singlehandedly unlock the very chain reaction that eventually leads to allergic disease," said senior investigator Harry Dietz, M.D.
Researchers say that people with allergies and LDS are not unable to make the other types of T cells that are able to fight off pathogens. However, their body's natural ability to turn off an immune response at an inappropriate time is what worsens symptoms. Losartan is a drug that has been shown to reduce TGFB levels when tested in mice, and has implications for use in humans. Though normally used to treat high blood pressure, losartan has been found to alleviate TGFβ signaling alterations to T cell production and restore normal immune response activity. When losartan was administered, the T cells that mitigate immune response were lessened while the T cells that incite immunity were at higher levels.
Thanks to identification of the harm in overexpression of the TGFβ gene, a new treatment strategy exists for those with allergies and disorders of the immune system.
Source: Frischmeyer-Guerrerio PA, Guerrerio AL, Oswald G, et al. TGFβ Receptor Mutations Impose a Strong Predisposition for Human Allergic Disease. Science Translational Medicine. 2013.