Busted! Foiling the inside job

Imagine realizing that a trusted security guard has burglarized your house. A similar discovery in the lab may help researchers identify novel treatments for multiple sclerosis.

by Mary Powers

Thirumala-Devi Kanneganti, PhD

In the battle against illness, the innate immune system serves as the body’s first responder. This branch of the disease-fighting immune system acts swiftly and broadly at the first hint of trouble, whether from bacteria or some other infectious agent. New evidence indicates part of that system plays a role in the disease flare-ups that are a hallmark of multiple sclerosis (MS). Such a scenario is like learning your house has been burglarized by a security guard.

Thirumala-Devi Kanneganti, PhD, of Immunology expects her work to have a happier ending. She led the recent effort that identified the pathway whose activation triggers the fresh immune assault and a new wave of symptoms for MS patients. The finding offers insight into the mechanisms involved in MS and other debilitating illnesses that stem from similarly misguided immune attacks on healthy tissue. Work is already underway to turn these findings into novel treatments for MS and other diseases.

“My dream is to find a way to block this disease and stop its progression,” Kanneganti says. “This pathway provides an opportunity to do just that and develop novel therapies that complement existing MS treatments by targeting a different part of the disease process.”

New insights into MS

That is good news for the world’s estimated 2.5 million MS patients, often young adults left to cope with this chronic, frequently debilitating illness. MS is thought to begin when a genetically susceptible individual comes in contact with an environmental trigger. The encounter stimulates production of specialized white blood cells known as T cells. In MS, those T cells target a molecule called myelin.

Myelin is essential for normal functioning of the brain and nervous system. It forms the protective insulation that surrounds nerve fibers, helping to ensure nerve impulses travel smoothly. As MS progresses and the T cells launch periodic attacks on myelin, the insulation is gradually replaced by scar tissue. Nerves can be damaged and the nervous system disrupted. For patients, it means symptoms often come and go, a process known as relapsing and remitting, along with inflammation and the T cell assaults. The disease that begins by causing fatigue and numbness can eventually affect organs throughout the body, leading to memory problems, blindness and paralysis. Current medications target the myelin-specific T cells.

Investigators believe the initial encounter between at-risk individuals and environmental triggers is enough to launch MS and send the T cells across the blood-brain barrier meant to protect the central nervous system. But sustaining the disease requires periodic reactivation of T cells against myelin. Research led by Kanneganti and published recently in the scientific journal Immunity sheds new light on that process.

Uncovering the mastermind

Kanneganti studies the innate immune system, both how it recognizes and responds to germs and how errors in the system can trigger excessive inflammation, autoimmune attacks and other health problems. This latest advance in understanding MS began as an effort to untangle the circumstantial evidence linking MS disease flare-ups with bacterial infections.

The study builds on earlier observations that a piece of the bacterial cell wall is present in specialized regulatory immune cells found in the brains of MS patients but not in healthy individuals. The bacterial component is called peripheral peptidoglycan, or PGN. The reports were intriguing in part because immune cells called dendritic cells were shown to harbor PGN. Dendritic cells are also known as antigen-presenting cells. These cells can ramp up production and activity of T cells that target myelin and drive MS. Until now PGN’s role in the process was unclear.

Working in a laboratory model of the disease, Kanneganti and her colleagues linked the renewed immune attacks to recognition of PGN by proteins that are part of the innate immune system. The recognition sets off a biochemical cascade within the dendritic cells. The result is a new round of inflammation in the central nervous system and new crop of T cells bent on myelin’s destruction.

“Our observations provide a mechanism by which PGN present in the brain or prior bacterial infection could contribute to MS progression. This fills a major gap in MS research and understanding,” Kanneganti says. The pathway she and her colleagues identified also offers a promising target for drug development.

Nabbing the culprit

Kanneganti’s laboratory has a long-standing interest in molecules that are key players in the pathway. Those include the proteins NOD1 and NOD2, whose recognition of PGN investigators now believe triggers the biochemical cascade that starts the renewed immune assault. Once activated, NOD1 and NOD2 work through RIP2, another molecule in the pathway, to activate the process.

In the lab, investigators showed that eliminating NOD1, NOD2 and RIP2 eased MS symptoms, but did not prevent the disease. The mildest symptoms were associated with a lack of RIP2. The findings suggest that without RIP2 dendritic cells did not recognize or respond to PGN. No recognition means no new immune assault.

Although no drugs are currently on the market that specifically target RIP2, Kanneganti says work on experimental compounds is already underway.

“I am sure we could stop MS disease progression by targeting RIP2,” she says. “Such a drug could be used synergistically with current MS treatments. A RIP2 inhibitor might also be important for treatment of other autoimmune diseases.”

Promise magazine, Summer 2011

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