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Putting the Brakes on Allergic Response

Published on April 21, 2016 in Cornerstone Blog · Last updated 3 months 1 week ago


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When you have a chronic allergic disorder, it’s easy to blame the trigger — an early pollen season or furry pet — but the real culprit is your own immune system. Designed to attack foreign substances such as bacteria and viruses, T cells are the immune system’s watchdog to recognize serious threats. But sometimes T cells can be too zealous and set in motion a signaling cascade that can cause allergic reactions to everyday things and even attack your body’s healthy cells by mistake.

“Inappropriate activation of immune cells is common in autoimmunity and also in allergic disease,” said Claire O’Leary, PhD, a postdoctoral fellow at The Children’s Hospital of Philadelphia. “Your immune system needs to learn to tolerate non-pathogenic immune insults while recognizing pathogenic organisms that it should mount a strong defense against.”

As a graduate student in the Cell and Molecular Biology program at the Perelman School of Medicine at the University of Pennsylvania, Dr. O’Leary completed her research in the lab of Paula Oliver, PhD, in the Cell Pathology Division of CHOP, to learn more about what is occurring at a basic cellular level to drive inappropriate immune cell responses. Dr. Oliver also is an associate professor of Pathology and Laboratory Medicine at Penn.

Dr. Oliver’s lab had previously demonstrated that when an enzyme, called an E3 ubiquitin ligase did not function in mice, these deficient mice developed characteristics of allergic disease. Two small adapter proteins, Ndfip1 and Ndfip2, are required to activate this E3 ubiquitin ligase, which can then send proteins to the cell’s degradation machinery. Their research revealed that if certain proteins are not degraded, then the buildup could lead to aberrant T cell responses, precipitating allergic or autoimmune disease.

Dr. O’Leary’s new work, which appeared in Nature Communications, went a step further to describe how Ndfip1 and Ndfip2 contribute to the braking system that keeps T cells from instigating hyperactivity of the immune system and producing proinflammatory cytokines that are involved in ramping up inflammation.

“We think of these proteins as being negative regulators of inappropriate activation,” Dr. O’Leary said. “In the absence of these proteins, the cells are accelerating immune reactions without a lot of guidance. They become self-directed and differentiate toward a path that is highly proliferative. They produce a lot of Th2 type cytokines associated with allergic disease.”

The research project provided novel insight into how the molecular braking system works in two distinct stages. Ndfip1 comes on early when the immune system perceives a substance as being foreign or dangerous, and its expression skyrockets as T cells are stimulated. When the T cells are re-exposed to the antigen and stimulated a second time, they initiate a more aggressive and rapid memory response that requires both Ndfip1 and Ndfip2 to be activated in order prevent an overly exuberant immune response.

“Somehow, the protein degradation complex is helping during T cell stimulation to keep the cytokine signaling limited,” Dr. O’Leary said.

The Protein and Proteomics Core Facility at CHOP’s Research Institute helped the study team to dig deeper into the protein interactions that enable T cells to proliferate and produce too much cytokine. They found that when Ndfip1 and Ndfip2 were not functioning, it halted degradation of a protein called Jak1, which is essential for signaling via certain types of cytokine receptors. Without appropriate down regulation of Jak1, expansion and survival of pathogenic effector T cells increased. The study authors suggest that Ndfip1 and Ndfip2 work together to regulate the cross talk between the T cell receptor and cytokine signaling pathways to prevent inappropriate T cell responses.

As scientists learn about the basic mechanisms of T cells’ negative regulatory pathways, these findings could point the way to future drug therapies. Already, drugs are available that inhibit the Jak1 pathway in treating immune-mediated diseases, including rheumatoid arthritis, inflammatory bowel disease, and psoriasis. However, they also disarm the immune system and reduce its ability to respond to viral or bacterial infections. An alternative could be to develop drugs that promote activity of the E3 ubiquitin ligase.