'Suicide Molecule' Offers Hope for Rheumatoid Arthritis

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There is a tiny town called Incydau where the inhabitants don’t die. Nobody knows why or when it started or if it will ever end. Each new generation moved in with the one before it.

When the dwellings got to be too crowded, they built new dwellings around them. When they ran out of space to build, they added floors to the existing structures so more Incydians could live upstairs. The cycle repeated itself, over and over again. Food ran short, disease ran rampant and foundations wasted away. Still, no inhabitants died.

This is similar to the way rheumatoid arthritis affects the joints, only the inhabitants are immune cells and the tiny town is the bone and cartilage to which they become attached.

Researchers hope that the "suicide molecule" will offer hope to people who suffer with rheumatoid arthritis. (photo: National Institutes of Health)Researchers hope that the "suicide molecule" will offer hope to people who suffer with rheumatoid arthritis. (photo: National Institutes of Health)In a study published in the February issue of Arthritis and Rheumatism, Northwestern University researchers found a way to end the story of these inhabitants that cannot die using  BIM protein, what the rheumatology field calls the “suicide molecule.”

The process of cell death is called apoptosis. Researcher Harris Perlman, of the Division of Rheumatology at Northwestern’s Feinberg School of Medicine, explained: “In apoptosis, a cell quietly dies off and gets removed from the system. That’s the way our body has of renewing itself all the time. In your stomach you have it, in your skin you have it. Almost all of your cells eventually die off and you get new cells.”

In joints affected by rheumatoid arthritis this process no longer occurs. The result is that macrophages, a certain kind of immune cell, don’t die. Macrophages are one of the body’s first lines of defense against infection. They eat everything around them and produce proteins called cytokines, which account for the prolonged nature of this rheumatic condition.

“It’s like a persistent inflammation,” said Perlman who specializes in the areas of rheumatoid arthritis and lupus. “In a normal infection, the cells die off and the infection clears.”

Macrophages are one of the building blocks for the lining of the joint. Because they don’t die, but new cells are growing, the macrophages take up residence on top of existing cells. The joint lining gets bigger and bigger,  and over time it can become 10-12 layers thick.

One of the proteins that regulates the life and death of the cells is BCL-2 interacting protein, also known as BIM, the suicide molecule.

Perlman showed that BIM also determines how active the cell will become, the more active, the more harmful. Lacking BIM, the hypothesis goes, the cells become aggressive like cancer, and attach themselves to the bone, eventually eating away at bone and cartilage.

“Our idea was the cells are missing this [BIM] so that’s why they are living longer and more active,” Perlman said. “So we developed a therapy to put back that protein and cause the cells to die off.”

For the therapy, the researchers had to mimic the BIM protein. Proteins are made up of amino acids. These are critical to their functions. BIM only needs a small portion of its amino acids to perform the death function, so it could be replicated for the therapy.

In this study, performed on mice, researchers found that the BIM therapy not only prevented the disease, but also acted to stop the disease from continuing.

“[The research] presents a new way of thinking in rheumatoid arthritis. If we eradicate these cells you can treat the disease. You remove the bad stuff and you only have the good cells remaining.”

Perlman likens this approach to cancer treatments in which you remove the tumor and keep the healthy tissue.

Dr. Nadera Sweiss, a specialist in rheumatology at the University of Chicago Medical Center, said in an e-mail: “This study provides a new hope for a treatment that targets a novel pathway, not only for rheumatoid arthritis, but for other autoimmune diseases.”

The next step for Perlman and his team is to create a better delivery system, so that the BIM is more targeted and lives longer in the body. He estimates that it will be five to ten years before a viable drug would be available if the therapy lives up to its promise.

Sweiss wrote that most of the FDA approved therapies work on aspects of the immune system other than macrophage and not all patients respond well to these therapies. She added that it is too early to comment on the safety issues of BIM therapy.

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