Interaction between Susceptibility Polymorphisms, Cigarette Smoke, and PAD4 Autoantibodies in RA
Abstract
This research project is highly relevant to the rheumatoid arthritis (RA) and respiratory health topic areas, as well as members of the military due to the focus on cigarette smoking. Cigarette smoking is a growing health concern and is more common among members of the Armed Forces and Veterans compared to the civilian population. Smoking can increase the risk of developing severe health problems including cancer, cardiovascular disease, and rheumatoid arthritis (RA). A group of enzymes called peptidyl arginine deiminases (PADs) are thought to be key drivers of disease in RA. These enzymes modify proteins in the body in such a way that they become targets of the immune system in patients with RA and contribute to the joint damage, pain, and swelling seen in this disease. One of the PAD enzymes, PAD4, is also a target antibody in a group of patients with RA who have the most damage to their joints as well as inflammation in their lungs. These antibodies seem to turn the PAD4 enzyme on and allow it to modify more proteins. Cigarette smoking increases the amount of the PAD enzyme and modified proteins in lung and puts people at even higher risk for developing lung disease. Our hypothesis is that cigarette smoke may directly enhance the amount of enzyme and modified protein in the lung by attracting and turning on inflammatory cells. Once the enzyme and modified proteins accumulate in the lungs, the immune system begins to attack these proteins leading to inflammation in the lungs, which then spreads to the joints. This proposal aims to understand how this process may work by studying patient samples as well as a model of how immune cells respond to cigarette smoke in the laboratory. A mutation in a gene that normally helps to reduce the harmful effects of cigarette smoke increases the risk of developing RA. We will look at the DNA and antibodies of patients with RA to see if patients who have this mutation are more likely to develop the PAD4 antibodies that are linked to severe joint and lung disease. We will also expose immune cells to cigarette smoke in a smoke chamber to mimic the conditions that cells in the lung of a smoker would experience to see if cigarette smoke increases the amount of PAD4 enzyme or turns on its ability to modify proteins. This new way of thinking about the study of RA has the potential to increase the understanding of how and why people develop this disease and may lead to the development of new drugs to treat patients with RA.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510159
Entities
People
- Erika Darrah
Organizations
- Johns Hopkins University
- United States Army