Autoimmune diseases linked to elimination of dying cells

By Graciela Gutierrez

The secret to treating autoimmune diseases such as systemic lupus erythematosus could rest with understanding how dying cells are eliminated from the body, said researchers at Baylor College of Medicine in a recent publication in the journal PLoS Biology.

Once, scientists thought the process happened spontaneously. Phagocytic cells that help digest and dispose of unwanted cellular elements engulf the cells that undergo programmed cell death called apoptosis, a form of cell suicide.

Event trigger needed

"It was once thought that digestion happened automatically once a dying cell was engulfed," said Zheng Zhou, assistant professor of biochemistry and molecular biology at BCM. "Our research shows that the digestion of a dying cell requires an initiation signal to trigger a series of events involving different molecules with the end result of digestion. If one signal is malfunctioning, that's when illness can happen."

Improper removal of dying cells can cause autoimmune diseases such as systemic lupus erythematosus as well as chronic inflammatory responses.

How do cells know?

"We asked the question, how do engulfing cells know when and what cells to destroy since there are so many different types of cells in the body, "said Zhou. "A few signals that the dying cells send out to attract their engulfing cells have been discovered. Researchers jokingly call this kind of signals the 'eat-me' signals."

Using the small roundworm the nematode Caenorhabditis elegans, Zhou previously discovered that the engulfing cell detects the "eat-me" signals and initiates the engulfment of dying cells using a receptor known as CED-1. Now, with the lead author of the study, Xiaomeng Yu, who recently graduated with a Ph.D. from the graduate program biochemistry and molecular biology at BCM, and Nan Lu, a current graduate student in the same program, Zhou found that CED-1 is responsible for more than just the engulfment of dying cells. CED-1 has an additional, independent function as the initiator in the digestion process. When researchers mutated the function of CED-1, engulfment occurred but digestion never began.

Time-lapse

To view the process more closely, Zhou's team developed a time-lapse imaging technique using a high-resolution microscope. The nematode Caenorhabditis elegans was used as a model organism because these roundworms are transparent and all cells can be seen clearly, and because the exact same cells die at exactly the same time of development in every single worm.

Dying cell detection

Once CED-1 detects a dying cell, the engulfing cell attaches to the dying cell, and the chain reaction begins. CED-1 activates another protein known as DYN-1. The mammalian counterparts of DYN-1, known as dynamins, play essential roles in a number of events that transport lipid vesicles to different compartments of a cell.

"Imagine that the engulfing cell is quite big," Zhou said. "When one part touches the dying cell and CED-1 recognizes it, DYN-1 is activated and accumulates at the touch site helping to promote the engulfment process."

After the dying cell is engulfed DYN-1 has another function. It helps to attract intracellular organelles such as endosomes and lysosomes, which have digestive enzymes, to where the dying cell is.

Chain reaction

"They meet the dying cell and begin to chop up the proteins, lipids, sugars and the digestion process is under way," Zhou said.

Zhou's team found that once activated by CED-1, DYN-1 attracts two signaling molecules, RAB-7 and PI(3)P, which tell endosomes and lysosomes what location to attach to. Through further genome manipulation Zhou's team found that without DYN-1 the two molecules are not activated to initiate endosomes and lysosomes to begin digestion.

"It's a chain reaction with each molecule and enzyme working together throughout the entire digestion process," Zhou said. "If at any point a molecule or cellular organelle malfunctions, it throws off the entire process."

Understanding the mechanisms that allow the engulfment and degradation of dying cells to function properly will help researchers understand what goes wrong and help pinpoint a possible target for therapies for those diseases. In the long term, it will also shed light on how our immune system responds differently to self-generated garbage, such as the dying cells, and to invading pathogens.

The study was funded by the National Institutes of Health, the Cancer Research Institute, the March of Dimes Foundation and the Rita Allen Foundation.

The study can be found online at http://biology.plosjournals.org.