A research team led by investigators at New York University and NYU School of Medicine has determined how cells that cause inflammatory ailments, such as Crohn's disease, multiple sclerosis, and arthritis, differentiate from stem cells and ultimately affect the clinical outcome of these diseases.
"We've found that hundreds of new genes are involved in the function and development of these cells," said co-author Richard Bonneau, an associate professor at New York University's Center for Genomics and Systems Biology and the Courant Institute of Mathematical Sciences. "This expansion in our understanding can be used as a framework for designing new therapies to combat a range of ailments where the immune system attacks self."
These cells, called T-cells by immunologists, play a role in fighting off infection, but can also induce inflammation and other processes that damage tissues and contribute to several common inflammatory diseases. T-cells are also key cell types in new immune-cell based therapies for fighting cancer. There are many types of T-cells, and how they differentiate from stem cells in the human body lies at the center of understanding several diseases.
"We have been striving for several years to understand what makes inflammatory T-lymphocytes special," said lead investigator Dan Littman, MD, PhD, the Helen L. and Martin S. Kimmel Professor of Molecular Immunology and a professor of pathology, microbiology and molecular pathogenesis at NYU School of Medicine and a faculty member of the Skirball Institute on Biomolecular Medicine. "They can protect us from microbes, but they also have the potential to cause autoimmune disease.
"We were fortunate to be able to bring together a team of immunologists, computational biologists, and genomics experts to begin to solve this puzzle. Whereas before we only knew of a handful of genes that influence the function of these cells, we now know of hundreds of new ones that can serve as a resource for further studies by us and other laboratories. Our hope is that some of these new molecules will be the Achilles heel that we can target to treat these diseases."
The findings, which are reported in the latest issue of the journal Cell, lay the groundwork for understanding how these cells regulate their genomes through a regulatory network that connects many environmental stimuli to a large number of genes and their interactions. This large network model is essentially the brain that T-cell precursors, or stem cells, use to decide what they want to be when they grow up. Specifically, a network model can be used simulate what inhibiting a gene with a drug would do to different T-cells and, in this way, aid the development of new therapeutic measures to address these afflictions.
The study focused on T-helper 17 cells (Th17) and how they regulate the synthesis of gene products from thousands of regions of the chromosome. Th17 cells have previously been implicated in inflammatory diseases. Other studies have also identified hundreds of genes that roles in pro-inflammatory diseases. This new study places these implicated genes on a timeline of cellular development and ultimately puts them together in an integrated model of how genes interact.