The innovative work of Douglas Green, PhD, St. Jude Children's Research Hospital, probes the minute inner workings of the world of cells: their functions, their deaths — and their inextricable link to lupus.
Every day billions of cells die within the human body. The balance between cell survival and cell death is crucial to all of the body’s intricate systems. Nowhere is this equilibrium more critical than the immune system.
Cells called macrophages (big eaters) do the important job of eating and digesting dead cells — essentially removing debris from the body — in a process called phagocytosis. Much like the way amoebas eat, macrophages completely engulf the dead cells into a little vesicle — a sort of bubble inside the cell.
But the death of human cells is far more complex than this.
In the 1990s scientists made a key observation. They discovered a process where a cell removes bits of itself as a source of energy and as a way to clean up cell damage. "This is the process of autophagy," said Dr. Green. "It is a self-eating process."
Why is this crucial? Dr. Green revealed the connection: "Part of the reason why this is so significant is that a lot of diseases — including lupus — have been linked to polymorphisms, differences in the genes, for proteins in that autophagy pathway."
With Lupus Research Alliance funding, Dr. Green and his team have explored a new pathway that involves some of the same autophagy surface molecules. "We started studying it and, using genetic manipulations, we were able to remove this process we called LC3-associated phagocytosis (LAP)," shared Dr. Green.
In murine models, animals developed human-like lupus when Dr. Green removed LAP. The implications of this discovery are important. In the 1950s, a cell that contains an undigested cell, the LE cell, was discovered as a marker for lupus, but the connection was unknown.
Dr. Green's work may be that connection. When there are defects in LAP, dying cells are eaten but are not digested. This may be a significant link to lupus.
Going forward, Dr. Green's investigation will focus on how to manipulate LAP in cells — how to change the tendency of a cell to engage LAP or not, depending on the setting.
Learning more about LAP may help prevent lupus and develop ways to restore the control of cells with LAP defects. Dr. Green's exciting study may help pave the way to novel treatment strategies for lupus.
Dr. Green has nothing but praise for the Lupus Research Alliance and the individuals who support it. "Scientists are passionate about making discoveries and applying them to human disease," said Dr. Green, "and the Lupus Research Alliance enables us to bring our ideas to fruition. It allows us to move forward."
Dr. Green is the Peter C. Doherty Endowed Chair of Immunology at St. Jude Children's Research Hospital and a grant awardee of the Lupus Research Alliance.
After receiving his PhD from Yale University, Dr. Green has focused his career on the processes of active cell death and cell survival. This work began with his discovery of activation-induced apoptosis in T lymphocytes, the role of c-Myc in this process, and the finding that Bcl-2 cooperates with Myc in oncogenesis by blocking apoptosis. These are themes that he continues to study.
More recently, Dr. Green discovered the process of LC3-associated phagocytosis, which links the autophagy pathway to phagosome maturation.
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