Study finds innate immunity connection to rare, fatal childhood disease

The study results, posted online in the journal Immunity, could lead to new therapies for arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome. It also suggests connections to tuberculosis (TB): a hard-to-treat bacterial illness that the World Health Organization calls "a top infectious disease killer worldwide."

ARC syndrome is a rare, fatal genetic disease that results in liver, kidney, and bile duct dysfunction as well as abnormalities in the skin, joints, and musculoskeletal systems. There is no treatment, and most patients die before their second birthday. The syndrome is also associated with recurrent infections and sepsis, the latter of which the Centers for Disease Control and Prevention describes as an "overwhelming and life-threatening response to infection."

"Our findings indicate that, rather than being an indirect consequence of failures in other organ systems, ARC's inflammatory complications could reflect direct roles of the ARC gene Vps33B in innate immunity," said Dr. Chandrashekhar Pasare, Associate Professor of Immunology at UT Southwestern and co-senior author of the study.

"By identifying a novel and crucial role for Vps33B in regulating innate immunity, these findings point to the possibility of developing new therapies for treating ARC syndrome. It may be possible to identify drugs that target the pro-inflammatory pathways that our research indicates fail to get switched 'off' properly in ARC," said Dr. Helmut Krämer, Professor of Neuroscience and Cell Biology at UT Southwestern and co-senior author of the study.

Fewer than 300 cases of ARC have been reported worldwide, with the vast majority of them linked to inheriting two mutated copies of Vps33B, Dr. Krämer added.

The scientists generated fruit fly and mouse models of ARC syndrome by deleting the Vps33B gene. Cells from mice or flies lacking the Vps33B protein showed exaggerated inflammatory responses to lipopolysaccaride (LPS), a component of Gram-negative bacteria known to stimulate Toll-like receptors (TLRs) on the surface of immune system cells, which activate an immune response, Dr. Krämer said.

Their work fits into a decades-long innate immunity story based at UT Southwestern that features the research of Dr. Bruce Beutler, Director of the Center for the Genetics of Host Defense. Dr. Beutler, who is a Regental Professor and holds the Raymond and Ellen Willie Distinguished Chair in Cancer Research, in Honor of Laverne and Raymond Willie, Sr., shared the 2011 Nobel Prize in Physiology or Medicine for his work on the activation of innate immunity, the body's first line of defense against infection.

The current study looks at the other side of the innate immune response: the less-understood area of how the inflammatory response is inactivated or turned off, the researchers explained.

"We found that Vps33B is important for disease-fighting white blood cells (macrophages) to clear the invading bacteria from the cells after the TLRs have carried them inside. Normally, both the bacteria and the receptors are digested by the macrophage cell, thus switching off the inflammatory immune response before it goes out of control to become sepsis," explained Dr. Pasare, holder of the J. Wayne Streilein, M.D. Professorship in Immunology and a Louise W. Kahn Scholar in Biomedical Research.

The new study indicates that lack of Vps33B and the protein it encodes blocks that degradation step so that inflammation cannot be turned off, leading to enhanced inflammation and causing symptoms of sepsis and susceptibility to recurrent infections, the researchers said.

"Although ARC syndrome is very rare, other researchers have reported that in order to survive in the host, the mycobacterium that causes TB inhibits the function of the protein encoded by Vsp33B. This inhibition was thought to be due to a reduced ability of the immune cells to digest the TB bacteria; however, our study suggests that the exaggerated inflammation seen in TB could be a result of an inability to terminate inflammatory response," Dr. Pasare said. The scientists hope to investigate that question in future research.

Dr. Pasare and Dr. Krämer said this collaboration is an example of the unique research environment at UT Southwestern that facilitates investigators with diverse interests and expertise coming together to solve important scientific questions.