Studies reveal two new, important aspects of body’s immune response

By Deborah Wormser

UT Southwestern researchers have identified a new molecule in the Toll-like receptor (TLR) signaling pathway that dampens inflammation, an advance that could lead to new treatments for inflammatory bowel disease, rheumatoid arthritis, and other autoimmune conditions.

Dr. Chandrashekhar Pasare and graduate students

The findings from a mouse study published recently in the Proceedings of the National Academy of Sciences show that a protein called BCAP acts like a brake to keep the immune response from spinning out of control into life-threatening septic shock or chronic autoimmune disease, said Dr. Chandrashekhar Pasare, Assistant Professor of Immunology and the study’s senior author.

The study identifies BCAP as the “missing link” between the Toll-like receptors’ detection of bacteria and viruses and the activation of a key pathway to regulate the body’s response to the pathogen.

“This work establishes for the first time a clear molecular link between TLRs and the activation of PI3 kinase (which regulates the body’s response) and will enable further study as to how mammalian cells control the inflammatory response to infections,” Dr. Pasare said.

An earlier mouse study from Dr. Pasare’s laboratory, published in Immunity, could improve vaccine development. It provides the first evidence that T helper 17 (Th17) white blood cells are generated differently in the spleen than in mucosal organs such as the intestine and the lungs.

This study is the first to demonstrate tissue-specific requirements of cytokines – small cell-signaling proteins created in response to pathogens that regulate the immune response. The researchers found that the cytokine interleukin 1 is necessary to generate Th17 cells throughout the body while interleukin 6 is essential for the generation of Th17 cells in the mucosal tissues.

“This study implies that we need to take into account the site of infection when we design vaccines or therapies that make use of Th17 cells,” Dr. Pasare said.

Other UTSW researchers involved in the PNAS study were graduate student Ty Dale Troutman, who was lead author; graduate student Wei Hu; and former research technician Stephanie Fulencheck. Scientists from California-based Genentech and from Japan also were involved.

Ms. Hu was the lead author of the Immunity study. Others included Mr. Troutman and former postdoctoral researcher Ramakrishna Edukulla.

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Dr. Pasare is a Louise W. Kahn Scholar in Biomedical Research.

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